Khối U Ác Tính Dưới Da: Góc Nhìn Phẫu Thuật (Cutaneous Malignancies)

evaluated overall and recurrence-free survival and found no
statistically significant di erence between the arms.14 The
authors concluded that 5 cm margins were not necessary for a
melanoma 2 mm or less in thickness.
The Intergroup Melanom a Trial evaluated outcom es w hen
m argins of 2 cm versus 4 cm were used for patients with a
m elanoma between 1 m m and 4 mm in thickness. The study
evaluated local recurrence as the site of first relapse and at
any time, and found no significant di erence in outcomes
between the two arms. The local recurrence rates as first
relapse and at any tim e for a 2 cm margin (0.4 and 2.1%,
respectively) were not significantly di erent when com pared
to a resection m argin of 4 cm (0.9 and 2.6%, respectively). A
trend toward improved overall survival at 10 years was seen
in the 4-cm group, 70 versus 77%, but this was not statisti-
cally significant.15
In the second Swedish Melanoma Study Group Trial,
936 patients with a melanoma greater than 2-mm thick were
randomized to margins of either 2 cm or 4 cm. The authors
reported no statistically significant di erences in local recur-
rence or overall survival between the two arms.16
Haigh et al conducted a meta-analysis and systematic review
of three of these trials (WHO, Intergroup Trial, and the first
Swedish Melanoma Study Group Trial). When the data were
combined, local recurrence, disease-free survival, and mortality
were not statistically di erent between patients with primary
cutaneous melanoma up to 4 mm in thickness undergoing exci-
sion with 1 cm to 2 cm margins compared to those randomized
to 3 cm to 5 cm margins.17
Taken together, the data from all of these studies support the
recommendation of 1 cm margins for a thin melanoma and
1 cm to 2 cm margins for an intermediate thickness melanoma.
Although no randomized trials have directly compared 1 cm
versus 2 cm margins for an intermediate thickness melanoma,
we use a 2 cm margin for most melanomas that are 2 mm in
thickness or greater except in anatomically constrained areas
like the face, ears or distal extremities, where only a 1 cm mar-
gin can routinely be obtained. For a melanoma between 1.1 mm
and 2 mm in thickness, a 1 cm margin is acceptable when the
narrower margin allows for primary closure but a 2 cm margin
would require skin grafting or significant tissue undermining to
achieve closure. We are particularly likely to use a 1 cm margin
for melanomas in this thickness range that are nonulcerated,
with a relatively low mitotic rate and no evidence of angiolym-
phatic invasion. We have shown that using a 1 cm margin in
this setting was associated with an acceptably low rate of local
recurrence.18
4.3.3 Thick Melanoma
The NCCN recommends that thick melanomas, defined
as tumors greater than 4 in thickness, should be resected with a
2 cm margin.12 A large, multi-institution retrospective (non-
randomized) study of over 270 patients reviewed outcomes in
patients with a thick melanoma who had a resection margin of
either 2 cm or greater than 2 cm. Margins wider than 2 cm did
not improve outcomes, given that local recurrence, disease-free
survival, and overall survival were not significantly di erent
between the two treatment arms after a median follow-up of
27 months.19
Thomas et al randomized 900 patients with tumor thickness
of 2 mm or greater to excision with either a 1 cm or 3 cm mar-
gin. After a median follow-up of 60 months, there was increased
locoregional recurrence in the 1 cm arm (p =0.05), but no signif-
icant di erence in overall survival between the arms. This study
prohibited any form of nodal staging, be it elective lymph node
dissection or sentinel lymph node biopsy. The absence of nodal
evaluation raises an important point when considering the
impact of the results of this trial. If lymph node evaluation had
been conducted, there is a possibility that there would have
been an imbalance in regional nodal disease between the two
arms, which may have attributed more to the locoregional recur-
rence rate than the actual margin of excision. When only local
and in-transit recurrences were considered, there were 37 recur-
rences in the 453 patients on the 1-cm arm (8.2%) versus 25 in
the 447 patients on the 3-cm arm (5.6%), a di erence that was
not statistically significant. But there were 20 more nodal basin
recurrences in the 1 cm arm than in the 3-cm arm, reinforcing
the possibility that any observed outcome di erences were at
least partially related to imbalances in the number of stage III
patients in each arm rather than an e ect of the surgical treat-
ment.20 While there are no data directly comparing a 2 cm and
a 3 cm margin for thick melanoma, whenever a 2 cm margin
has been prospectively or retrospectively compared to a wider
(4 cm or 5 cm) margin, there has been no evidence of an advant-
age for the wider margin. Hence, we do not recommend either a
1 cm or a 3 cm margin for a thick melanoma, but rather rou-
tinely use a 2 cm margin whenever anatomically feasible, even if
it requires a reconstruction to achieve this margin.
4.4 Sentinel Lymph Node Biopsy
While the margin of resection is important for control of local
disease, melanoma frequently metastasizes via the lymphatic
system, and the regional nodal basins are the most common
site of melanoma metastasis. Evaluation of the nodal basin may
be indicated at the time of initial wide excision. The sentinel
lymph node represents the first lymph node in the lymph node
basin directly draining the primary tumor. If the melanoma has
metastasized via lymphatic channels, the sentinel lymph node
would be the first lymph node to contain tumor deposits. The
status of the regional nodes as determined by sentinel lymph
node biopsy to determine the presence or absence of metastatic
disease has been shown in a prospective randomized trial to be
the most important prognostic factor in patients with clinically
localized, intermediate-thickness melanoma.21
Sentinel lymph node biopsy should be performed in appro-
priately selected patients with clinically negative regional
nodes at the time of wide excision of the primary tumor. A dual
localization technique utilizing both injection of radiocolloid
and injection of vital blue dye, either isosulfan blue or methyl-
ene blue, is most commonly used. The blue dye allows for direct
visualization of the lymphatic channel and the sentinel lymph
node itself. The use of blue dye alone has allowed the sentinel
node to be identified in approximately 85 to 90% of cases, but
the combination of both radiocolloid and blue dye increases the
success rate to over 99%.22 We utilize isosulfan blue whenever a
vital blue dye is employed, and do not use methylene blue for
sentinel node localization at all due to higher reported local
Surgical Treatment of Cutaneous Melanoma
88

complication rates.23 One-half to 1 mCi of radiocolloid labeled
with 99mtechnetium is injected intradermally, generally 1 to
4 hours before surgery, but if necessary the injection may be
performed up to 24 hours prior to surgery.22 A variety of di er-
ent radiocolloids are used around the world (e.g., sulfur colloid,
tilmanocept, albumin nanocolloid and antimony trisulfide),
with little or nothing in the way of head-to-head comparison
data to determine which might be superior.24,25 Whichever and
whenever the radiocolloid is injected, planar or computed
tomographic lymphoscintigraphy is performed during the hour
immediately thereafter in order to delineate the number and
general location of the sentinel nodes. After the induction of
anesthesia in the operating room, the vital blue dye is injected
intradermally around the biopsy site or the primary tumor. A
total volume of 0.5 to 1.5 mL is generally su cient to identify
the sentinel lymph nodes. Intraoperatively, a handheld gamma
probe helps to direct the trajectory of dissection and guide the
surgeon down to the “hot” and usually blue sentinel node(s).
Despite the high rate of accuracy with a dual localization
technique, some surgeons do not routinely use blue dye. The
choice to use radiocolloid alone may be due to limited availabil-
ity of vital blue dye, concern that the use of blue dye will stimu-
late an allergic reaction, or because the patient is pregnant (we
do not use blue dye during pregnancy because a maternal aller-
gic reaction could be catastrophic for the fetus).23,26,27,28,29 In
the Multicenter Selective Lymphadenectomy Trial-I (MSLT-1),
the incidence of allergic reaction after isosulfan dye injection
was only 0.2%,30 and in our experience the incidence of allergic
reactions is even lower than that. Hence, we routinely utilize
isosulfan blue dye in nonpregnant patients. One other issue
relating to the use of vital blue dye is the presence of a tattoo on
the skin in the drainage area of the nodal basin(s) undergoing
sentinel node biopsy. Tattoo ink gradually leaches out of the skin
site and accumulates in the regional nodes, coloring them
enough to be easily seen. If the tattoo contained blue, green, or
black ink, pigments within the node can be confused with vital
blue dye or even metastatic melanoma.31 For this reason, we
sometimes do not use vital blue dye in cases where a large tat-
too is in the same draining basin as the primary melanoma, and
focus our attention only on the radioactivity within the nodes.
The morbidity associated w ith sentinel lymph node biopsy
is low, but potential complications include serom a, lympho-
cele, wound infection, and, in very rare cases, lymphe-
dem a.30,32 The m orbidity of sentinel lymph node biopsy has
been evaluated in prospective clinical trials. In MSLT-1, the
rate of complications for patients undergoing sentinel lymph
node biopsy was 10.1%.30 The Sunbelt Melanom a Trial eval-
uated complication rates for sentinel lymph node biopsy
alone and, for patients with positive sentinel nodes, sentinel
lymph node biopsy and completion lymph node dissection.
The complication rates were higher in patients undergoing
lymph node dissection, while the risk of complications was
low for sentinel lymph node biopsy alone (wound infection
1.1%, lymphedema 0.7%, and serom a/hem atoma 2.3% for sen-
tinel node biopsy versus 7, 11.7, and 5.9% for sentinel node
biopsy followed by lymph node dissection).33,34
While the utility of sentinel lymph node biopsy in deter-
m ining the spread of cancer and providing a prognostic ben-
efit is clear, the role it plays in providing a survival benefit
is not. One prospective, random ized trial has addressed this
question. In MSLT-1, patients were randomly assigned to
undergo either wide excision of the primary tum or with
observation of the nodal basin or wide excision w ith senti-
nel lymph node biopsy and subsequent completion lymph
node dissection if there was a positive sentinel lymph node.
Final analysis of the 1,347 patients w ith interm ediate thick-
ness m elanoma who were evaluated in the study dem on-
strated no di erence in m elanom a-specific survival at
10 years for patients w ho underwent sentinel lymph node
biopsy versus observation. There was, however, an improvement
in disease-free survival for patients undergoing sentinel lymph
node biopsy. Patients with a positive sentinel lymph node biopsy
who then had completion lymph node dissection were found to
have an improved distant disease-free survival compared to
patients in the observation group who failed in the nodal basin
with clinically obvious disease (54.8 versus 35.6%, p =0.02). Mel-
anoma-specific survival at 10 years was also improved in the
sentinel lymph node biopsy positive group compared to the
observation group of patients who failed in the nodal basin
(62.1 versus 41.5%, p =0.006).30
The NCCN currently recommends that sentinel lymph node
biopsy be discussed and o ered to patients with intermediate-
thickness melanoma (1–4 mm).12
Controversy still exists
regarding the routine recommendation for sentinel lymph node
biopsy in patients with thin melanoma (<1 mm). The risk of
having a positive sentinel lymph node biopsy in a patient with
a thin melanoma has been reported in the literature to be
around 5%, but there are clearly subsets of patients within the
broader group of T1 melanoma cases with a higher or lower risk
of a positive sentinel node. Since we and many others use a 5%
sentinel node positivity threshold as the level at which to con-
sider the procedure for an otherwise healthy patient, it is
important to identify which subsets of patients with T1 mela-
noma are or are not good candidates for sentinel node biopsy.
Studies have demonstrated that the percentage of cases with a
positive sentinel node increases when the melanoma is ≥0.76
mm in thickness, ulcerated, or mitotically active (mitotic rate
≥1/mm 2).35,36,37 The NCCN, American Society of Clinical Oncol-
ogy (ASCO), and Society of Surgical Oncology (SSO) all recom-
mend that sentinel lymph node biopsy be considered in
patients with melanomas that are 0.76 to 1 mm if the mela-
noma is ulcerated or the mitotic rate is ≥1/mm 2. Sentinel lymph
node biopsy, however, should still be considered in appropri-
ately selected patients with thin melanomas in this thickness
range (0.76–1 mm) that are not ulcerated or mitotically
active.12,38
Controversy also exists regarding sentinel lymph node biopsy
for patients with clinically node-negative thick melanomas
(≥4 mm). The final analysis of MSLT-1 evaluated 290 patients
with thick melanomas, defined as greater than 3.5 mm. Fifty-
seven (33%) out of the 173 patients in the sentinel lymph node
biopsy arm had sentinel lymph node metastasis, while 116
(67%) had no evidence of nodal metastasis. Twelve of the 116
sentinel node-negative patients eventually developed nodal
disease, bringing the overall incidence of nodal metastasis in
the sentinel lymph node biopsy arm to 39.9% (the rate of
nodal metastasis in the nodal observation arm was 37.6%). The
10-year disease-free survival rates for the sentinel lymph node
biopsy and observation arms were 50.7 and 40.5%, respectively
(p =0.03). In those patients with thick melanoma found to have
Surgical Treatment of Cutaneous Melanoma
89

sentinel lymph node metastasis, the 10-year melanoma-specific
survival was significantly worse (48%) compared to those with-
out sentinel lymph node metastasis (64.6%, p =0.03).39,40
More recently, Yamamoto et al published a single institution,
retrospective review of patients seen over a 10-year period
with melanoma ≥4 mm. The endpoints evaluated included
recurrence-free survival and disease-specific survival. Sentinel
lymph node biopsy was performed in 412 patients and of those,
161 (39%) had a positive sentinel lymph node. Forty-six other
patients presented with clinically palpable disease. Of the
251 patients who had a negative sentinel lymph node biopsy,
14 (6%) recurred in the mapped nodal basin, for a calculated
false-negative rate of 12.3%. The median disease-specific sur-
vival of 82 months for patients with a negative sentinel lymph
node was significantly better than for those with a positive sen-
tinel lymph node (41 months) or for patients with clinically
node-positive disease (27 months; p <0.0001). The authors also
reported a significant di erence in median recurrence-free sur-
vival between patients with negative sentinel lymph nodes
compared to patients with positive sentinel lymph nodes or
clinically palpable disease (32 versus 14 and 7 months, respec-
tively; p <0.0001). The authors concluded sentinel lymph node
biopsy should be considered in those with clinically node-
negative thick melanoma due to the prognostic information
obtained and the acceptably low false-negative rate.41
Some surgeons have advocated repeat sentinel lymph node
biopsy in the event of local recurrence or development of
resectable in-transit disease, assuming a prior sentinel lymph
node biopsy was negative.42,43,44 The technical feasibility of
repeat sentinel lymph node biopsy has been evaluated in two
separate studies, and the ability to detect a sentinel lymph node
using either 99mtechnetium sulfur colloid alone or in combina-
tion with blue dye was reported as 12 of 12 (100%) cases in one
study and 32 of 33 (97%) cases in another.42,45 However, the
prognostic significance and staging reliability of finding a “sen-
tinel” lymph node in the context of recurrence is not clear. At
present, we do not perform repeat sentinel node biopsy for
patients with local or in-transit recurrence, preferring instead
to evaluate and follow the nodal basin with serial ultrasonogra-
phy. If, however, a patient presents with local recurrence with-
out ever having undergone a sentinel node biopsy, we will
consider sentinel node biopsy in conjunction with wide exci-
sion of the local recurrence site in selected patients.
4.5 Lymphadenectomy
Lymphadenectomy broadly refers to the en bloc removal of all
lymph node tissue in a draining nodal basin. The most common
initial site of melanoma metastasis involves the regional lymph
nodes. Lymph node involvement has been shown to be the
most important prognostic factor in otherwise localized mela-
noma.38 Prior to the widespread use of sentinel lymph node
biopsy, the two options available to manage the draining nodal
basin were either an elective lymphadenectomy (i.e., the elec-
tive removal of all clinically negative nodes in the draining
basin[s]) or a therapeutic lymphadenectomy (i.e., deferring
lymphadenectomy until the time of clinically detected nodal
basin recurrence; Table 4.3). Both of these approaches have
significant drawbacks. Approximately 16 to 20% of patients
with an intermediate-thickness melanoma are expected to have
clinically occult nodal metastasis at the time of diagnosis of
their primary.46 This means many patients undergoing elective
lymphadenectomy are subjected to unnecessary operative mor-
bidity without any benefit in regional control or improved sur-
vival. Conversely, delaying lymph node dissection until clinical
recurrence may result in patients recurring with unresectable
disease in the regional nodal basin. Even if the disease is
resectable at the time of recurrence, prospective randomized
trial data suggest that such patients are at increased risk of
complications from their lymphadenectomy—including severe
lymphedema.47 They are also more likely to meet criteria for
adjuvant radiation,30,48 which again increases the likelihood of
lymphedema. Moreover, the results of the MSLT-1 study dem-
onstrated that patients in the observation arm with intermedi-
ate-thickness melanoma who developed nodal recurrence had
worse melanoma-specific survival than those who were found
to have microscopic disease in the sentinel node and under-
went completion lymphadenectomy at the time of diagnosis.39
Another disadvantage of deferring lymphadenectomy is that a
subset of patients who recur in the regional nodes also have
evidence of distant metastatic disease at that time. While it
may be true that some of these patients were spared the need
for a lymphadenectomy that would not have improved their
overall outcome, in other cases these patients will develop per-
sistent and often severe problems due to uncontrolled regional
disease that systemic treatments do not always completely
eliminate. Ultimately, due to the alternative provided by senti-
nel node biopsy with selective lymphadenectomy for only
node-positive cases, both elective and therapeutic lymphade-
nectomy have been abandoned as the primary strategy for
clinically node-negative melanoma cases. Therapeutic lympha-
denectomy, however, remains the gold standard in virtually all
cases of clinically node-positive melanoma without detectable
distant metastases.
The current standard of care for most clinically node-negative
melanomas greater than 0.75 mm thick is to perform a sentinel
lymph node biopsy at the time of wide excision, and comple-
tion lymphadenectomy for those patients with any positive
Table 4.3 Options for the surgical management of the regional lymph
nodes in melanoma
Types of lymph node evaluation
Sentinel lymph node
biopsy
Removal of lymph node(s) that are radioactive
and/or have blue dye uptake—the sentinel node is
thought to represent the first lymph node in the
drainage pattern of the primary tumor
Radical
lymphadenectomy
En bloc removal of all lymph node tissue in a
draining lymph node basin, for any indication
Elective
lymphadenectomy
Radical lymphadenectomy performed without
any clinical evidence of lymphadenopathy (by
exam or imaging) or histologic evidence of
microscopic lymph node evaluation
Completion
lymphadenectomy
Radical lymphadenectomy performed in a lymph
node basin after a positive sentinel node biopsy
Therapeutic
lymphadenectomy
Radical lymphadenectomy performed in a lymph
node basin containing clinically detected lymph
node involvement
Surgical Treatment of Cutaneous Melanoma
90

sentinel lymph nodes.12,38 Only about 15 to 18% of completion
lymphadenectomy specimens contain additional nodes (i.e.,
nonsentinel nodes) with metastatic disease.39 The impact of
completion lymphadenectomy after positive sentinel lymph
node biopsy on survival is being evaluated in MSLT-2, in which
patients with a positive sentinel lymph node biopsy were
randomized to either undergo completion lymph node dissec-
tion or nodal basin observation with serial ultrasounds. The
study finished accrual in 2014 and we are awaiting the final
results.39 Until those results are available, the standard of care
for sentinel node-positive cases remains completion lymph
node dissection. Reports of successful management of the senti-
nel node-positive basin by observation and serial ultrasonogra-
phy, combined with the morbidity of lymphadenectomy, have
led many patients to choose not to undergo completion lym-
phadenectomy.49,50 The preliminary results of a small European
randomized trial, showing equivalent 3-year survival outcomes
for sentinel node-positive patients whether or not completion
lymphadenectomy was carried out, have likely encouraged this
trend further.51 We believe that, until much more mature
results of larger studies are available, this conservative
approach should only be undertaken by a fully informed patient
who is aware of the risk of nodal basin recurrence and willing
to return for routine surveillance including nodal ultrasounds.
Even with ultrasound surveillance of the nodal basin, up to 50%
of nodal recurrences are first detected by the patient, so the pa-
tient must also be committed to self-examination and to return
promptly if palpable lymphadenopathy develops between
scheduled visits.52
Significance of In-Transit and Interval Nodes in Melanoma
In most cases, melanoma will drain to the major nodal basins,
that is, the cervical, axillary, and ilioinguinal nodal basins.53 The
use of preoperative lymphoscintigraphy as part of the sentinel
lymph node biopsy procedure has led to the increased recogni-
tion of draining nodes outside of these major nodal basins. Mel-
anoma may metastasize to nodes within minor lymph node
basins, which have been classified as epitrochlear, popliteal,
and internal mammary,53 or to nodes described as interval or in
transit. These nodes, when identified, can be routinely removed
during the sentinel node biopsy procedure.
This terminology can be confusing, and a classification sys-
tem to help more accurately define these has been proposed by
Zager et al. They defined “interval nodes” as any superficial (i.e.,
outside the chest and abdominal cavity) lymph nodes identified
by lymphoscintigraphy, other imaging studies, incidentally at
surgery or clinically based on involvement with tumor that are
not located within the defined confines of a major or minor
nodal basin. In keeping with the common terminology used to
describe regional recurrences, they defined “in-transit nodes”
as any nodes located between the primary cutaneous mela-
noma and the major basin that is traditionally considered to
drain that site.54 This definition would include any interval and
minor basin nodes that would not be removed with a standard
lymphadenectomy of the corresponding major basin. The
reported rates of minor basin or interval node drainage during
sentinel lymph node biopsy procedures have been between 2.1
and 9.8%.55,56 McMasters et al analyzed the Sunbelt Melanoma
Trial database and identified 62 (3.1%) patients with in-transit
nodes out of 2,332 patients undergoing sentinel lymph node
biopsy, and of those, 13 nodes (21%) were positive for
metastatic disease.57 In 11 of the 13 cases, only the interval
nodes, and not the sentinel nodes from the major basin, con-
tained tumor. An additional study by Puleo et al showed 75
(6%) out of 1,172 patients had in-transit nodes identified, and
of those 12 (16%) were positive for micrometastatic disease.58
These results justify an e ort to biopsy in-transit nodes, which
in both studies seemed to have the same prognostic impact as a
positive node in a major basin. An area of controversy deals
with the management of the upstream nodal basin after a posi-
tive in-transit node. As with the sentinel node-positive major
basin itself, we believe there are times when carefully selected
patients can be followed without major basin completion
lymphadenectomy.
4.6 Immediate versus Delayed
Reconstruction of the Primary Site
Reconstructive techniques with rotational or advancement
flaps or skin grafts may be necessary after excision of a mela-
noma in a cosmetically sensitive area or when large margins
are required in an area of skin tension that does not allow for
primary skin closure such as the scalp, hand, close to joints, etc.
In these situations, it is appropriate to ensure that negative
margins have been obtained before tissue rearrangement takes
place. Once tissue rearrangement occurs, the ability to deter-
mine which margin is involved by tumor becomes more di -
cult and sometimes impossible. Delayed reconstruction is one
e ective manner by which to allow adequate margin assess-
ment prior to a planned definitive reconstruction. Several
methods for margin assessment and temporary closure exist. In
general, we prefer either wide excision and temporary graft
placement (e.g., AlloDerm skin substitute59 or homograft skin)
or staged marginal excision and subsequent central tumor exci-
sion and reconstruction.60 There are advantages and disadvan-
tages to each strategy and patient selection is paramount to
achieving long-term success.
Staged contoured marginal excision and subsequent central
tumor excision is the process whereby the margins around the
tumor are the only tissue excised at the time of initial opera-
tion, and once these margins are determined to be free of mela-
noma or melanoma in situ, then definitive excision of the entire
lesion and appropriate reconstruction are performed. The iden-
tification of the margins of the lesion can be augmented intra-
operatively by using a Wood’s lamp. Then, beginning a distance
0.5 to 1 cm from the defined lesion perimeter depending on
whether the preoperative diagnosis is in situ or invasive dis-
ease, a small full-thickness strip of skin, usually 2 to 3 mm in
width, is either excised in a rectangular fashion around the pri-
mary or contoured to follow anticipated lines of reconstruc-
tion.60 The defect is closed, generally with a running suture
around the entire perimeter of the marginal excision. The thin
strips of tissue are oriented and sent to the pathologist for per-
manent histopathologic evaluation. The specimens are eval-
uated with standard hematoxylin and eosin staining, and
immunohistochemical stains are employed as necessary. If the
margins are all found to be negative for melanoma (invasive or
in situ), then the central lesion is excised and the defect recon-
structed at that time. Conversely, if any margins are found to be
positive for melanoma, then excision of those margins are
Surgical Treatment of Cutaneous Melanoma
91

repeated using a further 0.5 to 1 cm, until negative peripheral
margins are obtained and central excision and reconstruction
can be undertaken. This technique may be particularly useful in
the setting of lentigo maligna (which is melanoma in situ) and
lentigo maligna melanoma (invasive melanoma) on the face or
dorsum of the hands. The advantage of this approach is that it
obviates the potential risk of repeat surgery for positive margins
after significant tissue rearrangement or flap reconstruction
has been performed. In a series of 127 patients with lentigo
maligna of the head and neck, Glazer et al found that a 5 mm
margin was adequate for complete excision in only 77% of cases,
so immediate reconstruction after a standard wide excision
would have been associated with positive margins in roughly a
quarter of cases.60
Mohs surgery has been used by some dermatologic surgeons
to achieve complete excision of melanomas in cosmetically sen-
sitive areas, allowing subsequent reconstruction to take place
with the knowledge that the margins of excision are free of
tumor. A large prospective study evaluated 1,120 cases of mela-
noma in situ treated with Mohs surgery. In this study, the mini-
mum surgical margin taken as part of the initial Mohs
procedure was 6 mm, with an additional 3 mm of skin taken in
each area where a positive margin was encountered. In this
study, 98.9% of melanoma in situ cases were cleared with Mohs
surgery after two stages, that is, a 9-mm margin, versus only
86% cleared with the first-stage 6-mm margin.61 A major issue
limiting the application of Mohs surgery is the di culty di er-
entiating atypical but nonmalignant melanocytes from mela-
noma in situ, particularly in sun-damaged skin, using the
frozen section histopathology performed during the Mohs tech-
nique. The availability of rapid immunohistochemical staining
for frozen section specimens can address this issue. We believe
Mohs surgery for melanoma in situ should only be used in set-
tings that have this staging capability and only after an initial
defined margin first-stage excision is carried out. That notwith-
standing, our preference remains staged marginal excision
rather than Mohs surgery for melanoma in situ/lentigo maligna.
We do not use Mohs surgery at all for invasive melanoma.
4.7 Special Topics
Certain situations (i.e., based on histopathologic subtype, age of
the patient, or other considerations) arise where the standard
recommendations for melanoma treatment may be modified.
Several such situations are discussed below.
4.7.1 Desmoplastic Melanoma
Desmoplastic melanoma is a rare variant of cutaneous mela-
noma with an annual incidence rate of 2 per million. Risk fac-
tors associated with desmoplastic melanoma include extensive
and chronic sun exposure. The majority of desmoplastic mela-
nomas are found on the head and neck and occur in older
adults.62 Desmoplastic melanoma is characterized by malignant
spindled melanocytes within a collagenous myxoid stroma.
Desmoplastic melanoma is further divided into two histological
subtypes: pure and mixed desmoplastic melanoma. Two histol-
ogy-specific considerations arise in the management of desmo-
plastic melanoma: when should postoperative radiation to the
primary site be added and when should sentinel lymph node
biopsy be performed?
Desmoplastic melanoma has been reported to have a higher
rate of local recurrence than other histologic types of cutaneous
melanoma.62,63,64 This has led some authors to advocate for
adjuvant radiation to the primary site. Guadagnolo et al con-
ducted a retrospective review of 130 patients diagnosed with
desmoplastic melanoma (100 pure, 30 mixed). Of those 130, 59
(45%) were treated with surgery alone and 71 (55%) had sur-
gery and adjuvant radiation. Of the patients who underwent
surgery alone, 14 (24%) experienced a recurrence, while only 5
(7%) patients who received both surgery and radiation therapy
developed a local recurrence (p =0.009).65 On multivariate anal-
ysis, the authors found only a margin negative resection and
postoperative radiation to be associated with improved local
control.
Strom et al retrospectively reviewed a total of 277 patients
over a 21-year period with desmoplastic melanoma who were
treated by surgery with or without adjuvant radiation therapy.
The primary endpoint was local control, which was defined
as freedom from disease recurrence within the radiated field
of the primary tumor bed. Of the 277 patients, 113 (40.8%)
received adjuvant radiation therapy. The authors reported
patients with positive margins benefited the most from adju-
vant radiation therapy. Thirty-five patients had positive resec-
tion margins; 14% (3/22) of those who received radiation
therapy developed a recurrence, while 54% (7/13) who did
not receive radiation developed a recurrence (p =0.003). The
authors also demonstrated significantly improved local control
in patients with negative resection margins and high-risk fea-
tures, defined as Breslow thickness greater than 4 mm, Clark
level V, or a head and neck primary site. The authors concluded
radiation therapy may be safely omitted if the margins are ne-
gative, the Breslow thickness is less than 4 mm, no perineural
invasion is seen, and the tumor is in a non–head and neck
location.63
Chen et al reported adjuvant radiation to be beneficial in
patients with locally recurrent desmoplastic melanoma, and
those with gross residual disease, perineural involvement, or
after excision with narrow margins.62 We recommend adjuvant
radiation in all cases of desmoplastic melanoma with positive
or close margins after wide excision, and in most tumors with
perineural invasion or thickness ≥4 mm, especially on the head
and neck.
The role of sentinel lymph node biopsy in desmoplastic mela-
noma is controversial. Overall, desmoplastic melanoma has a
lower rate of regional nodal metastasis compared to other sub-
types of cutaneous melanoma. Desmoplastic melanoma has
been reported to have a sentinel lymph node positivity rate of
less than 10%.66 Various studies report conflicting data on the
impact of sentinel lymph node biopsy in desmoplastic mela-
noma on overall survival. Using the Surveillance, Epidemiology,
and End Results (SEER) database, Wasif et al found no signifi-
cant di erence in overall survival between sentinel node-nega-
tive and node-positive patients.67 Other studies have reported a
threefold increase in the risk of death when the sentinel lymph
node is positive.68 When broken down by subtype, mixed des-
moplastic melanoma has been shown to have rates of lymph
node metastasis that are comparable to nondesmoplastic cuta-
neous melanoma, but even pure desmoplastic melanomas may
Surgical Treatment of Cutaneous Melanoma
92

have a sentinel node positivity rate high enough to justify senti-
nel lymph node biopsy in healthy patients.69 NCCN guidelines
note that the role of sentinel lymph node biopsy remains con-
troversial in pure desmoplastic melanoma, whereas the ASCO/
SSO guidelines call for sentinel lymph node biopsy in desmo-
plastic melanoma.12,38
4.7.2 Pediatric Melanoma
The incidence of melanoma arising in children less than 18 years
of age is rising in the United States.70 The cause of this increase
is likely to be multifactorial and may stem from an increased
global awareness of melanoma, which prompts skin evaluation
at an earlier age, the use of tanning beds among teenagers, and
advances in pathologic evaluation that have allowed for more
accurate diagnosis. The diagnosis of melanoma in the pediatric
population can be a challenge because these lesions often lack
the characteristic properties typical of adult melanomas (asym-
metry, irregular borders, change in color, increase in diameter,
etc.).71 The histopathology of melanoma in this age range can
also present a diagnostic challenge even among expert derma-
topathologists.72 Despite the diagnostic challenges, pediatric
patients with melanoma tend to have a more favorable progno-
sis than adult patients with melanoma.73
The initial workup for a lesion suspected to be a melanoma in
the pediatric patient is essentially the same as in an adult. A full
skin exam evaluating the presence of typical and atypical nevi
as well as congenital nevi is useful to assist in future skin evalu-
ations. A detailed family history may be useful as some cases
have been linked to an inherited melanoma susceptibility gene.
The operative management of pediatric melanoma is similar
to adult melanoma.74 Younger patients tend to have a higher
incidence of nodal metastasis but less risk of local recurrence,
so a 1-cm margin is commonly employed in children even for
thicker lesions. Sentinel lymph node biopsy is generally utilized
according to the same standards and principles as in cases of
adult melanoma. The decision to pursue completion lymph
node dissection after a positive sentinel lymph node biopsy
must be done weighing the potential lifelong implications of a
node dissection versus the alternative of serial lymph node sur-
veillance with ultrasound. The standard of care recommenda-
tion remains a completion lymph node dissection for most
pediatric patients with positive sentinel nodes and all patients
with palpable nodal involvement.
Although pediatric patients with stage III melanoma have a
relatively better prognosis as compared to adults, adjuvant
therapy is often recommended.75 Interferon is relatively well
tolerated in younger patients, and the patients and their fami-
lies are often highly motivated to pursue adjuvant treatment. At
our center, pediatric patients treated with interferon commonly
receive the standard 1 month of intravenous interferon used in
the adult high-dose interferon regimen, but this is followed by
11 months of weekly treatment with pegylated interferon.76
This hybrid regimen takes advantage of the favorable pharma-
cokinetic properties of pegylated interferon as a maintenance
therapy, while minimizing the number of injections the young
patient must endure. Adjuvant radiation is less likely to be rec-
ommended in this patient population due to the potential
e ects on growth and development.
4.8 Conclusion
Surgery in the form of radical wide excision of the primary
tumor with appropriate negative margins remains the gold
standard of treatment for melanoma. Sentinel lymph node
biopsy is recommended as part of the staging workup for
patients with intermediate-thickness and thick melanoma
without clinical evidence of nodal disease. Controversy still
exists regarding the approach to the regional nodal basin for
patients with thin melanoma, where the decision to perform a
sentinel lymph node biopsy should be individualized. Comple-
tion lymph node dissection is recommended for patients with
positive sentinel lymph node disease; however, the impact lym-
phadenectomy has on overall survival remains uncertain. Plas-
tic surgeons often find themselves on the front lines of the
surgical management of melanoma and should be familiar with
standard recommendations as well as those special situations
where modifications to those recommendations might be
appropriate.
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Surgical Treatment of Cutaneous Melanoma
95

5 Treatment of Rare Skin Malignancies
Karri Adamson and William W. Dzwierzynski
5.1 Introduction
The skin is the largest organ in the body, and it is not sur-
prising that skin cancer is the m ost com m on type of cancer.
The skin has a multitude of functions; these include being a
protective barrier, a structure of m echanical support, an
organ for temperature regulation, a system for excreting
toxic substances, an organ for im munologic function, and a
sensory organ. While skin cancer usually presents as basal
cell and squamous cell cancers or m elanoma, cancerous
changes can develop in any of the cells that perform the var-
ied functions of the skin. Like the m ore comm on skin can-
cers, m ost are more com mon in the Caucasian population,
and ultraviolet (UV) exposure is thought to be a risk factor
in m any of these malignancies. Although these cancers are
rare compared to com m on cutaneous cancers, knowledge of
them is important for their treatment.
5.2 Merkel Cell Carcinoma
5.2.1 Background
Friedrich Merkel first described Merkel cells in 1875. These
slowly adapting mechanoreceptors are derived from the neural
crest and reside in the basal layer of the epidermis. Cyril Toker
reported a tumor of these cells in 1972, initially describing it as
a trabecular skin carcinoma. Six years later, Tang and Toker dis-
covered dense core granules in some of those tumors, which in
the skin are only found in Merkel cells.1 The name Merkel cell
carcinoma was introduced in 1980.
5.2.2 Epidemiology
Merkel cell carcinoma is a rare tumor with an incidence of less
than 1/100,000 in the United States. Caucasian men are a ected
most commonly, at an average age of around 70 years. Cauca-
sian patients account for 94% of cases, with an incidence rate
11.3 times greater than African American patients. Over 75% of
cases occur in patients over the age of 64 years, with almost half
of the cases a ecting patients over the age of 74 years. Men are
a ected about twice as often as women and are diagnosed at an
earlier age. Sun exposure (particularly UVB light) seems to play
a role, with the highest incidence in the United States occurring
in Hawaii, the state with the highest UVB index. The location of
tumors correlates with sun-exposed regions, with the head and
neck (most commonly the face) a ected most often.2 Mucosal
lesions account for 4.5% of cases. Arsenic and infrared have also
been theorized to have a role in the development of Merkel cell
carcinoma.3
Immunocompromised patients are at greater risk, including
those with chronic lymphocytic leukemia, acquired immunode-
ficiency syndrom e, and organ transplant patients. Immuno-
compromised patients develop Merkel cell carcinoma earlier,
with a mean age of 53 in transplant patients, and may have
worse outcomes.4
The AEIOU mnemonic may be useful for remembering pa-
tient demographics. It stands for Asymptomatic, Expanding,
Immunosuppression, Older than 50 years, and Ultraviolet expo-
sure in fair-skinned patients.5
5.2.3 Diagnosis
Merkel cell carcinoma is di cult to diagnose clinically, lacking
distinctive characteristics. The head and neck are most com-
monly a ected, followed by the extremities, and, less com-
monly, the trunk. It may occur anywhere on the skin or mucosa,
and usually presents as a skin toned, red, or purple intradermal
nodule that has rapidly grown (Fig. 5.1a, b). The epidermis
may be ulcerated. Most tumors are less than 2 cm at the time of
diagnosis.6
As with most suspicious skin lesions, a biopsy should be per-
formed using punch, incisional, or close-margin excisional tech-
nique depending on the lesion location and size. The most
common initial clinical suspicion is usually an epidermal cyst,7
Fig. 5.1 (a) A 73-year-old female with 3 months’ history of nodule on
her nasal sidewall that was confirmed to be Merkel cell carcinoma on
biopsy. (b) Following excision by Mohs micrographic surgery. The
lesion was larger than its clinical appearance.
Treatment of Rare Skin Malignancies
96

but the di erential diagnosis includes basal cell carcinoma,
squamous cell carcinoma, amelanotic melanoma, adnexal
tumors, and cutaneous metastases.3
A dermatopathologist
should be requested for analysis of the biopsy. Hematoxylin and
eosin (H&E) stains show small, round, blue cells, common in
neuroendocrine tumors (Fig. 5.2a, b). Immunohistochemistry
must be completed to confirm the diagnosis, since metastatic
small cell lung carcinoma (SCLC) can be indistinguishable on
H&E. Cytokeratin-20 (CK-20) is found in 89 to 100% in cases of
Merkel cell carcinoma, and is uncommonly seen in SCLC
(Fig. 5.3). Merkel cell carcinoma stains are positive for neuro-
filaments in most cases, but SCLC stains are not. Conversely,
thyroid transcription factor 1 is positive in most SCLCs, but it is
seen rarely in Merkel cell carcinoma.8 For lesions that test
equivocally, additional stains including chromogranin, synapto-
physin, CD56, and neuron-specific enolase may be used to eval-
uate for other diagnoses.9
About 5% of Merkel cell carcinomas present in a lymph node
with an unknown primary. Half of these are found in cervical
nodes and 40% in inguinal nodes, while known primary tumors
have positive nodes in the axillary or inguinal region more com-
monly than in the cervical region.10 Diagnosis in these cases is
made by pathology with the same stains mentioned earlier.
5.2.4 Workup
At the time of diagnosis, two-thirds of patients have local dis-
ease, one-quarter have lymph node involvement, and 7% have
distant metastases.11 A thorough review of systems should be
obtained, and a complete physical examination including skin
evaluation and palpation for lymphadenopathy should be per-
formed. Sixteen to 24% of patients have palpable regional
nodes.7,12 The National Comprehensive Cancer Network (NCCN)
recommends imaging studies for patients with clinically posi-
tive nodes. Positron emission tomography–computed tomogra-
phy (PET-CT) is preferred, which is sensitive and specific, but
CT or magnetic resonance imaging (MRI) is an option if PET-CT
is not available.9 PET-CT leads to a change in management in
one-third of patients. Upstaging is relatively common (22% of
total patients), most often with a finding of bone metastases,
but downstaging also occurs in 5% of the cases. The PET stage is
associated with survival, making it a useful test for prognosis.13
Another indication for imaging is when small cell carcinoma of
the lung with skin metastasis is a possible diagnosis. For exam-
ple, when a biopsy is suspicious for Merkel cell carcinoma on
histology, but is CK-20 negative, the NCCN recommends CT,
MRI, or PET-CT to evaluate for a di erent primary cancer.9
5.2.5 Merkel Cell Polyomavirus
In 2008, Feng et al identified a polyomavirus present in 80% of
Merkel cell tumors, compared to about 10% of control skin sam-
ples. This virus was named Merkel cell polyomavirus (MCV).14
This virus is a part of normal human flora, and infected patients
are asymptomatic. Most people acquire MCV by middle age.
The virus is then integrated into the genome.15 MCV infection
and high levels of antibodies against MCV are associated with a
higher risk of developing Merkel cell carcinoma; however, these
factors are associated with better survival rates.16
Fig. 5.2 (a) Hematoxylin and eosin (H&E) stain of Merkel cell carcinoma shows small round blue cells. (b) High-power view.
Fig. 5.3 Positive cytokeratin 20 stain, found in nearly all cases of Merkel
cell carcinoma.
Treatment of Rare Skin Malignancies
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5.2.6 Staging
The tumor, node, metastasis (TNM) Staging System is used for
Merkel cell carcinoma, as described by the American Joint
Committee on Cancer. T1 indicates tumors less than or equal to
2 cm, T2 tumors 2 to 5 cm, and T3 tumors over 5 cm. N0 indi-
cates no nodal involvement, and N1 indicates metastases to
regional nodes. M0 means no metastases, and M1 means dis-
tant metastasis (beyond lymph nodes).17 Stage 0 tumors are in
situ. Stages I and II are local, with stage II including tumors
greater than or equal to 2 cm. Stage III indicates nodal involve-
ment, and stage IV tumors have distant metastasis. Distant
metastases occur most commonly in the liver, followed by the
lungs, bones, and brain.3
5.2.7 Surgical Treatment
The NCCN guidelines recomm end w ide excision with 1- to
2-cm margins, removing the specimen down to fascia. Some
studies, however, found no change in local recurrence w ith
2-cm m argins compared to 1 cm , and therefore some
authors advocate for 2-cm m argins only in cases w here the
prim ary tum or is greater than 2 cm .3,12 Mohs or m odified
Mohs (Mohs excision, followed by a 0.5- or 1-cm margin
after the final section) is also acceptable in areas of cosm etic
concern, such as the face. The central portion of the speci-
m en should be sent as a perm anent specim en. The wound
should be closed with the goal of rapid healing if radiation
therapy is planned9 ( Fig. 5.4a, b).
Sentinel lymph node biopsy (SLNB) should be performed in
all patients at the time of the wide excision, both for staging
and for therapeutic reasons (Fig. 5.4c). Sentinel node status is
the most important information for staging (Fig. 5.5). Merkel
cell carcinoma spread is generally lymphatic rather than hema-
togenous. Lymph nodes are commonly involved at the time of
diagnosis, even in relatively small and/or superficial tumors
with up to 37% having a positive sentinel node.6,18 In patients
without palpable lymphadenopathy, micrometastases are found
in 23%.12 Positive sentinel nodes are more common in tumors
that spread below the dermis, and in older patients.18 Sentinel
nodes should be evaluated using the appropriate stains as men-
tioned earlier. Pathology should also note the amount of tumor
burden and whether the tumor spreads beyond the capsule of
the lymph node.9
Fig. 5.4 (a) Merkel cell carcinoma excision after biopsy. The scar was marked with 2-cm margins and injected with methylene blue for sentinel lymph
node biopsy. (b) After wide excision down to investing fascia, the wound was covered. (c) Sentinel lymph nodes were identified in the axilla. These
were identified by lymphoscintigraphy using a gamma probe and methylene blue.
Treatment of Rare Skin Malignancies
98

For patients with a positive sentinel lymph node or positive
clinical nodes on exam, therapeutic regional lymph node dis-
section is recommended. Improved survival is seen in some
studies.19
Type I interferons have been found to inhibit the proliferation
of MCV positive Merkel cell carcinoma, inducing apoptosis in
vitro and in vivo.20 More research is needed before treatment
recommendations can be made.
5.2.8 Radiation Therapy
Radiation to the primary site and/or the regional nodes may
decrease local recurrence and improve disease-free survival.6,21,22
This is controversial since other studies show no change in recur-
rence or overall survival.12,23 The NCCN recommends radiation to
the primary site (and the nodal basin in head and neck tumors)
for patients with negative SLNB. If SLNB is not obtained or is pos-
itive, the primary site and nodal basin should be radiated.9 Radia-
tion should be given as soon as the surgical wounds have healed.
5.2.9 Chemotherapy
Traditional chemotherapy regimens including carboplatin and
etoposide are poorly tolerated and have not been shown to
decrease mortality; they have therefore not been recom-
mended for routine use by the NCCN9. Immunotherapy has
recently shown promising results in both MCV positive and
MCV negative patients. These new medications include pem-
brolizumab and nivolumab, which inhibit programmed death-1
(PD-1), and avelumab, which inhibits programmed death
ligand-1 (PD-L1). Immunotherapy should be initiated early in
patients with metastatic disease.24
Fig. 5.5 Wide excision of Merkel cell carcinoma in the right cheek of a 68-year-old male. The skin around the lesion was injected interdermally with
technician-labeled sulfur colloid and methylene blue for sentinel lymph node localization. The planned reconstruction with (a) rhomboid flap is
marked. (b) The sentinel lymph node (x) in zone 3 of the neck was harvested through the reconstruction incision. (c) The rhomboid flap rotated and
sutured into place. (d) Lateral view 4 months postoperatively after completion of radiation therapy. The sentinel lymph node biopsy showed no
metastasis. (e) Oblique view 4 months postoperatively.
Treatment of Rare Skin Malignancies
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5.2.10 Prognosis
The overall 5-year survival rate is poor, at only about 50%.
Immunosuppressed patients have an even worse prognosis,
with only 43% alive 3 years after their diagnosis.7 Worse sur-
vival rates are seen in men and the elderly.19 Tumors on the
limb are often diagnosed at an earlier stage than those on the
trunk, and patients with tumors of the upper extremity have
improved survival.25 Most patients present with stage I or stage
II disease. Staging is indeed predictive of survival, with patients
diagnosed with stage I disease having an 86% 2-year survival
rate, compared to 32% in patients with stage II disease.2
Although patients with an unknown primary are stage III due to
nodal involvement, these patients have a better survival rate
than patients with a known primary who are stage III.10 Node
status and the corresponding pathologic stage are the most
important predictors for prognosis.
SLNB itself may be therapeutic in addition to being prognos-
tic, with SLNB patients having improved overall survival rate
compared to patients with positive nodes and also those who
did not have a lymph node evaluation. This is particularly true
for tumors that were not on the head and neck,22,26 whereas
head and neck tumors have less predictable drainage patterns,
possibly leading to a high false-negative SLNB rate.18
Up to half of patients have local or regional recurrence, usu-
ally in the nodal basin.7,12 This occurs in an average of 9 months,
with over 90% of recurrences occurring within 2 years. In
patients with distant metastases, average survival is less than
1 year.12
Patients should be evaluated every 3 to 6 months for the first
2 years after treatment, and then at least yearly.9
5.2.11 Summary
Merkel cell carcinoma is a rare, but locally and regionally
aggressive skin cancer that most commonly a ects elderly
white males. It is di cult to diagnose clinically, and histological
diagnosis is assisted by special stains. Merkel cell carcinoma
should be treated with wide local excision using at least 1-cm
margins. SLNB should be mandatory, given it determines stag-
ing, which predicts prognosis. Radiation therapy is often indi-
cated, while chemotherapy has not proven to be e ective. MCV
is often present in the tumor, but has yet to be e ectively
targeted therapeutically.
5.3 Dermatofibrosarcoma
Protuberans
5.3.1 Background
Dermatofibrosarcoma protuberans (DFSP) is a malignant cuta-
neous tumor characterized by a low risk of distant metastasis
but a high local recurrence rate if not treated appropriately. It is
a mesenchymal tumor, stimulated by mutations in stem cells in
skin appendages.27
DFSP was first described by Taylor in 1890 as a sarcoma
“resembling in some aspects keloids.” It was later given its
name by Ho man in 1925.28
5.3.2 Epidemiology
DFSP has an incidence of 1 to 4 cases per million people per
year in the United States, accounting for 0.1% of all cancers.29 It
a ects males and females nearly equally, with a slight predom-
inance in women. Among American Caucasians, the highest
incidence is in Hawaii29; however, a quarter of cases occur in
non-Caucasian patients, with African Americans being dispro-
portionately a ected. DFSP is most commonly diagnosed in
patients 30 to 50 years old,29 but up to 20% of cases occur in
pediatric patients. Congenital lesions are also reported.30
5.3.3 Diagnosis
DFSP lacks defining features, and is often present for many
years before it is biopsied and diagnosed. It usually presents as
an asymptomatic, firm plaque or nodule that has been slowly
enlarging for a long time, sometimes with a recent rapid
growth period.29 Some patients describe a history of trauma
preceding the lesion, but this has not been correlated with
development of DFSP.30 DFSP may be skin-toned, red-blue,
brown-yellow, erythematous, sclerodermiform, telangiectatic,
or atrophic. It is adherent to the skin but usually freely mobile
over deeper structures.31 Long-standing lesions may become
painful or develop ulcerations.28
DFSP can present anywhere, but most commonly is found on
the trunk. Thirty percent of tumors appear in the extremities
(upper more often than lower), and 15% in the head and neck.
The distribution in children is similar.32
Incisional or excisional biopsy should be performed. H&E stain
shows a uniform proliferation of spindle cells with low mitotic
activity. These form a characteristic “storiform” or “cartwheel”
pattern (Fig. 5.6), with projections invading underlying fat, fas-
cia, muscle, and even bone, like tentacles. This creates a honey-
comb appearance within subcutaneous fat. It may be di cult to
distinguish DFSP from dermatofibroma, fibrosarcoma, atypical
fibroxanthoma (AFX), and nodular fasciitis.28 Immunohistochem-
istry can be helpful. CD34 is often strongly expressed in DFSP
(Fig. 5.7) and is used to di erentiate it from dermatofibromas,
which do not express CD34. Conversely, dermatofibromas
Fig. 5.6 Storiform pattern of dermatofibrosarcoma protuberans.
Treatment of Rare Skin Malignancies
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express coagulation factor XIIIa, while DFSP does not.28 Other
stains including stromolysin-3, S100, CD68, and apolipoprotein
D may also be used to rule out other diagnoses.
The di erential diagnosis may also include neurofibroma,
leiomyoma, epidermal cyst, malignant melanoma, basal cell
carcinoma, keloid, desmoids, Kaposi’s sarcoma, and sarcoido-
sis.28 In children, DFSP may be confused with vascular malfor-
mations and hamartomas, as well as congenital aplasia cutis,
dermoid cyst or teratoma, and infantile fibromatosis.32
5.3.4 Workup
A thorough history and physical exam is usually su cient prior
to treatment of DFSP, given it is generally a local disease. DFSP
metastasizes in only 1% of patients, mostly to the lungs. It does
not commonly spread to the lymph nodes, and therefore SLNB
is not recommended. MRI accurately depicts the depth of
lesions, but underestimates the lateral extent.33 The NCCN does
not recommend any diagnostic imaging.34
5.3.5 Subtypes
Several variants exist, including the Bednar’s tumor, a pigmented
variant making up 1% of DFSP cases, as well as myxoid, myoid,
granular cell, neuorfibromatous, sclerotic, giant cell fibroblas-
toma, and atrophic. A more aggressive subtype, fibrosarcoma-
tous DFSP (DFSP-FS), has more frequent mitoses and areas of
cellular atypia, with a herringbone pattern. This variant accounts
for 10 to 15% of cases and is aggressive, with higher local recur-
rence rates, more frequent metastasis, and greater mortality.35
5.3.6 Chromosomal Abnormalities
Over 90% of cases have supernumerary ring chromosomes or
translocations (t[17;22] [q22;q13]), combining parts of chro-
mosomes 17 and 22. This results in an oncogenic fusion of
collagen type I alpha 1 gene (COL1A1) with platelet-derived
growth factor B-chain gene (PDGFB), resulting in lack of regula-
tion of production of the PDGFB protein.36 In turn, the PDGFB
receptor, a tyrosine kinase, is overstimulated. The chromosomal
changes are confirmed with karyotype analysis and fluores-
cence in situ hybridization (FISH), and the gene fusion is discov-
ered with polymerase chain reaction (PCR).27
5.3.7 Staging
Several staging systems have been devised for DFSP, but none
accurately predict outcomes.27 The American Musculoskeletal
Tumor Society system uses histologic grade, local extension,
and metastases. The American Joint Committee on Cancer
includes tumor size and depth, lymph node involvement, and
distant metastasis. The Short German Guidelines are also avail-
able.28 Ninety-nine percent of cases present with local or
regional involvement only.29
5.3.8 Surgical Treatment
Treatment consists of complete excision of tumor. This can be
di cult due to projections coursing microscopically much fur-
ther than are visible clinically, sometimes over 10 cm.37 Recur-
rence rates after wide local excision are reported to be as high
as 60%.28 With careful analysis of margins, recurrence rates
after wide local excision can be as low as 1%, but may require
multiple excisions and delayed wound closure.38 The NCCN rec-
ommends margins of 2 to 4 cm when performing wide local
excision, taking specimens down to investing fascia.34
Due to the di culty in obtaining clear margins, Mohs micro-
graphic surgery (MMS) has become the standard of care for
DFSP, particularly in the head and neck. Recurrence rates after
Mohs controlled excision are reported at about 0 to 1%.39,40
Mohs defects are on average four times larger than the clinical
lesion.40 Treating all patients with conventional wide excision
results in excessive resection in 80% of patients and inadequate
resection in 5%, supporting MMS as the treatment of choice.31
While MMS is e ective, it takes longer, requires a dermato-
logic surgeon who is familiar with DFSP frozen sections, and is
expensive. Frozen sections can be di cult to interpret for an
inexperienced dermatopathologist, with about 90% accuracy
when compared to permanent pathology.38 Many surgeons
send the final stage as a permanent specimen for confirmation
of negative margins (modified Mohs), especially in recurrent
cases.
Reconstruction with tissue rearrangement should be delayed
until negative margins are confirmed34 ( Fig. 5.8a-h).
5.3.9 Radiation Therapy
DFSP is radiosensitive; however, due to the reasonably low
recurrence rates with adequate resection, radiation therapy
should be reserved for unresectable, recurrent, or metastatic
cases.34 Patients with microscopically positive margins have a
33% recurrence rate.41 Treating all of these patients can poten-
tially confer more risk than benefit, as the majority do not go
on to develop local or distant metastases.
Fig. 5.7 Positive CD34 stain, typically found in dermatofibrosarcoma
protuberans.
Treatment of Rare Skin Malignancies
101

5.3.10 Chemotherapy
Patients w ith the COL1A1-PDGFB fusion gene m ay benefit
from imatinib m esylate, a tyrosine kinase inhibitor. Up to
two-thirds of patients will have tum or regression. Neoadju-
vant therapy m ay make reconstruction simpler, but can
change the appearance on histology by decreasing cellular-
ity.27 While this drug is well tolerated by m ost, patients
should be screened for the fusion gene prior to treatment to
prevent side e ects in patients who will not have a
response.42 The NCCN recomm ends im atinib in unresectable,
recurrent, or m etastatic cases.34
Traditional chemotherapy is only recommended in patients
with metastatic disease.34
5.3.11 Prognosis
Although DFSP is known for high recurrence rates, distant
spread is rare, with only about 1% of patients developing distant
metastasis. Metastases usually follow local recurrences, often in
Fig. 5.8 (a) A 38-year-old
female with a 2-year history
of a painless enlarging
nodule on her scalp. She
sought the attention of
several physicians who
treated her for eczema. A
biopsy revealed a derma-
tofibrosarcoma protuber-
ans. (b) Because of the
slow-growing nature of the
lesions, two tissue expand-
ers were placed prior to
definitive excision and ex-
panded over 3 months.
Shown is the patient posi-
tioned prone on the oper-
ating table with the
expanders fully inflated. (c)
Marking of the palpable
lesion and first stage of the
excision with Mohs con-
trolled margins. (d) Final
excision after two stages of
Mohs processing. The pa-
tient remained asleep in
the operating room during
the Mohs processing. (e)
Additional rim of tissue
with deep main is removed
after completion of the
Mohs processing and sent
for permanent section
evaluation. (f) Tissue ex-
panders are removed and
the flaps are rotated to
close the defect. Results
1 week after surgery.
(g) One year after surgery,
the scar is well hidden.
(h) Minimal incisional
alopecia is present.
Treatment of Rare Skin Malignancies
102

DFSP-FS.35 Patients have an overall 5-year survival of 99%, and a
disease-specific 5-year survival of over 99%.29 Recurrent disease
is associated with decreased disease-free survival.41
Patients with DFSP are at increased risk for a second DFSP le-
sion, as well as for subsequent primary malignancies of other
types. These are most often skin cancers, but also include breast
cancer.43
Patients should be seen for follow-up every 6 to 12 months.
Twenty percent of recurrences occur over 3 years after resec-
tion of the primary lesion.27 Because of the possibility for late
recurrence, as well as the increased risk of other cancers, fol-
low-up should continue indefinitely.
5.3.12 Summary
DFSP is a locally aggressive skin cancer that a ects men and
women in their 30s to 50s, with an increased prevalence in
African Americans. It often presents in a delayed fashion due to
its slow growth and indistinct form, and is diagnosed with a
biopsy using H&E and immunohistochemistry. Treatment con-
sists of complete excision, either by wide local excision or with
MMS. Imatinib may be useful in some patients with a specific
gene fusion. Overall survival is excellent, and distant metastasis
is rare.
5.4 Cutaneous Angiosarcoma
5.4.1 Background
Cutaneous angiosarcoma is a rare mesenchymal malignancy of
vascular origin. It is one of the most aggressive skin cancers,
with high rates of local recurrence and distant metastases, as
well as high mortality rate.
5.4.2 Epidemiology
Cutaneous sarcomas account for 5% of skin malignancies, and
angiosarcomas account for less than 2% of all soft tissue sarco-
mas.44,45 More than half of angiosarcomas occur in the skin and
superficial subcutaneous tissues,46 with an overall incidence of
0.01/100,000 per year.47 Cutaneous angiosarcoma occurs in
three settings: spontaneously, following radiation therapy, and
in the setting of chronic lymphedema (known as Stewart–
Treves syndrome). The spontaneous category includes malig-
nant degeneration of a vascular malformation.48 Other possible
contributing factors are excessive UV light,49 immunosuppres-
sion,45 and polyvinyl chloride, arsenic, or thorium dioxide
exposure.50 Spontaneous cases a ect men more often; however,
many of the cases related to radiation and lymphedema occur
in women after breast cancer treatment. Cutaneous angiosar-
coma usually occurs in Caucasian patients over 50 years old,
peaking in the seventh or eighth decade of life. It has also been
reported in children as young as 6 weeks, accounting for 0.3% of
pediatric sarcomas.51
5.4.3 Diagnosis
Cutaneous angiosarcoma often looks like a bruise initially,
which seems to enlarge over time. It may become nodular,
painful, edematous, friable, or ulcerate.46 Patients often have
symptoms for several months prior to diagnosis.46 At the time
of diagnosis, the size of the lesion can range from less than 1 cm
to over 10 cm.45,48 The di erential diagnosis includes pyogenic
granuloma, Kaposi’s sarcoma, lymphoma, malignant melanoma,
recurrent breast cancer, or radiation-related morphea.48,52
Lesions occur most commonly on the scalp and face, followed
by the trunk, lower extremity, and upper extremity.45 The
high propensity for the scalp is thought to be influenced by
increased UV exposure to this area combined with a relatively
increased vascularity.48 Lesions on the breast are most com-
monly associated with prior radiation for treatment of breast
cancer, and lesions on the arm are often in the setting of Stew-
art–Treves syndrome.
Diagnosis is made by excisional or incisional biopsy. Histol-
ogy shows vascular channels lined by endothelial cells, often
dissecting collagen in the dermis and extending into the subcu-
taneous tissue46,52 ( Fig. 5.9). Blood-filled channels or clefts are
sometimes present with hemorrhage and necrosis.52 Lesions
range from well to poorly di erentiated. On histology, the
lesion may be di cult to distinguish from other vascular and
epithelial tumors including spindle cell carcinoma, malignant
melanoma, and AFX; therefore, immunohistochemistry, and in
particular vascular markers, should be used.53 Cutaneous angio-
sarcoma often stains positive for CD31 and Ets family transcrip-
tion factor (ERG).54
Less sensitive stains include vascular
endothelial growth factor receptor 3 (VEGFR-3), factor VIII, and
D2–D40 monoclonal antibody.47,54 Angiosarcomas are usually
negative for cytokeratin, S100, and desmin. Cutaneous angio-
sarcoma subtypes including the epithelioid subtype are diag-
nosed by histology and immunohistochemistry.
5.4.4 Workup
A careful history and physical exam should be performed,
searching for multifocal or satellite disease, which is present in
over one-third of patients, as well as locoregional and distant
metastases. Metastasis eventually occurs in over 50% of
patients, with metastasis most commonly to the lungs, as well
as bone, liver, spleen, and less commonly to lymph nodes.48
MRI may be used as an adjunct, but it shows greater local
Fig. 5.9 Vascular channels are prominent in cutaneous angiosarcoma.
Treatment of Rare Skin Malignancies
103

involvement than seen grossly.46 MRI, CT, or PET-CT can detect
local or distant metastases.
5.4.5 Radiation-Associated Cutaneous
Angiosarcoma and Stewart–Treves
Syndrome
Twenty-six percent of patients with cutaneous angiosarcoma
have a prior primary cancer, with about 50% of these patients
having a history of breast cancer.45 In most of these instances,
the lesion is ipsilateral to the previous breast cancer.45 Stewart
and Treves reported cutaneous angiosarcoma in six women
with lymphedema after breast cancer treatment in 1948. The
first report of cutaneous angiosarcoma attributed to radiation
therapy was in the 1980s.55 The lag between initial breast can-
cer treatment and development of angiosarcoma in these
patients is often 5 to 15 years.44
Radiation-associated angiosarcoma presents as late edem a
or thickening of the radiated mastectomy skin flap with vio-
laceous or erythem atous m acules or nodules.52 In contrast,
patients with Stewart–Treves syndrome have a history of
lymphedema, m ost comm only from m astectomy with axil-
lary lymph node dissection, and these angiosarcomas occur
in the ipsilateral shoulder or upper extremity, not in the
previously irradiated tissue. They present with variable
changes in the lymphedem atous skin, w ith a nodule or non-
healing eschar.56 Stewart–Treves syndrome has also been
described in patients with lower extrem ity lymphedema and
congenital lymphedem a. It is speculated to occur due to a
relative im m unodeficiency locally from lymphatic disrup-
tion.44,56 Stewart–Treves syndrome occurs in less than 0.5%
of patients who have a radical m astectomy, and its incidence
is decreasing due to the relatively conservative surgical
treatments for breast cancer favored today.56
5.4.6 Staging
There is no accepted staging system for cutaneous angiosar-
coma. Histologic grade is not very predictive of prognosis.
5.4.7 Treatment
Surgical treatment is associated with improved survival and
consists of wide local excision, with at least 1-cm margins
(Fig. 5.10). Patients with radiation-associated angiosarcoma
of the breast should have a mastectomy.52 MMS is an option;
however, current data do not show improved outcomes com-
pared to conventional surgery.50
Adjuvant radiation is also recommended. It should be deliv-
ered to the primary site and regional nodal basins. When the
primary lesion is located on the scalp, it should target the entire
scalp.46
Chemotherapy has not been shown to improve outcomes,
and should be reserved for palliative or unresectable cases.
5.4.8 Prognosis
After proper treatment, patients have about 40% 3-year and
30% 5-year recurrence-free survival.44 The overall survival is
51% at 5 years and 43% at 10 years.45 Recurrence occurs
after a median of 1 year.44 Patients with distant m etastases
have less than a 10% chance of surviving 5 years.45 Those
who die of the disease have a m edian survival of less than
2 years.44 Pediatric patients have sim ilarly dismal survival
rates.51
Tumor size less than 5 cm, single focus disease, age less than
50, and negative surgical margins are associated with improved
survival.44,45,46,47 Tumors on the scalp and neck have a worse
prognosis.45
5.4.9 Summary
Cutaneous angiosarcoma is a very rare skin cancer, a ecting
elderly males, most often on the scalp. It also occurs in previ-
ously radiated sites, as well as in the setting of chronic lymphe-
dema. It is one of the most aggressive skin cancers, with very
poor recurrence-free and overall survival rates. Recommended
treatment includes wide local excision and radiotherapy.
5.5 Cutaneous Leiomyosarcoma
5.5.1 Background
Leiomyosarcoma is a rare malignant mesenchymal tumor that
arises from the arrector pili in the superficial subtype, and from
the smooth muscle of blood vessels in the deep subtype.57
5.5.2 Epidemiology
Patients present at an average age of 50 to 70 years.58 The dis-
ease has a male predilection.58 Some patients have a history of
prior radiation therapy in the same location.59
5.5.3 Diagnosis
The lesion is typically an erythematous, brown, or skin-toned
nodule. Pain, ulceration, and bleeding are present in some.58
The superficial subtype has a predilection for the head and
neck, while the deep subtype is more commonly found on the
lower extremities.59
The di erential diagnosis is broad, and the lesion is com-
monly clinically misdiagnosed as a dermatofibroma.57 On his-
tology, fascicles of spindle-shaped cells within an eosinophilic
cytoplasm are seen. Cigar-shaped nuclei are present, as are
mitotic figures.60 Immunohistochemistry shows near 100%
expression of smooth muscle actin, and high expression of des-
min and caldesmon.59
Three-quarters of these neoplasms are confined to the der-
mis (superficial subtype), and one-quarter extend into the
superficial subcutaneous fat (deep subtype).57
5.5.4 Treatment
Most surgeons perform wide local excision with lateral margins
of at least 2 cm 61 with the fascia as the deep margin. Success
has been reported with MMS.62 Radiation therapy is used as an
adjunct in high-risk tumors, but with little evidence to support
its e cacy.
Treatment of Rare Skin Malignancies
104

Fig. 5.10 (a) An 80-year-old male with a 1-year history of lesion on his nasal dorsum. Biopsy showed a cutaneous angiosarcoma. (b) Inner dotted line
delineates palpable margins of the lesion, outer line shows planned 2-cm margin of excision. (c) Defect after resection. (d) Surgical specimen. (e)
Bilateral facial flaps are used to cover the cheek defects. (f) Left paramedical forehead flap reconstruction of nasal defect. (g) Lateral view at
completion of surgery. (h) Two weeks postoperative. Final pathology report showed a positive deep margin in the center of the specimen. The
forehead flap donor site is allowed to heal by secondary intension. (i) The forehead flap was divided at 3 weeks and radical thinned with skeletonization
of the nasal dorsum. Permanent sections showed no residual tumor. Photo is 2 weeks postdivision.
Treatment of Rare Skin Malignancies
105

5.5.5 Prognosis
Reported recurrence rates after wide local excision range from
6 to 70%. Recurrence is much more common in the deep sub-
type, and inadequate margins are correlated with recurrence.57
Most recurrences are found within 1 year of initial treatment.
Distant metastases are exceedingly rare, and survival rates are
above 90%.63
5.5.6 Summary
Primary cutaneous leiomyosarcoma is a rare cutaneous malig-
nancy with variable presentation. Diagnosis is made by histol-
ogy, and treatment consists of wide local excision. Local
recurrence rates are low in purely dermal tumors, but moderate
in those that extend into the subcutis. Distant metastases are
rare and overall prognosis is favorable.
5.6 Cutaneous Adenoid Cystic
Carcinoma
5.6.1 Background
Adenoid cystic carcinoma is most often a tumor of the salivary
glands, but can also present primarily in other locations includ-
ing the skin. Primary cutaneous adenoid cystic carcinoma is a
rare, indolent adnexal neoplasm, first described by Boggio in
1975.64
5.6.2 Epidemiology
Patients are diagnosed at a median age of 63 years. Most cases
occur in Caucasians, a ecting men and women equally.65
5.6.3 Diagnosis
Cutaneous adenoid cystic carcinoma lacks characteristic fea-
tures. It typically presents as a slow-growing, flesh-colored
nodule, and most often occurs on the scalp. Other common
locations include the ear, face, and eyelid.65 Lesions may be
asymptomatic, but can cause local alopecia or pain.64
Diagnosis is made by histology, which shows basaloid cells
with an “adenoid or cribiform [sic] pattern occupying the mid
to reticular dermis.”64 Glandlike spaces or pseudocysts have
secretions that frequently stain positive for Alcian blue, a
marker for sialomucin.66 Perineural invasion is common and is
associated with higher recurrence rates.64 Immunohistochemis-
try is positive for epithelial membrane antigen (EMA), and often
S100 and cytokeratin as well.64 The histological di erential
diagnosis includes adenoid cystic carcinoma that is metastatic
to the skin, cylindroma, adenoid basal cell carcinoma, and muci-
nous apocrine carcinoma.64
5.6.4 Treatment
Treatment is surgical and consists of wide local excision with
negative margins. There are reports of successful treatment
with MMS.67
5.6.5 Prognosis
Seventy percent of patients have localized disease at the time of
presentation, and only 5% have distant metastases.65 The 5-year
overall survival is 96%, and is better in patients with lesions on
the head and neck than those with lesions on the trunk.65
Local recurrence is common, with rates from 20 to 40%.64 As
recurrence can occur many years after excision, long-term fol-
low-up is necessary.64
5.6.6 Summary
Cutaneous adenoid cystic carcinoma is a slow-growing adnexal
tumor. Diagnosis is made by histology, and treatment consists
of wide local excision. Recurrence rates are relatively high;
however, distant metastases are rare and overall survival is
excellent.
5.7 Sebaceous Carcinoma
5.7.1 Background
Sebaceous carcinoma is a rare adnexal tumor with occasionally
aggressive behavior, also known as sebaceous gland carcinoma,
sebaceous cell carcinoma, and meibomian gland carcinoma.68
5.7.2 Epidemiology
Sebaceous carcinoma accounts for less than 1% of skin cancers
in the United States.68 In the United States, it predominantly
a ects Caucasians with a slight predilection for men. Patients
are diagnosed at an average age of 72 years.69 There may be a
higher incidence in Asian patients worldwide.68
Sebaceous carcinoma is associated with Muir–Torre syndro-
me, which is a hereditary disorder that leads to the develop-
ment of cutaneous tumors and visceral tumors. Other risk
factors include a history of radiation, immunosuppression, and
familial retinoblastoma.68
5.7.3 Diagnosis
Sebaceous carcinoma usually presents as a painless nodule.68 It
occurs most often on the eyelid where there is a high density of
sebaceous glands. Other common locations include the face,
scalp or neck, ear, and lip.69
The clinical di erential diagnosis includes chalazion, kerato-
conjunctivitis, blepharoconjunctivitis, basal cell carcinoma, and
squamous cell carcinoma.68 A biopsy should be obtained, par-
ticularly if the lesion becomes symptomatic.
Histology shows unencapsulated, lobular neoplasms com-
posed of sebaceous and undi erentiated cells. Vacuolated cells
are present in the epidermis and dermis with lipid granules in
the cytoplasm, giving a frothy appearance68 (Fig. 5.11). Paget-
oid spread is common.68 Adipophilin expression is common on
immunohistochemistry.
Histologic di erential diagnosis includes sebaceous ade-
noma, sebaceom a, and basal cell carcinoma with sebaceous
di erentiation.68
Treatment of Rare Skin Malignancies
106

Patients with sebaceous carcinoma should be screened for
Muir–Torre syndrome for increased suspicion and early detec-
tion of visceral malignancies.
Imaging may be considered in patients with palpable lym-
phadenopathy or lesions with aggressive histological features.68
5.7.4 Staging
The American Joint Committee on Cancer TNM Staging System
is used for sebaceous carcinoma.
5.7.5 Treatment
Treatment consists of wide local excision with at least 5-mm
margins70; however, local recurrence occurs in up to a quarter
of patients. MMS is also an option,70 with similar disease-spe-
cific survival rates.69 At this time, SLNB is not required, but
should be considered in periorbital cases, given that these have
a greater tendency to metastasize.68 Patients with positive
nodes often undergo completion lymphadenectomy.68
Radiation therapy is reserved for patients unable to undergo
surgical excision and for patients with recurrence or metastasis.
5.7.6 Prognosis
Lymph node metastasis occurs in up to a quarter of patients
with sebaceous carcinoma.68 Distant metastases are diagnosed
in about 1%.69 On histology, pagetoid spread, multicentric
tumors, tumors over 10 mm, and tumors with perivascular,
perineural, or perilymphatic invasion have worse prognosis.68
Overall disease-specific mortality is about 5%.68
5.7.7 Summary
Sebaceous carcinoma is a rare adnexal tumor associated with
Muir–Torre syndrome. It occurs most commonly in elderly Cau-
casians, with a predilection for the head and neck, particularly
the eyelid. Diagnosis is made by histology, and treatment is
excision. Local recurrence rates are relatively high, and regional
metastases are not uncommon; however, overall survival is
very good.
5.8 Microcystic Adnexal
Carcinoma
5.8.1 Background
Microcystic adnexal carcinoma is a rare adnexal tumor with
both follicular and sweat gland di erentiation, first described
by Goldstein et al in 1982.71 Other names used to describe this
tumor include sclerosing sweat duct carcinoma, malignant
syringoma, and syringomatous carcinoma. It is believed to
begin as a pluripotent adnexal keratinocyte.72 It is slow growing
but locally aggressive, and typically does not metastasize.
5.8.2 Epidemiology
Microcystic adnexal carcinoma has an incidence of 1.6 to 6.5
per 10,000,000. It disproportionately a ects Caucasians.72 The
tumor has a slight predilection for females. The diagnosis is typ-
ically made in older patients, with an average age of 62 years72;
however, the disease has been described in all ages; a congeni-
tal case has even been reported.73 Significant sun exposure may
be a risk factor, given that Americans tend to be a ected on the
left side of the face more often than the right.72,74 This is
believed to be due to increased sun exposure on the left side of
the face when driving. A history of radiation also seems to be a
risk factor for developing microcystic adnexal carcinoma.75
5.8.3 Diagnosis
Microcystic adnexal carcinoma presents as a slow-growing sub-
cutaneous, yellow to flesh-colored nodule or plaque. Tumors
can occur anywhere on the body, but most often on the face,
specifically the central region of the face including the lips and
nose.72,75 Patients may experience pain or paresthesias.71 The
clinical di erential diagnosis includes squamous cell carcinoma,
cyst, and morpheaform basal cell carcinoma.71
Fig. 5.11 (a) Sebaceous carcinoma, with vacuolated cells in the epidermis and dermis. (b) Sebaceous cell differentiation.
Treatment of Rare Skin Malignancies
107

Diagnosis is m ade by incisional or excisional biopsy. Ad-
equate biopsy depth is critical; superficial biopsies result in
a m isdiagnosis rate of up to 27%.74 Because of its lack of
characteristic features both clinically and by histology when
an inadequate superficial biopsy is obtained, the diagnosis of
m icrocystic adnexal carcinom a is often delayed for years.71
On biopsy, the tum or involves the skin and m ay invade the
subcutaneous fat, m uscle, and bone.72
It involves tissue
beyond w hat is clinically apparent, especially on lateral m ar-
gins.76 Perineural invasion is present in about half of cases.77
Histology shows keratinous cysts superficially w ith strands
of cells penetrating deeper, surrounded by dense fibrous
strom a78 ( Fig. 5.12). Cellular atypia and m itoses are rare.79
The histological di erential diagnosis includes m orpheaform
basal cell carcinom a, trichoadenoma, eccrine carcinom a,
m etastatic breast carcinom a, syringom a, and desmoplastic
trichepithelioma.71,80
Immunohistochemical stains can be used to di erentiate
microcystic adnexal carcinoma from other cutaneous neo-
plasms. Microcystic adnexal carcinoma usually stains positive
for carcinoembryonic antigen, EMA, and cytokeratin.80
5.8.4 Treatment
Treatment consists of complete excision with negative margins.
Because of its indistinct borders and unpredictable lateral
spread, MMS is often utilized, particularly in areas of cosmetic
concern.81 Slow Mohs (using para n sections) or modified
Mohs (frozen sections until negative margins, followed by one
layer sent as a permanent specimen) may increase sensitivity,
especially when operating on a persistent tumor.82
Microcystic adnexal carcinoma is thought to be relatively
radioresistant, but radiation therapy may be considered when
negative margins cannot be obtained.83
Chemotherapy has no role in treatment for microcystic
adnexal carcinoma.
5.8.5 Prognosis
Local recurrence is comm on, w ith up to a 60% recurrence
rate with local excision; this is improved to 12% with
MMS.77 Perineural invasion is associated w ith higher recur-
rence rates.80
Metastases to regional lymph nodes and distant sites are
extremely rare. Morbidity is usually due to local e ects of
the tum or, and m ortality is alm ost always from other causes,
with no di erence in relative survival when comparing
a ected patients to those w ithout microcystic adnexal
carcinom a.72
Lifelong follow-up is a must, as tumors may recur up to 30
years after treatment.79
5.8.6 Summary
Microcystic adnexal carcinoma is an adnexal tumor with follic-
ular and sweat gland components. It typically a ects older Cau-
casian patients with a history of sun exposure. It is often
misdiagnosed, and an adequate biopsy is required for accurate
diagnosis. This tumor is locally aggressive, but usually does not
metastasize.
5.9 Atypical Fibroxanthoma
5.9.1 Background
AFX is a rare spindle cell cutaneous malignancy, first described
in 1961 by Helwig. It has previously been called many names,
including the following: pseudocarcinoma, paradoxical fibro-
sarcoma, pseudosarcomatous dermatofibroma, and superficial
malignant fibrous histiocytoma.84 It has an intermediate malig-
nancy potential, with a low local recurrence rate and very rare
metastases.84
Fig. 5.12 (a) Low-power view of microcystic adnexal carcinoma with keratinous cysts present in the superficial dermis. (b) Higher-power view of
keratinous cysts.
Treatment of Rare Skin Malignancies
108

5.9.2 Epidemiology
Atypical fibroxanthoma most commonly a ects elderly men,
often around the seventh decade of life.85,86 Caucasians are dis-
proportionately a ected, particularly those with excessive
UV light exposure and solar elastosis.85 Prior radiation, trauma,
and immunosuppression also seem to infer increased risk84
(Fig. 5.13).
5.9.3 Diagnosis
The lesion does not have a characteristic appearance. It often
appears as a yellow, tan, or erythematous nodule on the scalp,
ears, face, or neck.86,87,88 Less commonly, it may occur on the
trunk or extremity. It grows rapidly, and 50% ulcerate as they
outgrow their blood supply.89,90 At the time of diagnosis, it is
typically less than 2 cm in diameter87 (Fig. 5.14).
An incisional or excisional biopsy should be obtained. The
diagnosis is one of exclusion. The di erential diagnosis includes
squamous cell carcinoma, basal cell carcinoma, keratoacan-
thoma, melanoma, leiomyosarcoma, DFSP, and pyogenic
granuloma.
Histology shows a well-circumscribed dermal nodule with lim-
ited subcutaneous infiltration. Atypical spindle cells are present
with multinucleated giant cells, pleomorphism, and mitoses85
(Fig. 5.15). Immunohistochemical stains are useful for ruling out
other diagnoses. Atypical fibroxanthoma is often positive for
vimentin and CD68, and it is negative for S100 and CD34.90
5.9.4 Treatment
Treatment consists of complete excision of the tumor, either by
wide local excision with 1- to 2-cm margins, including some of
the subcutaneous tissue, or by MMS.88 Excision is typically
curative when negative margins are achieved. Radiation ther-
apy may be considered for patients who are not candidates for
surgery or for patients with recurrence or metastasis.84,91
Fig. 5.13 A 68-year-old male with a history of renal transplantation
presented with a 4-week history of a rapidly enlarging mass on his
back. Biopsy confirmed the diagnosis of atypical fibroxanthoma.
Fig. 5.14 A 79-year-old male with a 6-month history of asymptomatic,
growing, pink papule on the L zygomatic cheek. Biopsy showed an
atypical fibroxanthoma.
Fig. 5.15 Atypical fibroxanthoma with pleomorphic spindle cells.
Bizarre nuclei and mitotic figures are present.
Treatment of Rare Skin Malignancies
109

5.9.5 Prognosis
Prognosis is favorable, with recurrence rates around 8% and
metastasis in less than 2%. Local recurrences usually occur less
than a year after initial presentation, and more often in patients
with positive margins.86
5.9.6 Malignant Fibrous Histiocytoma
Malignant fibrous histiocytoma, or undi erentiated pleomorphic
sarcoma, is considered to be a deeper and more aggressive variant
of atypical fibroxanthoma.91 It also occurs more commonly in
older men, but is found more often on the extremities, and usu-
ally within the subfascial or subcutaneous tissue layers.92 These
tumors are similar to atypical fibroxanthoma histologically, with
the exception that malignant fibrous histiocytoma extends into
the subcutaneous tissue and may have vascular and perineural
invasion.87 Malignant fibrous histiocytoma has high rates of recur-
rence (30–40%) and distant metastasis (40%).92 Some authors
argue that any case of atypical fibroxanthoma that metastasizes
should be reclassified as malignant fibrous histiocytoma.84,87
5.9.7 Summary
Atypical fibroxanthoma is a cutaneous malignancy that typi-
cally occurs in older men with a history of excessive sun expo-
sure. It is usually cured by a conservative excision with negative
margins, with low local recurrence and rare metastasis. Histo-
logically, it is similar to and may be confused with malignant
fibrous histiocytoma.
5.10 Spitz Nevus, Atypical Spitzoid
Neoplasm, and Spitzoid Melanoma
5.10.1 Background
Sophie Spitz first described the Spitz nevus in 1948, noting it to
be benign and naming it “juvenile melanoma.”93 It was later
found to exist on a continuum with atypical spitzoid neoplasm
(also known as atypical Spitz nevus or atypical Spitz tumor)
and spitzoid melanoma, which are proliferations of spindled or
epithelioid melanocytes.94 While these lesions have similar his-
topathologic characteristics, they clinically range from benign
to malignant and therefore must be distinguished. The termi-
nology can be confusing, and proper histological review must
be performed to distinguish benign from malignant disease.
5.10.2 Epidemiology
Spitz nevi can present at any age, but they occur most com-
monly in children and adolescents. They are most often
described in Caucasians; however, they can occur in any ethnic-
ity. Lesions occur anywhere, but are most often found on the
face and thighs.94
In contrast, spitzoid melanomas are more likely to appear in
adulthood and do not appear to have a predilection for a spe-
cific location.94
5.10.3 Diagnosis
Spitz nevus presents as a solitary erythematous, tan, brown, or
black macule, nodule, papule, or plaque.93 The pigmented
lesions form a subtype known as pigmented spindle cell Spitz
nevi or Reed’s nevi, which is the most common variant.93 Spitz
nevus grows rapidly and then remains stable in size, most often
less than 6 mm in diameter.94 Bleeding or pruritus may occur95
(Fig. 5.16).
Spitzoid melanoma is usually greater than 6 mm at the time
of presentation. It also presents as a papule, nodule, or plaque,
and may have variable pigmentation or be amelanotic.94 Unlike
Spitz nevus, it may change in appearance after a stable phase.95
Atypical spitzoid neoplasms are indistinct neoplasms and
may be mistaken clinically for Spitz nevus or spitzoid
melanoma.
Clinical features are correlated with histopathology. Even
experienced dermatopathologists can have di culty determin-
ing the accurate diagnosis.95 On histology, Spitz nevus is
Fig. 5.16 (a) A 14-year-old male with nonhealing tan nodule on his left ear. Biopsy showed an atypical spitz neoplasm with moderate atypia.
Fluorescence in situ hybridization (FISH) suggested a malignant tumor and Sentinel lymph node biopsy (SLNB) was recommended. (b) The tumor was
excised with a 1-cm margin and SLNB was performed. The ear was reconstructed with a helical advancement (Antia) flap.
Treatment of Rare Skin Malignancies
110

symmetric, well circumscribed, and has uniform nests and cells
that are smaller and deeper in the dermis.94 It is associated with
Kamino bodies, pericellular clefts, and epidermal hyperplasia.94
It may have mitotic figures; however, usually these are few and
superficial.93
The histology of spitzoid melanoma is very similar to Spitz
nevus, but is more asymmetric and has interruption in circum-
scription. It usually lacks Kamino bodies and has more frequent
and deeper atypical mitotic figures.94 Ulceration or necrosis
may be present.95
Atypical spitzoid neoplasm has dense cellularity, cellular
atypia, and mitotic figures.94
Immunohistochemistry shows expression of S100 protein
and Melan-A (MART-1) in Spitz nevi and spitzoid melanomas,
and is therefore of limited help.94 Comparative genomic hybrid-
ization and fluorescence in situ hybridization (FISH) may be
increasingly helpful in the future; although expensive, they can
detect genome alterations present in melanoma94 (Fig. 5.16).
5.10.4 Treatment and Prognosis
Conservative management for children with lesions that are
small and stable and consistent with Spitz nevus is appropri-
ate.93 For all other cases, excisional biopsy is recommended,
taking 5-mm margins if possible.95 This allows for adequate his-
tological examination.
Sentinel lymph node biopsy (SLNB) is controversial in atypi-
cal spitzoid neoplasm and spitzoid melanoma. It is positive in a
quarter of patients with atypical spitzoid neoplasm and in one-
third with spitzoid melanoma. In children and adolescents with
spitzoid melanoma, distant metastases are exceedingly rare. A
positive biopsy, then, does not appear to change prognosis. In
adults, spitzoid melanoma has a similar prognosis as other
malignant melanomas of similar Breslow’s depth,94 and there-
fore SLNB should be performed.95 Completion lymph node dis-
section has not been shown to alter disease-free or overall
survival, but may be o ered to patients with significant disease
burden or atypia found within their sentinel lymph nodes.95
Radiation therapy and chemotherapy do not currently have a
role in the treatment of spitzoid lesions.
5.10.5 Summary
Spitz nevus is a benign cutaneous proliferation of melanocytes
that most often occurs in children and adolescents. It is part of
a spectrum that includes atypical spitzoid neoplasm and spit-
zoid melanoma, which do have malignant potential. These
lesions are di cult to distinguish clinically and histologically,
and should be excised.
5.11 Websites
5.11.1 Patient Resources
●
●
●
●
5.11.2 Physician Resources
●
●
●
●
5.11.3 Acknowledgments
Special thanks to Dr. Jose Plaza for providing histology images.
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Treatment of Rare Skin Malignancies
113

6 Mohs Micrographic Surgery’s Role in the Treatment of
Skin Cancer
Charlene Lam, Christine Poblete-Lopez, and Elizabeth M. Billingsley
6.1 Introduction
Mohs micrographic surgery (MMS) is a specialized skin cancer
excision technique that combines surgery with pathology. It is
most commonly performed under local anesthesia in an outpa-
tient setting and o ers the advantages of higher cure rates for
cutaneous tumors ( Table 6.1) along with maximal tissue
preservation. Conceptualized by general surgeon, Dr. Frederic E.
Mohs, the method is based on the theory that a tumor arises
from a single focus and has contiguous spread. By utilizing fresh
frozen tissue processing and horizontal sectioning techniques,
the Mohs surgeon excises the tumor and examines 100% of the
microscopic tissue margin. The complete surgical margin
examination in MMS provides the highest, evidence-based cure
rate for cutaneous malignancies, while conserving the maxi-
mum amount of normal tissue (tissue-sparing). From a func-
tional, aesthetic, and reconstructive perspective, tissue-sparing
is especially important for skin cancers near the orbit, nose, lips,
ears, anogenital region, and digits (Fig. 6.1a, b). The proven
higher cure rate provided by MMS is especially valuable for
recurrent tumors and those with more aggressive histologic
features and subclinical extension (see list below).
Advantages of Mohs micrographic surgery:
● Tissue sparing.
● Superior cure rates.
● 100% margin examination.
● Continuity of care: surgeon and pathologist.
● Outpatient.
● Local anesthesia.
● Closure after histologic confirmation of clear margins.
● Cost-e ective.
Skin cancer is the most common cancer. Of the nonmelanoma
skin cancers (NMSCs), 95% are basal cell carcinomas (BCCs) and
squamous cell carcinomas (SCCs). MMS has an evidence-based,
5-year cure rate of 99% for BCC9,10 and 94% for cutaneous SCC
(Table 6.1).1,11 MMS is also the preferred treatment method
for skin cancers that are clinically poorly defined, recurrent,
and/or have a higher risk of recurrence because of higher-risk
histologic features, or specific anatomic location ( Fig. 6.2a,b).
The mounting evidence of the benefits of MMS provides
patients with quality, evidence-based care (see list above).
However, MMS is one treatment modality in the large arma-
mentarium of a cutaneous surgical oncologist. It is important to
understand the advantages and disadvantages of multiple tech-
niques including standard excision, MMS, radiotherapy, chemo-
therapy, and oral hedgehog pathway inhibitors. The objective of
this chapter is to familiarize one with the MMS technique, illus-
trate histologic examination of the surgical margins in MMS,
and discuss variations as well as tactics to allow integration in a
multidisciplinary setting.
6.2 Training
Mohs surgery training can be obtained through an Accredita-
tion Council for Graduate Medical Education (ACGME) approved
fellowship,12 which has been renamed “micrographic surgery
and dermatologic oncology” in September 2014. These fellow-
ship-trained Mohs surgeons undergo 1 to 2 years of additional
training after a 4-year dermatology residency. The fellowship
involves gaining proficiency in cutaneous oncology, tumor
resection with orientation on maps, tissue preparation, derma-
topathology and histologic interpretation on frozen sections,
and wound reconstruction. Dermatology residency, as a prereq-
uisite, establishes a substantial clinical, surgical, and pathologic
foundation for fellows to achieve expertise in clinicopathologic
correlation. The dermatologic surgeon must also develop a mas-
tery of frozen section histology interpretation, cutaneous and
soft tissue anatomy, and advanced facial reconstruction.
6.3 Surgical Margins: Tissue
Processing Techniques
Central to surgical treatment of cutaneous neoplasms is the
concept of surgical margins. It is crucial for the surgeon to
be familiar with histologic grossing techniques and their
Table 6.1 Cure rates for skin cancers depending on treatment modalities
Method

Tumor type
BCC1
SCC1
MIS2
5 y (%)

3–5 y (%)
Mohs surgery

99

96.9

92.7–100
Surgical excision 91–95

91.9

80–94
Cryotherapy

92.5

NA

66–93
Electrodessica-
tion and curet-
tage
74–92

96.3

NA
Radiotherapy

89–96.1

90

81–100
Imiquimod3
694
715,a
56–1006,7
5-Fluoruracil3
NA

858,b
NA
Abbreviations: BCC, basal cell carcinoma; MIS, melanoma in situ; SCC,
squamous cell carcinoma.
aInvasive SCC and follow-up period was 28 months.
bSquamous cell carcinoma in situ (SCCIS) with mean follow-up of 4.6 years.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
114

implications. The final histologic reading of a surgical margin is
only as informative as the method in which tumor tissue is
processed and what is actually examined. Developing a false
sense of security regarding negative margins may result in
unexpected tumor recurrence. Strong communication between
the surgeon and the pathologist is critical given there may be
subjectivity and inconsistencies in the histologic interpretation
of surgical margins. A clinical margin is defined as the clinically
apparent edge of the tumor, while a surgical margin refers to
the specific measurement of the tissue surrounding the
Fig. 6.1 (a, b) Examples of tissue sparing poten-
tial of Mohs micrographic surgery while achieving
clear margins.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
115

clinically evident tumor.13 The term “close to the margin” illus-
trates the existing ambiguity. In a survey of pathologists, the
definition of “close” surgical margins varied from tumor
involvement of within a few cells to 0.1 to 5 mm adjacent to the
tumor edge. In these cases of “close” surgical margins, SCCs
were re-excised, while BCCs were not.14 Surgeons need to be
aware of pathologists’ interpretation of margins because it will
a ect the need for subsequent surgical therapy or adjunctive
therapy. Furthermore, regardless of the surgical technique, with-
out clear understanding of how the tissue is processed, the final
reading of clear margins is limited by the processing technique.
A thorough discussion regarding laboratory techniques is dis-
cussed in Chapter 11. The focus here will be on the comparison
between the most commonly used histological grossing
method, vertical (perpendicular/bread loafing), and horizontal
(Mohs) sectioning.
6.3.1 Vertical (Bread Loafing)
Sectioning
The routinely utilized technique to process excision speci-
m ens involves transverse, vertical sections often compared
to slices in a loaf of bread (“bread loafing”). This technique
allows great visualization of both the tum or and the m argins
of each exam ined section. Its lim itation is only a small per-
centage of the true surgical margin is viewed with this
sectioning technique ( Fig. 6.3). The specim en is typically
placed in form alin, divided into 2 to 3 m m in width sections,
placed in num bered cassettes and em bedded in para n (for-
m alin-fixed, para n-em bedded [FFPE]). Within each section,
a sample of tissue is sliced with the knife perpendicular to
the epidermis and cut down to the base. Step sectioning
cuts tissue at specified intervals, which can allow a faster
view of di erent levels but can result in skip areas, w hile
serial sectioning completely processes the specim en w ith
unbroken sequence. With vertical sections, it is estim ated
that approxim ately 1% of the true surgical margin is eval-
uated. In theory, serial vertical sectioning could be done in a
fashion that 100% of the m argin is evaluated. This would be
highly impractical, requiring sectioning and exam ination of
hundreds of slices, and is not normally done in practice.15
For example, 1 cm of tum or would produce 2,000 5-µm sec-
tions. One study demonstrated that vertical sectioning is
about 44% sensitive for distinguishing residual facial BCC at
the surgical m argin excised with a 2-mm m argins.16
It is important to note that many laboratories are willing to
cut more sections at narrower intervals to gain more precise
important diagnostic information on specimens when indi-
cated. Good communication is key and may require discussion
with the dermatopathologist prior to grossing of the specimen.
Of note, the actual grossing of the specimen may not actually be
done by the dermatopathologist but may be done by a techni-
cian or resident.15
Fig. 6.2 Areas of the body divided according to risk. (a) Head and neck divided into H Area (central face, eyelids, eyebrows, nose, chin, ear,
periauricular skin/sulci, and temple) and M Area (cheeks, forehead, scalp, and jawline). (b) Full body divided into H Area (genitalia, hands, feet, nail
units, ankles, and areola), M Area (pretibial surface), and L Area (trunk and extremities). Reprinted with permission from CCF.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
116

6.3.2 Horizontal (Mohs) Sectioning
With the Mohs processing technique, 100% of the deep and
peripheral m argins are evaluated ( Fig. 6.4). Tissue is
excised w ith a surgical bevel of approxim ately 45 degrees.
After the layer is removed and inked, the epiderm al edge is
pressed down to be in the sam e plane as the deep m argin.
The tissue is embedded in mounting m edium (optim um cut-
ting temperature [OCT] compound) and frozen. This frozen
tissue block is sectioned in a horizontal fashion so that the
knife is parallel to the deep m argin of the subcutaneous tis-
sue and the newly pressed epidermis. This bottom -up
approach represents the true deep and peripheral surgical
margin. Therefore, the specim en represents the entire deep
and peripheral m argin in one plane. Som e critics argue that
no tissue processing technique including Mohs consistently
exam ines 100% of the m argin due to incomplete sections,
fragm ented tissue, or orientation problem s.15 However, w ith
Mohs sectioning, at least 95 to 99% of the margin can be
evaluated, which is far more precise than the 1% margin
exam ined in the vertical sectioning.17,18 This complete mar-
gin exam ination is the basis for the maxim al normal tissue
preservation and higher cure rate for challenging tum ors.
Tumors may have contiguous but asymm etric growth pat-
terns and m argins may be di cult to predict. The surgical
m argin is determ ined by the clinical m argin, and with asym -
m etrical and infiltrative growth patterns, som e tum ors may
extend histologically beyond the clinically evident m argins.
With standard vertical sectioning technique, areas of asym -
m etric infiltrative tumor growth m ay be missed ( Fig. 6.3).
Another advantage of MMS is the same physician serves as
the pathologist and surgeon. The physician is in control of the
specimen and is directly involved in sectioning and inking, and
may assist in the grossing of the specimen. The Mohs surgeon is
able to appreciate the histology during the procedure, which
can be overlooked with the sampling errors in biopsies. For
example, a biopsy of a tumor may reveal nodular BCC, but with
the Mohs processing, it is common to discover that the tumor is
actually an infiltrative BCC with further histologic extension
than originally predicted. Mohs surgeons can correlate the clin-
ical appearance of the tumor and note any discordance between
the diagnosis of the biopsy sample and the tumor seen under
frozen sections. Certain staging criteria like perineural invasion
can also be appreciated during MMS, and adjunctive treatment
can be recommended.
6.4 Indications and
Contraindications for Mohs
Micrographic Surgery
Currently, approximately 25% of skin cancers are treated with
MMS.19 MMS is ideally suited for skin cancers at high risk of
recurrence, those located in regions requiring tissue conserva-
tion, and/or when complete margin control is necessary. Many
NMSCs have aggressive local growth patterns and can invade
vital structures such as the eye, nose, lips, and ears, leading to
significant destruction and impairment. With time and neglect,
metastasis may develop in more aggressive tumors. Fortunately,
Fig. 6.3 Surgical elliptical excision of tumor and pathologic examination of tissue margins with vertical sectioning (“bread loafing”). Serial transverse
cross-sectioning is utilized to section the specimen at specified intervals and embedded in paraffin. The cross-sections are cut and stained. This
method can miss tumor at the surgical margin. The horizontal parallel lines indicate where transverse sections would be cut. There is tumor at the
incision line that is not transected by the cross-section cuts; therefore, the tumor would be histologically missed. Reprinted with permission from CCF.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
117

many of the NMSC are low risk and can be treated with super-
ficial ablative techniques (e.g., electrodesiccation and curettage)
with comparable cure rates and cost-e ectiveness (see Section
6.4.3 Cost-E ective Care). Cutaneous tumors that can be treated
with MMS are listed in Table 6.2. The indications for MMS are
not absolute, and any treatment decision needs to be made in
collaboration with the patient’s preferences, performance sta-
tus, and understanding of other available treatment options
and cure rates ( Table 6.1).
The definition of “high-risk” skin cancer is dependent on
multiple factors: clinical and histologic characteristics of the
tumor, the anatomic site, and history of prior treatments (see
text box). MMS has the ability to track unpredictable superficial
or deep projections of tumor with the meticulous and complete
histologic examination of the surgical margins. Additionally,
tumors that involve embryonic fusion planes, periorbital,
nerves, and bone can be followed with MMS. In these situa-
tions, the adeptness of this technique is most evident as deep
and irregular tumor extensions are responsible for the higher
recurrence rates with other techniques. With recurrent tumors,
it is especially di cult to achieve clear margins with recom-
mended margins, given that the subclinical extension is often
prominent and clinically it is di cult to delineate the tumor
from scar. MMS has a superior cute rate for recurrent tumors
(Table 6.2). The dilemma to clear the tumor with larger surgi-
cal margin resulting in a larger surgical defect and possible less
aesthetic outcome and reduced functionality versus a more
conservative margin with the possibility of positive margins
and another surgery is a constant challenge for those treating
facial tumors.37
Fig. 6.4 Mohs layer excision with narrow margin and subsequent
flattening of skin edges. The tissue is horizontally sectioned so the skin
edge (epidermis) is in the same plane as the deep margin, thus
ensuring complete lateral and deep margin assessment. As 100% of
the margin is examined, there is no concern that tumor may be missed
with serial sectioning. Reprinted with permission from CCF.
Table 6.2 Cutaneous tumors treated with Mohs surgery and reported
cure rates
Cutaneous tumors treated with Mohs surgery and reported cure rates
Cutaneous tumors

Cure rates
5 y

10 y
Basal cell carcinoma
● Primary
● Recurrent
● 99%9
● 93%10
● 95.6%20
● 96.1%20
Squamous cell
carcinoma
● Primary
● Recurrent
● Erythroplasia of Queyrat
● Keratoacanthoma
● 92–99%11
● 90%1
● 90%21
● 97.5%22 (2 y)
Melanoma in situ,
including lentigo
maligna
92.7–100%23,24,25
Atypical
fibroxanthoma
93–100%26
Dermatofibrosarcoma
protuberans
98–100%27,28,29
Merkel cell carcinoma

84%30
Microcystic adnexal
carcinoma
90%31,32,33
Sebaceous carcinoma

89%34
Extramammary Paget’s
disease (EMPD)
92%35
Leiomyosarcoma
(superficial)
87%36
Malignant fibrous
histiocytoma
–
Angiosarcoma

–
Melanoma

–
Apocrine carcinoma

–
Lymphoepithelioma-like
carcinoma
–
Eccrine porocarcinoma

–
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
118

Indications for Mohs Surgery for Basal Cell
Carcinoma and Squamous Cell Carcinoma38
Tumor Characteristics
● High-risk* anatomic location (Area H): “Mask areas” of face
(central face, eyelids, eyebrows, nose, lips, chin, ear, and peri-
auricular skin/sulci, temple), genitalia (perineal and perianal),
hands, feet, nail units, ankles, and nipples/areola
(Fig. 6.2a, b).
● Large size: Area L≥20 mm, Area M≥10 mm, Area H≥6 mm
(Fig. 6.2a, b).
● Aggressive histologic subtype:
○ BCC: morpheaform (sclerosing), micronodular, or infiltrating.
○ SCC: poorly or undi erentiated, spindle cell, acantholytic,
sclerosing, metatypical, small cell, clear cell, desmoplastic,
KA type (central face), lymphoepithelioma-like, and
sarcomatoid.
● Recurrent.
● Positive margin on excision.
● Poorly defined clinical border.
● Perineural/vascular* invasion.
● Breslow depth ≥2 mm.*
● Rapid growth.*
● Neurologic symptoms.*
Patient Characteristics
● Prior exposure to ionizing radiation.*
● Chronic inflammatory process (scar).*
● Immunocompromised: human immunodeficiency virus
(HIV), organ transplant, hematologic malignancy, or pharma-
cologic immunosuppression.
● Predisposing genetic syndromes: xeroderma pigmentosa,
basal cell nevus syndrome.
● Patient known to have high-risk tumors without other health
risk factors.
*Squamous cell carcinoma (SCC) specific.
According to the National Comprehensive Cancer Network
(NCCN), a multidisciplinary expert panel, MMS is the preferred
surgical technique for high-risk BCCs and SCCs as it provides
superior intraoperative surgical margin analysis.39 This signifies
the importance of complete tissue margin analysis for high-risk
tumors. If MMS is not available, a viable alternative would be
excision with recommended margins and complete circumfer-
ential peripheral and deep-margin (CPDM) assessment using
intraoperative frozen sections. A meta-analysis of MMS demon-
strated a 5-year disease-free survival rate of 99% for BCC and
97% for SCC.1,9 A prospective, randomized controlled trial with
10-year follow-up revealed significantly lower recurrence rates
for recurrent and primary facial BCC treated with MMS com-
pared to standard excision.20
In addition to BCCs and SCCs, MMS has been utilized e ec-
tively for recurrent benign tumors that tend to recur, such
as desmoplastic trichoepithelioma, infantile digital fibroma,
and granular cell tumor, as well as other rare cutaneous malig-
nancies26,27,28,29,30,31,32,33,34,35,36 (Table 6.2). In these cases, the
complete margin examination MMS provides enhanced tumor
clearance.
6.4.1 Melanoma Including Lentigo
Maligna
The role of MMS with only frozen sections for the treatment of
cutaneous melanoma is controversial because the margin taken
is often narrower than published guidelines as well as the chal-
lenge in detecting atypical melanocytes in frozen sections
(freeze artifact).40 The use of special immunohistochemical
(IHC) stains, such as human melanoma black 45 (HMB-45),
Mel-5, Melan-A (MART-1), and S100, can increase histologic
sensitivity during MMS for melanocytic lesions ( Table 6.3).41
Many dermatologic surgeons still advocate for the examination
of FFPE tissue margins to confirm that the final MMS margin is
negative.42 Some Mohs surgeons with extensive experience
with management of melanoma with MMS suggest that out-
comes are equivalent to standard margins.43,44 MMS for mela-
noma may be advantageous in certain clinical scenarios such as
locally recurrent melanoma, large diameter tumors, ill-defined
or amelanotic melanoma, and melanoma near critical anatomic
structures such as the genitals, digits, eyelids, nose, and ears.
The lentigo maligna subtype of melanoma in situ is consid-
ered an exception and MMS as a treatment is becoming increas-
ingly accepted. Lentigo maligna (melanoma in situ) is often a
clinically ill-defined tumor typically found on the head and
neck with a high local recurrence rate with standard wide local
excision, due to the unpredictable histologic tumor extension
beyond the clinically predicted margins. Several studies have
found the recommended 5-mm margin for melanoma in situ
inadequate for complete removal of lentigo maligna.40,45 Given
these challenges, conventional MMS is one possibility for treat-
ment of lentigo maligna because it o ers the possibility of com-
plete margin examination and higher cure rate along with
tissue sparing in critical areas. A challenge is that frozen tissue
processing may result in morphologic artifacts where keratino-
cytes can resemble melanocytes and the true margin can be dif-
ficult to interpret. Rapid IHC stains41 are helpful, but it still may
be challenging to reliably detect single cell change and nests
without significant training and experience. One review
demonstrated that nearly 25% of lesions initially diagnosed as
melanoma in situ were found to have a dermal component
upon re-excision.23 Therefore it is recommended that the
debulked clinical tumor be sent for permanent sections to eval-
uate for dermal invasion.
Due to these challenges, there are several modifications to
MMS for treatment of lentigo maligna and melanoma. Some
techniques include wide excision Mohs surgery, “slow” Mohs
staged excision using FFPE sections, and geometric staged exci-
sion (GSE; see the “Modifications of Mohs Micrographic
Table 6.3 Commonly used rapid immunohistochemical stains for Mohs
micrographic surgery
Tumor

Immunohistochemical stains
Melanoma

HMB-45, Melan-A (MART-1), S100
Squamous cell carcinoma

Cytokeratin (AE1/AE3)
Extramammary Paget’s disease

Cytokeratin 7
Dermatofibrosarcoma protuberans CD34
Abbreviation: HMB-45, human melanoma black 45.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
119

Surgery” section),41,42,45 which aim to achieve complete margin
control with FFPE pathology.46,47
6.4.2 Appropriate Use Criteria
In 2012, evidence-based appropriate use criteria for Mohs
micrographic surgery (Mohs AUC) was developed using the
RAND Corp protocol with direction of the NCCN guidelines.38,48
Two hundred and seventy clinical scenarios based on tumor
location ( Fig. 6.2a, b), size, recurrence history, histology, and
patient health status were presented to an expert panel to be
graded as appropriate, inappropriate, or uncertain based on
available evidence. The goal of the Mohs AUC was to provide
guidance in the rational use of MMS.38,49 The Mohs AUC tables
can be downloaded at the American Academy of Dermatology
World Wide Web site (
ate-use-criteria/mohs-surgery-auc). There is also a smartphone
app (Mohs AUC) that can be downloaded and referenced for
point-of-care decisions (
priate-use-criteria/mohs-auc-app).
6.4.3 Cost-E ective Care
With the escalating cost of health care, it is important to be
mindful of meaningful use of therapies while providing evi-
dence-based quality care to patients. The studies on the cost-
e ectiveness of MMS compared to standard excision with local
anesthesia are variable depending on the study location and
methods.50,51 With the use of the Mohs AUC in addition to the
aforementioned advantages of the procedure, MMS is a cost-
e ective treatment for skin cancer.9,10 When standard excision
with FFPE sections and immediate repair is compared with
MMS, the cost di erential is comparable or slightly less expen-
sive with the former (standard excision with immediate repair).
However, when factoring the physical location of where the
surgery is performed (o ce-based vs. ambulatory center vs.
operating room), type of anesthesia used (local vs. general),
processing method for the specimen (frozen vs. permanent),
type of reconstruction (immediate vs. delayed), the size of the
defect (tissue-sparing vs. wide local excision), the need for
additional surgery for recurrence, and the intangible aspects
(stress associated with waiting for the results of permanent sec-
tions, returning for a second surgery), MMS is an economical
skin cancer treatment.19,50,51,52,53
6.4.4 Contraindications
There are no absolute contraindications to MMS. There are limi-
tations and challenges to the technique such as discontiguous
tumors, certain histologic features, and patient characteristics.
As the basis of MMS is grounded on a contiguous tumor, discon-
tiguous tumors can result in false-negative margins and inad-
equate margin control. However, this is also a concern with
other methods of evaluating surgical margins. If a tumor cannot
reliably be identified histologically, especially on frozen sec-
tions, this can also be a relative contraindication. Patients who
are unwilling or unable to undergo a time-intensive surgery
may do better with a nonsurgical approach such as
radiotherapy or standard excision. Nevertheless, for some
patients with complex medical conditions and comorbidities,
MMS done under local anesthesia may be preferable over sur-
gery performed under general anesthesia.54,55,56 MMS may not
o er a decreased morbidity or mortality in cases of metastases
or tumors deeply invading structures such as the orbit, parotid,
or bone. MMS can assist in peripheral margin clearance in con-
junction with surgical colleagues performing the more exten-
sive deep tumor resection possibly under general anesthesia.
These cases are rare and MMS can be utilized to decrease tumor
burden and prevent possible invasion of vital structures57 or
assess peripheral margins (see below, Case 2).
6.5 Mohs Micrographic Surgery
Technique
During MMS, the Mohs surgeon has complete control of the
excised tissue, including laboratory processing and interpreta-
tion of the tissue sections, as well as precise mapping. MMS
involves four major components: tumor extirpation, histopa-
thologic examination, precise mapping, and wound manage-
ment (Fig. 6.5 and Fig. 6.6). The tumor extirpation
component consists of removing a disc of tissue, often referred
to as “layer” or “stage,” with a beveled surgical margin
(Fig. 6.6c). This ensures that the entire 360 degrees of tumor
margin is circumferentially removed and examined. A beveled
plane of excision allows the tissue specimen sides to be flat-
tened completely into a single plane, allowing complete exami-
nation of the peripheral and deep margin of the excised tissue
(Fig. 6.4 and Fig. 6.6d). The histopathologic component
involves cutting horizontal sections and mounting them onto
glass slides, followed by staining and microscopic examination
for residual tumor ( Fig. 6.6f). Precise mapping involves
marking any residual tumor on the “map” of the excision
(Fig. 6.6g). This three-step process is then repeated until there
is no residual tumor identified microscopically (Fig. 6.5). In
the fourth step, wound management, the tumor-free defect is
surgically closed ( Fig. 6.6k) or allowed to heal by second in-
tention. The specific way each step is achieved may vary
between individual surgeons.
6.5.1 Preoperative Assessment
After a given tumor is deem ed appropriate for MMS, a consulta-
tion including a history and focused skin examination should
be performed, which may be done the same day as the surgery.
Indications for preoperative and postoperative antibiotic pro-
phylaxis should be evaluated.58
The management of any
implanted devices including pacemakers, defibrillators, and
deep brain stimulators should be considered and a ect choice
of hemostatic device. Medication and supplement history is
noted. The use of anticoagulants should be managed accord-
ingly. Typically, patients are asked to continue anticoagulants
especially if used to prevent a life-threatening event as the risk/
benefit ratio favors anticoagulation.59,60 However, in collabora-
tive cases, it is important to discuss with other physicians
involved. Patient should be thoroughly questioned regarding
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
120

allergies including local anesthetics, antibiotics, iodine, latex,
and tape products. A social history regarding smoking, alcohol
use, and home assistance with wound care is necessary. Chronic
alcohol dependence or abuse can result in increased intraope-
rative bleeding, and smoking can result in poor wound healing
due to decreased tissue oxygenation. Gaining an appreciation of
the patient’s understanding of the procedure will be important
to prevent patient dissatisfaction.
Based on the tumor’s characteristics (extremely large, recur-
rent, fixed, deeply invasive tumors) or clinical symptoms (pain,
numbness, facial muscle asymmetry), preoperative radiologic
imaging may be warranted.61 Preoperative consultations with
other subspecialties (e.g., oculoplastics, otolaryngology, neuro-
surgery, plastic surgery) may be considered for complicated
cases.
Photographs of biopsy sites and patient identification of pre-
cise biopsy location are extremely important to prevent wrong-
site surgery.62 All treatment options are discussed including
wide local excision performed by a non-MMS physician. Most
patients prefer to know that their tumor is completely removed
prior to reconstruction.63 Wound management and options for
defect repair should be explained. Typically, patients are asked
to continue regular medications and eat a light meal on the
morning of surgery, unless conscious sedation is planned. Most
patients spend approximately 3 to 4 hours from same-day
consultation to discharge, dependent on size of the tumor,
number of layers required for clearance, and type of closure.
Intraoperative considerations include anxiety, pain (with
local anesthesia injection), bleeding, nerve damage, and allergic
reactions need to be managed appropriately. If warranted, oral
midazolam can be given in the range of 5 to 15 mg for healthy
adults. Knowledge of vascular, muscular, and neural anatomy,
especially in “danger zones” of the face, will help surgeons avoid
complications and improve outcomes. Hemorrhage can be mini-
mized with the addition of epinephrine (adrenaline) in local anes-
thetic, meticulous hemostasis, and pressure bandaging. Injury to
cutaneous sensory nerves occurs during all cutaneous surgery.
Transection of significant motor nerves may be occasionally neces-
sary for invasive tumors, especially in the temporal region. During
consultation, patients should be informed of the possibility of loss
of function if the tumor lies over or in proximity to a motor nerve.
There may also be temporary sensation loss or paresthesias.
6.5.2 Tumor Extirpation
MMS is considered a “clean” rather than “sterile” procedure.
After the patient verifies the site of the biopsied tumor, the clin-
ically apparent tumor margins are marked with a surgical pen
along with skin tension lines or cosmetic subunits ( Fig. 6.1a).
Fig. 6.5 Mohs micrographic surgery flow sheet.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
121

Fig. 6.6 Mohs micrographic surgery technique. (a) Preoperative appearance of a basal cell carcinoma on the nose. (b) Debulking of the tumor via
curettage. (c) Beveled excision (with scalpel at a 45-degree angle) of all clinically evident tumor plus a small margin of normal-appearing skin.
Placement of skin notches at 10 and 4 o’clock positions in adjacent surrounding tissue. (d) Orientation of the excised specimen on an anatomic card.
(e) Specimen sectioned into two pieces and flattened. The superior portions of the specimens are marked as blue and the inferior aspects are marked
as green. Matching Mohs map and tissue specimen ready for histologic preparation. (f) Histopathologic section with positive tumor.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
122

Local anesthetic typically 1 or 0.5% lidocaine with 1:100,000
epinephrine is infiltrated in the area. The lidocaine can also
be bu ered with sodium bicarbonate (10 lidocaine:1 sodium
bicarbonate) to alkalinize the pH and minimize the discomfort
of the injection. The anesthetic is usually allowed to penetrate
for 10 to 15 minutes, enabling anesthesia for the larger nerves
and vasoconstrictive e ects of epinephrine. The identified sur-
gical site is cleansed with surgical scrub (povidone-iodine or
chlorhexidine).
Debulking of the tumor is the initial step. Typically, a curette
is utilized to remove the friable tissue of the tumor and delin-
eate it from the normal tissue (Fig. 6.6b). This helps the sur-
geon estimate the tumor width and depth prior to removing
the initial Mohs specimen (layer/stage). Not all surgeons curette
the tumor as they argue that curettage does not reliably
delineate the tumor.64 Large tumors may be removed with a
scalpel or scissors.
Initial (A) Layer
A scalpel is used to score around the tumor with a 1- to 2-mm
margin of clinically normal skin ( Fig. 6.6c). Margins may vary
depending on the tumor type, tumor location, patient charac-
teristics, and other factors. Small skin incisions (hash marks)
are made on the skin and the tumor for orientation purposes.
The scalpel is then beveled at 45 degrees to cut through the der-
mis and subcutaneous tissue, and the base is transected, main-
taining the same plane in the deep margin. Hemostasis is
achieved if necessary. A temporary pressure bandage is placed
on the wound while the tissue is processed in the Mohs lab. At
(g) Mohs map marked with red at the site of cancer. (h) Re-excision of the area of residual basal cell carcinoma (second “B” layer) and accompanying
Mohs map from the second layer with corresponding tissue. (i) Mohs map for second layer denoting the tumor is clear. (j,k) Postoperative tumor-free
defect and repair.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
123

this point, the bandaged patient can comfortably rest and join
his/her family members or friends in the waiting room.
6.5.3 Mapping
The layer is carefully placed on a blotter that may have a draw-
ing of the patient’s tumor site to maintain orientation
(Fig. 6.6d). The Mohs map is a schematic representation of
tumor and its relation to the patient. This map will detail the
site, size, specimen orientation, number of pieces, and ink
markings on the specimen. The accuracy and precision of the
Mohs map is critical to the Mohs procedure. Specimens are typ-
ically bisected and ink applied to the medial (cut) edges of the
specimens ( Fig. 6.6e). Often one color is applied to the supe-
rior or medial aspect and another color used for the inferior or
lateral aspect of the specimen. The specimens are then num-
bered. The Mohs map is marked to reflect the specimen num-
bers and ink placement. The number of specimens depends on
the size of the resected tissue. Tissue shrinkage is about 20% in
frozen sections.16 Smaller specimens can be processed in toto.
6.5.4 Histologic Examination/
Interpretation
The inked tissue sections are given to the histotechnician who
begins to process the tissue by grossing it or flattening it so that
the epidermis is laid down in the same plane as the dermis and
subcutaneous tissue. With the orientation preserved, the speci-
men is embedded with embedding medium, and attached to a
specimen holder button or chuck.65 Once the embedded speci-
men is frozen, it is mounted on the stage of the cryostat. It is
sectioned in the microtome and placed on the slide. The histo-
technician obtains sections that contain a complete layer
extending from the epidermis to the deepest section of the
resected tissue. Multiple complete sections are normally har-
vested and placed on each slide. The slides are then stained
with hematoxylin and eosin (H&E). Some surgeons utilize tolui-
dine blue66 or other immunostains depending on the tumor
type. The number of slices and slides per specimen vary with
the preference of the surgeon. Cartee and Monheit reported
that on average, Mohs surgeons prefer three to six slices per
specimen with the average thickness of the slices of 5 to 6 µm.67
With the usual 5- to 6-µm thickness of slices, most prefer to
view at least four full successive slices to establish that the sec-
tions are clear from the tumor.68 If residual tumor is present,
then an additional Mohs layer is required.
Understanding tissue orientation and embedding is crucial to
interpretation and localization of any residual tumor in the
layer. When viewing the slide, it is important to remember as
one looks from the top to bottom of the slice (epidermis to der-
mis to subcutaneous tissue), it also moves centripetally from
the margins (epidermis) to the tumor center (subcutaneous tis-
sue). Therefore, if residual tumor appreciated at the epidermis
and dermis, it means that in the subsequent layer, the surgical
margin needs to be laterally extended (Fig. 6.6h). However, if
the tumor is only appreciated in the deep subcutaneous tissue,
then in the subsequent layer, only the base needs to be excised.
A small rim of epidermis may be taken to help orient the subse-
quent layer.
6.5.5 Wound Management
When complete tumor removal has been achieved, reconstruc-
tion or wound management can be planned ( Fig. 6.6jk).
Closure techniques are discussed in Chapter 9. Large defects,
certain anatomic locations, depth of the defect, and detection of
perineural involvement are factors that may require collabora-
tion with other specialties, such as plastic surgery, oculoplastic
surgery, otolaryngology, neurosurgery, and radiation oncology.
Mohs surgeons generally manage the majority of the surgical
defects with second intention healing, primary closure, skin
grafts, and flaps (Fig. 6.7abc). Allowing wounds to heal by
secondary intention or granulate with epithelialization espe-
cially those that are superficial or in concave areas can produce
acceptable if not superior cosmetic results (Fig. 6.8ab). Other
advantages of secondary intention healing include lack of donor
site involvement, less postoperative pain, lower costs, greater
safety, and fewer complications.69 Additionally, many patients
prefer second intention healing and are pleased with the cos-
metic result. Second intention healing can also be used in high-
risk tumors where a complex flap or graft may hinder surveil-
lance of recurrence. Possible disadvantages of secondary inten-
tion healing of large wounds are the following: delayed healing,
longer wound care, and possible distortion of nearby structures
due to contraction. Second intention healing with delayed clo-
sure is also an option for deep wounds. The wound contracts,
shrinking the size of the defect and the base granulates,
improving the survival of grafts and flaps.
Fellowship-trained Mohs surgeons are educated on advanced
facial reconstructive techniques. The confirmed clear surgical
margins prior to wound reconstruction and maximal preserva-
tion of normal skin are significant advantages of MMS. These
advantages are particularly important for the head and neck re-
gion where recurrences and/or positive margins can be devas-
tating and reconstructions especially challenging.
6.5.6 Postoperative Evaluation
Antibiotics may be given postoperatively for wound infection
prophylaxis if indicated.58 Substantial pain following MMS is
uncommon and acetaminophen is often su cient for postope-
rative discomfort, especially for smaller defects and simple
repairs. Oral narcotic analgesics may be necessary for larger
tumors, complex reconstruction, or wounds in anatomic loca-
tions of high tension or sensitivity (e.g., lip, nose, scalp, and
ear).70 A randomized controlled trial comparing acetamino-
phen, acetaminophen and ibuprofen, and acetaminophen with
codeine demonstrated the combination of acetaminophen and
ibuprofen was superior in controlling postoperative pain com-
pared to the other two arms.70
Patients are also recommended to have ongoing surveillance
at least annually for new primary and recurrent skin cancers,
given that 50% of patients with NMSC will experience another
skin cancer during the subsequent 5 years.
Complications
Serious complications and adverse events due to MMS are
rare. MMS is a safe procedure with an undetected mortality
rate.71,72 A large, m ulticenter, prospective cohort study of
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
124

Fig. 6.7 (a–c) Examples of typical closures done by fellowship trained Mohs surgeons.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
125

adverse events in MMS found the rate of adverse events was
less than 1%, with the m ajority of events being m inor.71
Postoperative complications include infection, dehiscence,
partial or full necrosis, bleeding, and hem atom a/serom a
form ation. The infection rate post-MMS is very low (0.7%)
despite being a “clean” procedure and the duration of the
procedure.73
6.6 Modifications of Mohs
Micrographic Surgery
There are several m odifications/variations in the MMS tech-
nique to improve the speed of tissue processing,66 the e -
ciency of tum or rem oval, and the recognition of individual
tum or cells in order to increase cure rates. Surgical modifi-
cations include (1) the single section method; (2) “slow”
Mohs/GSE; (3) nonbeveled 90-degree incisions; and (4) wide
excision. Variations to better recognize tum or cells include
(1) IHC stains for frozen sections ( Table 6.3) and (2) sub-
m ission of tissue specim ens for routine histology (“rush”
FFPE sections) and im m unohistochem istry.
6.6.1 Single Section Method
The single section method can be used for smaller tumors.74
The single section involves a highly beveled specimen with
relaxing incisions on the superior, tumor-bearing portion that
allow all peripheral edges to fold outward into a single plane. It
can be particularly useful for small, superficial tumors where a
shallow Mohs layer can be taken, with the goal of allowing the
resulting wound to heal by second intention. Additionally, the
unaltered examination of the complete deep margin reduces
the possibility of areas missed by tissue subdivision.
6.6.2 “Slow” Mohs and Geometric
Staged Excision for Melanoma
“Slow” Mohs staged excision is a technique where the tissue
specimen is sent for “rush” FFPE sections that are read by a der-
matopathologist the next day.40 This variation of MMS is
typically used for melanomas, but it can also be utilized for
challenging tumors that can be di cult to read under frozen
histology such as dermatofibrosarcoma protuberans (DFSP),
extramammary Paget’s disease (EMPD), and poorly di erenti-
ated SCC. FFPE sections require an average of 7 hours of
Fig. 6.8 Examples of defects left to heal by second intent. (a) Large defect on the ear that healed with second intent. There was some contraction, but
the patient was very satisfied with the results. (b) Example of tissue sparing potential at lip with second intent healing.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
126

processing time.40 If there are residual tumor cells, another
layer is removed until a negative (tumor-free) margin is
achieved. A close working relationship with the dermatopathol-
ogist is essential.40 This technique avoids the keratinocyte
freeze artifact in frozen sections and the margin evaluation is
performed by a dermatopathologist. The persistence rate for
staged excision of melanoma ranges from 0 to 7%.40
GSE is a technique that involves excising the tumor with per-
pendicular skin margins.45 Some surgeons use two closely
spaced, parallel blades to create a square-shaped defect (thin
and frame-like) with the tumor and presumed adequate mar-
gins left intact. If the excised peripheral tissue is found to con-
tain no tumor cells, then the central square is excised. Others
have found it easier to excise the entire specimen in a geometric
pattern, ink the margins, and then cut o strips along the mar-
gins; the latter are then oriented, inked, processed, and cut en
face, while the central portion is cut vertically to determine the
thickness of the tumor. Some dermatopathologists prefer GSE
method because it may be easier to process the tissue to exam-
ine the entire perpendicular epidermal margin.40 A recent ret-
rospective study and review of literature of this technique
found GSE to be optimal for removal of lentigo maligna and len-
tigo maligna melanoma because of its low rate of recurrence
(1.7%) and ability for complete examination of peripheral and
deep margins.45 In order to maintain the straight lengths of tis-
sue, a few millimeters of skin may be sacrificed. In smaller
tumors, this disadvantage is marginal. Cases requiring several
layers may result in an irregularly shaped defect, leading to a
more complex reconstruction.
6.6.3 Wide Excision Mohs Surgery
In wide excision MMS (“wide Mohs”), a larger, clinically tumor-
free margin (5–20 mm) is taken during the first layer. It can be
used for tumors that have a high propensity for recurrence or
metastases (including satellite metastases), in particular mela-
noma, Merkel cell carcinoma, and cutaneous sarcomas,21 and
when tissue sparing is less of a concern.15 In these challenging
cases, tissue sparing is not the primary goal, but the advantage
of precise margin evaluation o ered by MMS is extremely
valuable.
6.6.4 Rapid Immunohistochemical Stains
Rapid IHC stains can be utilized to assist in histologic evaluation
of NMSC, melanocytic neoplasms, DFSP, EMPD, microcystic
adnexal carcinoma (MAC), as well as other rare tumors.76 They
can be especially helpful in these challenging and high-risk
tumors (Table 6.2).41,77,78 Conventional immunoperoxidase
staining technique on FFPE sections requires several hours to
process. In comparison, rapid IHC staining technique done on
frozen tissue in MMS requires approximately 30 to 90 minutes
depending on the protocol and can prevent the loss of antigens
on the tissue.77 However, rapid IHC stains are not without con-
straints. A recent survey of fellowship-trained Mohs surgeons
found many barriers to routine use of IHC in Mohs labs includ-
ing time consumption, lack of experience with IHC, and costs.76
Nonetheless, the introduction of IHC stains has advanced the
field of MMS in recent years and can be extremely helpful in
locating tumor with subtle histologic features or those hidden
in brisk inflammation. With continued use and research, the
use of IHC may be routine for challenging tumors.
6.7 Integrating Mohs
Micrographic Surgery into Your
Practice
Collaboration between a Mohs micrographic surgeon and plas-
tic surgeon can go beyond the traditional approach where the
plastic surgeon repairs the defect after the cutaneous tumor is
cleared.79 By understanding the methods used by Mohs sur-
geons to process the tissue and read the histology, the tech-
nique can be tailored to provide optimal care for the patient.
The following two cases are excellent examples of e ective
multidisciplinary collaboration.
6.7.1 Case 1
A 57-year-old Caucasian female presented as a plastic surgery
consult for a tumor on her nose. It started as a pimple approxi-
mately 8 years ago and has progressively grown in size. She has
been smoking for 45 years. On physical exam, a 4 ×4 cm pink,
translucent, ulcerated tumor on the nasal dorsum extending
through bilateral alar rims down onto columella and over bilat-
eral nasal sidewalls and upper third of nasal dorsum was appre-
ciated. There were no signs of intranasal involvement and the
septum appeared intact (Fig. 6.9abc). There was no lympha-
denopathy. A computed tomography (CT) scan with and with-
out contrast of the head and neck demonstrated soft tissue
thickening and irregularity present along the nasal ala bilater-
ally, nasal septum, and dorsal aspect of the nose with no adja-
cent bony destruction. A screening chest radiograph was also
obtained and found to be within normal limits. Dermatology
was consulted and options were discussed including wide local
excision, MMS, radiotherapy, and medical therapy with vismo-
degib. With the extensive soft tissue and cartilage damage,
radiotherapy and oral vismodegib would not allow normal
cutaneous tissue to recreate the nasal structure. Wide local
excision would likely require complete rhinectomy with mar-
gins encroaching the orbits, leaving the possibility of incom-
plete resection and a challenging repair. The patient, therefore,
agreed to MMS with reconstruction by plastic surgery.
The patient presented for MMS and was premedicated with
diazepam. Infraorbital nerve blocks were placed with 1% lido-
caine with 1:100,000 epinephrine. The area was also infiltrated
with 1% lidocaine with 1:100,000 epinephrine and 0.5% bupiva-
caine. The “A” layer was removed, carefully mapped, and div-
ided ( Fig. 6.9d–f). Eight specimens were found to be positive
with infiltrative and nodular BCC ( Fig. 6.9g). The “B” layer was
removed for a total of seven specimens and 1 specimen was
found to be positive ( Fig. 6.9h, i). The “C” layer was excised
and found to be clear of tumor (Fig. 6.9j, k). Her final defect
was extensive including bilateral medial cheeks and the entire
surface of the nasal dorsum, a portion of the caudal septum,
bilateral lower lateral cartilages, and columella ( Fig. 6.9l, m).
The patient tolerated the whole 7-hour procedure without di -
culty. She was alert and awake through the entire process and
had a family member present for support.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
127

Fig. 6.9 Case 1. (a–c) Middle-aged female with large basal cell carcinoma (BCC) on nose. (d) Initial layer. (e) Map of “A” layer. (f) Defect after “A” layer.
(g) Marked tumor positivity on “A” layer map. (h) Map of “B” layer.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
128

Fig. 6.9 (continued) (i) Marked tumor positivity on “B” layer map. (j) Map of “C” layer. (k) Tumor clearance as indicated by “C” map. (l, m) Final defect
with tumor clearance. (n–p) Ongoing reconstruction with radial forearm free flap.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
129

The patient was then placed under general anesthesia for
staged reconstruction by the plastic surgeon. Initially, bilateral
cheeks were advanced over the defect to the nasal sidewall and
anchored to the nasal periosteum. A split thickness skin graft
was placed over the nasal defect. Approximately, 3 weeks later,
the patient returned for nasal reconstruction with a radial fore-
arm free flap and is still in the process of reconstruction
(Fig. 6.9n–p). At two-year follow up, patient was doing well
with no signs of clinical recurrence.
6.7.2 Case 2
An 86-year-old Caucasian male with a significant past medical
history for hypertension, atrial fibrillation, and blindness in the
left eye was admitted to the hospital for failure to thrive. The
patient had a large tumor on his forehead, which was recently
biopsied at an outside facility. The duration of time the patient
had the tumor was unknown given the patient hid it under his
hat. On examination, a 10 ×6 cm large ulcerative plaque with
overlying hemorrhagic crust and rolled border extended from
the left brow line inferiorly to the frontal hairline superiorly
(Fig. 6.10a). No lymphadenopathy was appreciated. The CT of
the brain without contrast demonstrated a soft extracranial
tissue mass on the left frontal region with underlying calvarial
destruction. There was no hypermetabolic cervical lymphaden-
opathy or distant metastasis. The MRI of the brain showed
extensive soft tissue prominence and ulceration overlying the
left frontal region with underlying marrow infiltration in addi-
tion to a focal skull defect (Fig. 6.10bc–e). There were no
intracranial metastases. Subsequent biopsy demonstrated an
invasive, moderate di erentiated SCC, which was staged as
pT3NxMx.
A multidisciplinary team involving a plastic surgeon, a neuro-
surgeon, a Mohs surgeon, and a radiation oncologist was
assembled. The patient was placed under general anesthesia
(Fig. 6.10f) and the plastic surgeon resected the tumor and
performed a left orbital exenteration ( Fig. 6.10g). The Mohs
surgeon was present to assist in the mapping of the tumor and
processed the excised tumor (Fig. 6.10h). Since the underlying
calvarium was involved, a craniectomy was performed by neu-
rosurgery. The tissue was processed with the Mohs technique
(frozen sections and horizontal sectioning), in which complete
peripheral margins were examined. The deep margins were not
assessed as the underlying bone was removed. After the periph-
eral margins were found to be clear, the plastic surgeon closed
the defect with a vertical rectus abdominis myocutaneous and
Fig. 6.10 Case 2: elderly male with neglected SCC (squamous cell carcinoma) on forehead. (a) Initial presentation. (b) T1-weighted scan with
gadolinium. Scalp thickening in midline/left frontal region. Mild nonspecific dural thickening. (c) Axial postgadolinium T1 scan. Irregular scalp mass
and focal penetration of skull by neoplasm in left frontal bone. Dural thickening is relatively uniform, and may be reactive or related to chronic low
cerebrospinal fluid pressure. (d) Sagittal T1-weighted scan without gadolinium. Scalp mass is visible. Normal marrow hyperintense fat signal in the
posterior calvarium is present, but is replaced adjacent to the scalp mass. (e) Axial T2 scan. Phthisis bulbi left globe.
Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
130

latissimus myofascial free flaps ( Fig. 6.10i). The patient was
discharged to a skill nursing facility and plans to follow up with
radiation oncology. At nine-month follow up, patient's flap was
healing well with no signs of recurrence.
6.8 Conclusion
The beauty of the MMS technique lays in the simplicity of each
step that, when integrated, has transformed our view and con-
sequent expectations of margin assessment in surgical cutane-
ous oncology. This is reflected in the highest cure rates of NMSC
with MMS in both primary and recurrent tumors while simul-
taneously achieving maximal tissue conservation. For appropri-
ate tumors, it is a cost-e ective surgery that allows tumor
clearance and reconstruction on the same day. Most commonly,
this is done in the outpatient setting with local anesthesia.
Patients also value these advantages and are very satisfied with
the procedure.63 In more complex cases, a multidisciplinary
team involving Mohs surgery for the extirpation of the tumor
and/or tissue processing is invaluable for complete margin con-
trol with conservation of tissue, followed by reconstruction
expertise of colleagues in other surgical subspecialties.
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Mohs Micrographic Surgery’s Role in the Treatment of Skin Cancer
133

7 Role of Radiotherapy in the Treatment of Skin
Malignancies
Shlomo A. Koyfman, Bindu V. Manyam, Nikhil Purushottam Joshi, and Sue S. Yom
7.1 Introduction
Non-melanomatous skin cancers (NMSC), specifically basal cell
carcinoma (BCC) and squamous cell carcinoma (SCC), are the
most common malignancies in the United States. They are pri-
marily managed surgically and carry an excellent prognosis,
with a 1 to 5% rate of disease recurrence after complete excision
and only exceedingly rare instances of distant metastasis. His-
torically, radiotherapy played a prominent role in the definitive
management of these cancers as an alternative to surgical
resection, especially in cosmetically sensitive areas. With the
improvement in surgical techniques in recent decades, espe-
cially the widespread use of Mohs micrographic surgery
(MMS), the use of curative radiation for skin cancers has
declined. However, radiation is still commonly used in the
definitive setting for patients with NMSC who are poor surgical
candidates or have larger lesions in cosmetically sensitive
regions of the face, and in the postoperative setting for more
advanced tumors that have high-risk pathologic features that
are associated with excessive risks of locoregional recurrence
after surgery alone. Radiotherapy plays a similar role in the
postoperative management of cutaneous melanoma. Radiation
also o ers excellent palliation for noncurable patients. This
chapter reviews common indications, dose and fractionation
schedules, techniques, and oncologic and cosmetic outcomes
for radiotherapy for NMSC and melanoma ( Fig. 7.1).
7.2 Indications for Radiotherapy
for NMSC
7.2.1 Indications for Definitive
Radiotherapy
Both surgery and RT can o er excellent cure rates for the
management of early-stage NMSC. Surgery is typically the pre-
ferred method of treatment, given it can be performed in a
single session, and has been associated with superior oncologic
and cosmetic outcomes. One prospective randomized study
compared the outcomes of MMS and definitive RT in 347
patients with less than 4 cm BCC of the face. The local failure
rate was 0.7% for patients treated with MMS and 7.5% for
patients treated with RT. Additionally, the cosmetic outcome
was rated “good” or better more often in those patients who
underwent surgery (87 vs. 69%).1 Though the technique of RT
was not controlled (55% received interstitial brachytherapy and
45% received orthovoltage therapy), which could have a ected
the quality of the comparison, as the only randomized study,
this trial remains pivotal in guiding medical decision making.
A variety of factors can influence the decision to favor RT
rather than surgery for NMSC. Typical contraindications to
definitive RT include very large tumors and those with bone
and/or cartilage invasion, given that control rates are typically
inferior, as well as recurrent tumors that have been previously
radiated or arise in an area of previous radiotherapy. Radiation
should also be avoided in patients with genetic radiosensitivity
syndromes, such as xeroderma pigmentosum and basal cell
nevus syndrome, and in those with active connective tissue dis-
eases, such as scleroderm a and systemic lupus erythematosus.2
Patients who are candidates for definitive RT include those with
unresectable disease, older patients with comorbidities limiting
their surgical options, and patients with lesions involving the
eyelid, canthi of the eye (especially those who carry surgical
risk to the lacrimal duct), external ear (Fig. 7.2 and Fig. 7.3),
nose (Fig. 7.4 and Fig. 7.5), brow (Fig. 7.6), temple
(Fig. 7.7), or lip, which may incur significant cosmetic or func-
tional defects from surgical resection.
A robust literature, much of it older when RT was more com-
monly used, supports the safety and e cacy of definitive RT for
many of these aforementioned types of patients. A review of
Fig. 7.1 A modern linear accelerator, capable of delivering photon and
electron radiotherapy with image guidance provided by cone beam CT
(red arrow).
Role of Radiotherapy in the Treatment of Skin Malignancies
134

986 BCC and SCC of the skin overlying the eyelid treated
with definitive RT demonstrated a 5-year cure rate of 96.4%.3
A review of 334 BCC and SCC of the external ear at the
Princess Margaret Hospital treated with definitive RT demon-
strated a 2-year local control rate of 87%, with severe late toxic-
ity noted in only 7% of patients.4 A review of 100 patients with
SCC of the nasal skin at the Princess Margaret Hospital treated
with definitive RT demonstrated a 2-year local control rate of
90%, with no severe toxicities observed.5
While definitive RT monotherapy can provide e ective tumor
control for T1–3N0 NMSC, T4 tumors and those with nodal
metastases demonstrate inferior outcomes. Initial surgical
management is recommended in these patients, often followed
by adjuvant radiotherapy. T4 disease is defined as tumor inva-
sion into the axial or appendicular skeleton or perineural inva-
sion (PNI) of the skull base. The University of Florida reported a
local control rate of just 53% at 5 years in patients with T4 BCC
and SCC.6,7 In a review of 68 T4 BCC and SCC of the skin of the
head and neck treated with definitive RT, local control rates
were lower in patients with recurrent disease, compared to
primary lesions (41 vs. 67%; p =0.07) and the three most
important prognostic indicators for inferior local control and
cause-specific survival rates were bone involvement (p <0.01),
recurrent lesions (p <0.01), and nerve involvement (p <0.02).6
Fig. 7.2 (a) SCC of the helix of the left ear with bleeding (baseline). (b) After treatment with definitive radiation therapy (50 Gy in 20 fractions with
electrons). There was complete remission with excellent cosmesis.
Fig. 7.3 (a) A 96-year-old patient with right
retroauricular BCC, T2N0M0 (baseline). (b) One
month after treatment with definitive radiation
therapy (50 Gy in 20 fractions with electrons).
Role of Radiotherapy in the Treatment of Skin Malignancies
135

Even the more favorable lesions had local control rates of less
than 70%. Similarly, a large retrospective review which included
531 BCC and SCC treated with definitive RT demonstrated local
control rates of 94 and 89% for primary BCC and SCC tumors,
respectively, and 86 and 68% for BCC and SCC recurrent tumors,
respectively.8 In patients with nodal metastases, locoregional
recurrence rates with definitive RT alone range from 30 to 50%
and cancer-related mortality is as high as 30%.9 Such subopti-
mal outcomes support the use of intensification of treatment
and multimodal therapy for these patients with advanced dis-
ease. In patients who are not eligible for initial surgical resec-
tion, concurrent cisplatin-based chemotherapy can be
considered to enhance the e ectiveness of radiotherapy. While
there is no high-quality evidence demonstrating clear benefit
to such an approach in cutaneous malignancies, many head and
neck oncologists extrapolate from the mucosal SCC of the head
and neck, where concurrent chemotherapy significantly
improves disease control and survival in the setting of locally
advanced disease treated nonoperatively.10
Indications for Postoperative Radiotherapy
Postoperative RT is rarely used for BCC. Patients with BCC have
an exceedingly low risk of recurrence after surgery alone, and
even patients with a positive margin, focal cartilage invasion, or
PNI are often still candidates for close observation and salvage
re-resection if needed.11,12 However, postoperative RT is often
considered in cases where there are persistently positive mar-
gins after multiple resections, T4 disease that extensively
invades bone or soft tissue, lymph node metastasis, or clinically
apparent PNI ( Fig. 7.8).13
Postoperative RT is much more commonly used in resected
SCC ( Fig. 7.9). Postoperative RT is indicated for patients with
high-risk resected disease, such as T4 disease, in transit or satel-
lite metastases, nodal metastases, persistently positive margins,
and recurrent disease (Fig. 7.10 and Fig. 7.11). In addition,
patients with two or more intermediate-risk factors, including
tumor size greater than 2 cm, poorly di erentiated histology,
ear and hair-bearing lip location, PNI, and immunosuppressed
status, may also benefit from adjuvant RT.
Retrospective data have demonstrated high rates of local
recurrence in patients with T4 tumors managed with surgery
alone.7 In addition, the rate of occult lymph node metastasis is
high, ranging from 29 to 50%, in patients with advanced T-stage
Fig. 7.4 A patient with multifocal BCC (baseline).
Fig. 7.5 A patient with multifocal BCC 3 months after treatment with
definitive radiation therapy (40 Gy in 10 fractions with electrons).
Role of Radiotherapy in the Treatment of Skin Malignancies
136