Phẫu Thuật Tạo Hình (Tập 1): Nguyên Lý Cơ Bản – Neligan (2018)

531
Diagnosis
with malignant or nonmalignant tumor invasion into bones
can be observed by using X-rays.
CT detects metastatic lesions in the bone, lymph nodes, and
lungs better than MRI. Helical CT or multidetector low CT
can generate three-dimensional and high-resolution images.
Contrast-enhanced CT and CT angiography are useful for
detecting malignant tumors, vascular regions, and adjacent
vascular structures.
MRI detects soft tissues better than CT. In general,
malignant tumors present with low-iso signal intensity on
T2-weighted images (T2WI) and low signal intensity on
T1-weighted images (T1WI), while benign tumors exhibit high
signal intensity on T2WI and low signal intensity on T1WI.
Magnetic resonance angiography is superior to MRI in deter-
mining the nidus and exact nature of the collateral structures
in hemangiomas and vascular malformations.
Angiography is an invasive imaging method that was fre-
quently used in the past to investigate vascular lesions. While
it detects hemangiomas and vascular malformations readily,
its use with pediatric patients requires general anesthesia.
BOX 28.1  Typical skin tumor colors
Normal color
Epidermal origin (e.g., epidermoid cyst)
Mesenchymal origin (e.g., lipoma, soft fibroma, leiomyoma)
Neural crest origin (e.g., schwannoma)
Yellow–pale yellow
Appendage origin (e.g., sebaceous nevus, xanthoma, milia)
Erythematous
Epidermal origin (e.g., inflammatory atheroma, squamous cell
carcinoma)
Mesenchymal origin (e.g., keloid and hypertrophic scars, vascular
malformations, hemangioma, dermatofibrosarcoma protuberans,
angiosarcoma)
Blackish brown–black
Epidermal origin (e.g., basal cell carcinoma)
Neural crest origin (e.g., pigmented nevus, melanoma)
Blue
Epidermal origin (e.g., epidermoid cyst)
Neural crest origin (e.g., nevus of Ota, Mongolian spot, blue nevus)
Fig. 28.3  Two-step diagnosis using dermoscopy. BCC, basal cell carcinoma.
(Modified from Consensus Net meeting on Dermoscopy. Available at
dermoscopy.org/consensus/.)
Criteria for melanocytic lesion
Pattern analysis
Malignant melanoma
Clark’s nevus
Unna nevus
Miescher’s nevus
Spitz/Reed nevus
Congenital nevus
Blue nevus
Others
No
Criteria for seborrheic keratosis
Seborrheic
keratosis
No
Yes
Yes
BCC
Yes
Vascular
lesion
Yes
Criteria for BCC
No
Criteria for vascular lesion
No
BOX 28.2  Dermoscopic criteria used to diagnose melanocytic
lesions, seborrheic keratosis, basal cell carcinoma, and vascular
lesions
Criteria for melanocytic lesions
Pigment network
Negative network
Aggregated globules
Streaks
Homogeneous blue pigmentation
Pseudonetwork
Parallel pattern
Criteria for seborrheic keratosis
Multiple milia-like cysts
Comedo-like openings
Light-brown fingerprint-like structures
Fissures/ridges
Criteria for basal cell carcinoma
Pigment network is absent and one of:
Arborizing vessels
Leaf-like areas
Large blue-gray ovoid nests
Multiple blue-gray globules
Spoke wheel areas
Ulceration
Criteria for vascular lesions
Red–blue lacunas
Red–bluish to red–black homogeneous areas
(Reproduced from the Consensus Net meeting on Dermoscopy, 2000. Available
at: )
of benign skin tumors. The resolution of power Doppler
imaging is higher than that of CDI. M-mode and duplex (a
combination of B- and M-mode) scanning are useful for
observing hemangiomas or vascular malformations.
X-ray, CT, MRI, angiography, scintigraphy, and
positron emission tomography (PET)
X-ray analysis is useful for detecting calcifying lesions such
as pilomatricoma and malignant tumors that have necrosis-
induced calcifications. Moreover, bone deformation associated

532
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
that the lymph node has undetectable cancerous cells should
be considered. In addition, there is no compelling evidence
that the survival of patients who have a full lymph node
dissection as a result of a positive sentinel lymph node biopsy
is better than that of those patients who do not have a full dis-
section until later in the disease, when the lymph nodes can
be felt by a physician. Thus, such patients may be subjected
unnecessarily to full dissection, which is associated with
lymphedema.
The TNM clinical classification system and
the pTNM pathologic classification system
The TNM clinical classification5,6 applies only to malignant
tumors (Figs. 28.4 & 28.5). T indicates the size of the tumor
and whether it has invaded nearby tissue, N indicates whether
regional lymph nodes are involved, and M indicates the pres-
ence of distant metastasis. The TNM classification system is
based on clinical evidence acquired before definitive treat-
ment. Once intraoperative and surgical pathologic data
become available, the pathologic TMN (pTNM) classification
system can be used. The pT, pN, and pM categories corre-
spond to the T, N, and M categories.
Regional lymph nodes are those that drain the site of the
primary tumor (Fig. 28.6). The pN assessment of the regional
lymph nodes requires that a sufficient number of lymph
nodes are removed for histologic examination (usually six or
more). If the examined lymph nodes are negative but fewer
than six lymph nodes were resected, the pN classification is
designated pN0.
Box 28.3 shows examples of the TNM classification system,
namely the systems used for eyelid, vulva, penis, and soft-
tissue sarcomas.
Clinical staging
The TNM system5,6 is used to show the anatomical extent of
malignant tumors. For purposes of tabulation and analysis, it
is useful to condense these categories into stages (Table 28.1).
To be consistent with the TNM system, carcinoma in situ is
categorized as stage 0. In general, tumors that are localized to
the organ of origin are categorized as stages I and II, while
those that exhibit extensive local spread, particularly to the
regional lymph nodes, are classified as stage III. The tumors
that have distant metastasis are classified as stage IV. For
pathological stage groups, if sufficient tissue has been removed
for pathological examination to evaluate the highest T and N
categories, M1 may be either clinical (cM1) or pathological
(pM1). However, if only a distant metastasis has had micro-
scopic confirmation, the classification is pathological (pM1)
and the stage is pathological.
Treatment
Wide excision
With regard to wide resection of malignant tumors of skin,
the horizontal and vertical margins vary depending on the
type of tumor.7–9 Retrospective histopathologic studies have
supported reductions in the horizontal margin in recent
Scintigraphy can be used for metastatic lesion screening.
67Ga and 201TiCl are used in tumor- or inflammation-seeking
scintigraphy, while 99Tc-MDP and 99mTc-HMDP are used in
bone scintigraphy. Scintigraphy suffers from low resolution,
and this makes it difficult to detect lesions that are less than
2 mm in diameter by this method.
PET is also useful for detecting the metastatic lesions of
malignant skin tumors.3 2-deoxy-2-[18F] fluoro-d-glucose
(FDG) PET (FDG-PET) has been used for the diagnosis and
staging of cancers and for monitoring treatment, particularly
with regard to Hodgkin’s lymphoma, non-Hodgkin’s lym-
phoma, and lung cancer. PET can also sometimes detect many
other types of solid tumors that occasionally show up as very
highly labeled lesions. FDG-PET is particularly useful for
searching for tumor metastasis, or for recurrence after the
removal of a primary tumor that was known to be highly
active. However, since PET can also detect inflammatory
lesions, it will be necessary to exclude the possibility that a
PET-detected apparent tumor is not an inflammatory, erosive,
or ulcered area.
Pathologic diagnosis
A definitive diagnosis requires a pathologic diagnosis.
However, biopsies should only be performed for a clear
purpose, such as for the differential diagnosis of benign
tumors or to analyze the stage and grade of malignant tumors,
which would allow the area to be resected to be determined.
Moreover, biopsies should only take place after careful
inspection, palpation, and imaging analyses. Depending on
the purpose of a biopsy and the lesion characteristics, the
surgeon can choose from a range of different biopsy tech-
niques, including punch, incisional, excisional, and mapping
biopsies. In the case of incisional biopsies, normal skin
should be excised together with early-stage lesions and the
characteristic areas of lesions (e.g., inflammatory, erosive, or
ulcered areas).
In the case of a possible malignant tumor, an excisional
biopsy is recommended to prevent malignant cell dissemina-
tion into blood. However, surgeon judgment is needed to
determine the amount of normal skin that should be removed.
In general, the normal skin margin of an excisional biopsy
should be as minimal as possible, especially if the tumor
is suspected to be benign. However, if the margins of an
excisional biopsy of a malignant tumor are wide enough,
such biopsies could actually serve the same purpose as
radical resections. Such extensive excisional biopsies could
also reduce the number of operations that are needed to
treat a tumor. Thus, if a low-grade malignant tumor (e.g.,
BCC) is suspected, an excisional biopsy that includes several
millimeters of normal skin margin may be considered.
For high-grade malignant tumors, excisional biopsies will
often lead to a pathologic diagnosis that indicates the need
for additional wide resection, radiation therapy, and/or
chemotherapy.
Sentinel node biopsy is increasingly being used to detect
lymph node metastasis, as it shows whether the cancer has
spread to the very first lymph node.4 If the sentinel lymph
node does not contain cancer, it is highly likely that the cancer
has not spread to any other area of the body. However, this
technique is only of therapeutic value for patients with positive
nodes: for patients who have negative nodes, the possibility

533
Treatment
Lymph node dissection
Axillary lymph node dissection
Since sentinel lymph node biopsy is now a widely practiced
technique, there are fewer occasions where preventive axillary
lymph node dissection is necessary. Metastatic squamous cell
carcinoma (SCC) is an example of a malignant nonmelanocytic
skin tumor that warrants axillary lymph node dissection.
Axillary lymph nodes can be classified into levels I, II, and III,
which relate to the lateral and internal edges of the pectoralis
minor muscle. Level I is the bottom level and lies below the
lower edge of the pectoralis minor muscle. Level II lies under-
neath the pectoralis minor muscle, while level III is above the
pectoralis minor muscle. Structures that should be preserved
years. The horizontal margins that are recommended for
particular tumor types are listed in Box 28.4. In the case
of malignant soft-tissue tumors, the type of excision can
vary with regard to the extent of the margins around the
tumor: curative wide, wide, and marginal excisions indicate
margins that are at least 5 cm outside the tumor-reactive
layer, 1–2 cm outside the tumor-reactive layer, and within
the tumor-reactive layer, respectively. It is now considered
that wide excision is the appropriate margin for soft-tissue
sarcoma. Moreover, Mohs micrographic surgery, where
tumors undergo histologic analysis during surgery in such a
way that almost all of the surgical margins can be examined
for tumor extensions, can help to obtain complete margin
control during the removal of a skin cancer and soft-tissue
sarcoma.10
Fig. 28.4  The T factor of the TNM classification system, as described by the Union for International Cancer Control (UICC). (Used with the permission of the Union for
International Cancer Control (UICC), Geneva, Switzerland. Original source: Wittekind CF, Greene FL, Hutter RVP, et al. TNM Atlas: Illustrated Guide to the TNM/pTNM
Classification of Malignant Tumours, 5th edition. Berlin: Springer; 2004.)
Epithelium
T1 pT1
T2 pT2
T2(5) pT2(5)
T3 pT3
T4 pT4
Tis pTis
Papillary
dermis
Reticular
dermis
Subcutaneous
tissue
<2 cm
>2–5 cm
>2–5 cm
>5 cm
Cartilage,
skeletal muscle,
bone
T – Primary tumor*
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
The greatest dimension of the tumor is 2 cm or less
T2
The greatest dimension of the tumor is more than 2 cm but less than 5 cm
T3
The greatest dimension of the tumor is more than 5 cm
T4
The tumor invades deep extradermal structures such as cartilage, skeletal muscle, or bone
* In the case of multiple simultaneous tumors, the tumor with the highest T category is used for the classification and the number of separate tumors is indicated in parentheses
(e.g., T2 (5))

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CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
Fig. 28.5  The N and M factors of the TNM classification system, as described by the Union for International Cancer Control (UICC). (Used with the permission of the Union
for International Cancer Control (UICC), Geneva, Switzerland. Original source: Wittekind CF, Greene FL, Hutter RVP, et al. TNM Atlas: Illustrated Guide to the TNM/pTNM
Classification of Malignant Tumours, 5th edition. Berlin: Springer; 2004.)
Primary tumor
Primary tumor
Primary tumor
Primary tumor
Primary tumor
M1
N1
M1
M1
N1
N1
N1
M1
M1
M1
M1
N1
M1
N1
N1
N1
N1
N = pN
M = pM
M – Distant metastasis
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
N – Regional lymph nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
during axillary lymph node dissection are the pectoral nerves,
the long thoracic nerve, the intercostobrachial nerves, the
axillary artery and veins, the thoracoacromial artery and
veins, and the subscapular artery and veins.
Inguinal lymph node dissection
Widespread use of sentinel lymph node dissection has also
reduced the frequency of inguinal lymph node dissection.
Representative indications for inguinal lymph node dissection
are metastatic SCC and extramammary Paget’s disease
(EMPD). Traditionally, the area of dissection is a triangle
composed of the inguinal ligament, the internal edge of the
sartorius muscle, and the internal edge of the long adductor
muscle. In the wide resection of inguinal lymph nodes, the
femoral vein is identified along with the saphenous vein. After
clamping the saphenous vein, the adductor longus muscle is
identified and should be cleaned of all fatty nodal tissue by
retracting the saphenous vein en bloc with the lymph nodes
until the adductor canal is reached.

535
Treatment
Fig. 28.6  The regional lymph nodes, as described by the Union for International Cancer Control (UICC). (Used with the permission of the Union for International Cancer
Control (UICC), Geneva, Switzerland. Original source: Wittekind CF, Greene FL, Hutter RVP, et al. TNM Atlas: Illustrated Guide to the TNM/pTNM Classification of Malignant
Tumours, 5th edition. Berlin: Springer; 2004.)
A
Axillary
Epitrochlear
Inguinal
Head, neck


Thorax
Upper limb

Abdomen, loins,
and buttocks
Lower limb
Anal margin and
perianal skin
Ipsilateral preauricular, submandibular, cervical,
and supraclavicular lymph nodes

Ipsilateral axillary lymph nodes
Ipsilateral epitrochlear and axillary lymph nodes
Ipsilateral inguinal lymph nodes
Ipsilateral popliteal and inguinal lymph nodes
Ipsilateral inguinal lymph nodes
Unilateral tumors
B
Auricular and occipital
Parotid, preauricular
and facial
Submandibular
(submaxillary)
Lymph nodes overlying
thyroid cartilage
Inferior deep jugular,
prelaryngeal and
paratracheal
Superior deep jugular
Spinal accessory
Supraclavicular
Retropharyngeal
Between

Right / left midline
Head and neck / thorax
Thorax / upper limb
Thorax / abdomen, loins, and
buttocks
Abdomen, loins, and buttocks /
lower limb
Clavicula–acromion–upper shoulder blade edge
Shoulder–axilla–shoulder
Front: middle between the navel and the costal arch.
Back: lower border of the thoracic vertebrae (midtransverse axis)
Groin–trochanter–gluteal sulcus
Tumors in the boundary zones
Reconstructive surgery
Reconstruction via skin grafting is a basic surgical technique
that is used to reconstruct the tissue defects that occur after
tumor extirpation, which is also useful for early detection of
local recurrence. The ideal approach after tumor extirpation is
to suture the wound margins directly together. However, this
can only be performed if the wound is not too big and the
adjacent skin can be extended sufficiently. One concern with
this approach is that malignant cells may be left in the deep
margins of the wound. Recent developments in reconstructive
techniques, including thin flap-based techniques and wound
coverage materials, mean that plastic surgeons can now choose
from a wide and rapidly evolving variety of primary and
aesthetic secondary reconstruction methods. Given this con-
stantly altering medical (and social) environment, it is difficult
to develop up-to-date reconstructive algorithms, and indeed,
previous algorithms such as the reconstructive ladder, eleva-
tor, and triangle quickly lose favor. Consequently, the tech-
niques that are chosen for primary and secondary reconstruction
are largely determined on a case-by-case basis. However, one
current and useful model is the reconstructive matrix,11 which
helps plastic surgeons to determine the best reconstructive
solutions for their patients in the context of particular medical
and socioeconomic environments by considering aspects of
surgical complexity, technological sophistication, and patient
surgical risk.
Radiation therapy
Malignant tumors vary in their sensitivity to radiation-induced
damage, which directly affects the success of radiation therapy.

536
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
BOX 28.3  The TNM classification systems for eyelid, vulva, penis, and soft-tissue sarcomas (Union for International Cancer Control)
Carcinoma of the skin of the eyelid
TX Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis Carcinoma in situ
T1
The tumor is of any size and does not invade the tarsal plate;
or the tumor is at the eyelid margin and its greatest dimension
is 5.0 mm or less
T2
The tumor invades the tarsal plate; or the tumor is at the eyelid
margin and its greatest dimension is more than 5.0 mm but
less than 10.0 mm
T3
The tumor involves the full eyelid thickness; or the tumor is at
the eyelid margin and its greatest dimension is more than
10.0 mm
T4
The tumor invades adjacent structures, including the bulbar
conjunctiva, sclera/globe, soft tissues of the orbit, perineural
invasion, bone/periosteum of the orbit, nasal cavity/paranasal
sinuses, and central nervous system
N1 Regional lymph node metastasis
Carcinoma of the skin of the vulva
TX Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis Carcinoma in situ
T1
The tumor is confined to the vulva, or the vulva and the
perineum, and its greatest dimension is 2 cm or less
T1a The tumor is confined to the vulva, or the vulva and perineum,
its greatest dimension is 2 cm or less, and it exhibits stromal
invasion that is no greater than 1.0 mm
T1b The tumor is confined to the vulva, or the vulva and the
perineum, its greatest dimension is 2 cm or less, and it exhibits
stromal invasion that is greater than 1.0 mm
T2
The tumor is confined to the vulva, or the vulva and the
perineum, and its greatest dimension is more than 2 cm
T3
The tumor invades the lower urethra, vagina, and/or anus
T4
The tumor invades the bladder mucosa, rectal mucosa, and/or
upper urethral mucosa, or is fixed to the pubic bone
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Unilateral regional lymph node metastasis
N2 Bilateral regional lymph node metastasis
Carcinoma of the skin of the penis
TX Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis Carcinoma in situ
Ta
Noninvasive verrucous carcinoma
T1
The tumor invades the subepithelial connective tissue
T2
The tumor invades the corpus spongiosum or cavernosum
T3
The tumor invades the urethra or prostate
T4
The tumor invades other adjacent structures
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single superficial inguinal lymph node
N2 Metastasis in multiple or bilateral superficial inguinal lymph
nodes
N3 Metastasis in deep inguinal or pelvic lymph nodes, unilateral or
bilateral
Soft-tissue sarcoma
TX Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
The greatest dimension of the tumor is 5 cm or less
T1a The tumor is superficial*
T1b The tumor is deep*
T2
The greatest dimension of the tumor is more than 5 cm
T2a The tumor is superficial
T2b The tumor is deep
N1 Regional lymph node metastasis
*Superficial tumors are located exclusively above the superficial fascia and do not
invade the fascia, while deep tumors are either exclusively beneath the superficial
fascia, or are superficial to the fascia but invade into or through the fascia.
Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors.
(Modified from Sobin LH, Gospodarowicz MK, Wittekind C (eds). TNM
Classification of Malignant Tumours (UICC: Union for International Cancer Control),
7th edn. Chichester: Wiley-Blackwell; 2009; and Wittekind CF, Greene FL,
Hutter RVP, et al (eds). TNM Atlas: Illustrated Guide to the TNM/pTNM
Classification of Malignant Tumours, 5th edn. Berlin: Springer; 2004.)
For example, malignant melanomas are less sensitive to radia-
tion and are therefore rarely treated with radiation therapy.
Malignant skin tumors that are relatively sensitive to radiation
and are therefore commonly treated with radiation therapy
include BCC,12 SCC,13 and Merkel cell carcinoma of the skin.14
Acute skin reactions to radiation therapy occur during the first
7–10 days after treatment and are characterized initially by
erythema that then progresses to pigmentation, epilation, and
desquamation; this is particularly the case when higher doses
are used. Subacute and late complications occur several weeks
after radiation therapy and can progress for long periods of
time. These complications include scarring, permanent pig-
mentation, depigmentation, atrophy, telangiectasis, subcuta-
neous fibrosis, and necrosis.
Chemotherapy
Chemotherapy can be either adjuvant or primary, and all
chemotherapies can be administered either systemically or
topically. Adjuvant chemotherapy is mainly used for malig-
nant melanoma, while primary chemotherapy is indicated for
SCC,15 angiosarcoma,16 and EMPD.17 However, the radical

537
Treatment
Table 28.1  Clinical staging (Union for International Cancer Control)
Carcinoma of the skin (general staging system)
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage II*
T2
N0
M0
Stage III
T3
T1, 2, 3
N1
M0
Stage IV
T1, 2, 3
N2, 3
M0
T4
AnyT
M0
AnyT
AnyN
M1
*The American Joint Committee on Cancer considers stage I tumors that have
more than one high-risk feature to be stage II tumors.
Merkel cell carcinoma of the skin
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage IA
T1
pN0
M0
Stage IB
T1
cN0
M0
Stage IIA
T2, 3
pN0
M0
Stage IIB
T2, 3
cN0
M0
Stage IIC
T4
N0
M0
Stage IIIA
AnyT
N1a*
M0
Stage IIIB
AnyT
N1b*, 2
M0
Stage IV
AnyT
AnyN
M1
*N1a: Microscopic metastasis (clinically occult: cN0 + pN1)
N1b: Microscopic metastasis (clinically occult: cN1 + pN1)
Carcinoma of the skin of the eyelid
Stage 0
Tis
N0
M0
Stage IA
T1
N0
M0
Stage IB
T2a*
N0
M0
Stage IC
T2b*
N0
M0
Stage II
T3a*
N0
M0
Stage IIIA
T3b*
N0
M0
Stage IIIB
AnyT
N1
M0
Stage IIIC
T4
N1
M0
Stage IV
AnyT
AnyN
M1
*T2a: >5–10 mm in its greatest dimension or located at the tarsal plate or lid
margin
T2b: >10–20 mm in its greatest dimension or located in the full-thickness eyelid
T3a: >20 mm in its greatest dimension, located in adjacent ocular/orbital
structures, or showing perineural invasion
T3b: Needs enucleation, exenteration, or bone resection
Carcinoma of the skin of the vulva
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage IA
T1a
N0
M0
Stage IB
T1b
N0
M0
Stage II
T2
N0
M0
Stage IIIA
T1, 2
N1a, 1b*
M0
Stage IIIB
T1, 2
N2a, 2b*
M0
Stage IIIC
T1, 2
N2c*
M0
Stage IVA
T1, 2
N3*
M0
T3
AnyT
M0
Stage IVB
AnyT
AnyN
M0
*N1a: 1–2 lymph node metastases, each with a greatest dimension less than
5 mm
N1b: 1 lymph node metastasis whose greatest dimension is 5 mm or greater
N2a: 3 or more lymph node metastases, each with a greatest dimension less
than 5 mm
N2b: 2 or more lymph node metastases whose greatest dimensions are 5 mm
or greater
N2c: Lymph node metastasis with extracapsular spread
N3: Fixed or ulcerated regional lymph node metastasis
Carcinoma of the skin of the penis
Stage 0
Tis
N0
M0
Ta
N0
M0
Stage I
T1a
N0
M0
Stage II
T1b
N0
M0
T2
N0, 1
M0
T3
N0
M0
Stage IIIA
T1, 2, 3
N1
M0
Stage IIIB
T1, 2, 3
N2
M0
Stage IV
T4
AnyN
M0
AnyT
N3
M0
AnyT
AnyN
M1
Soft-tissue sarcoma
Stage IA
T1a
N0
M0
Low-grade
T1b
N0
M0
Low-grade
Stage IB
T2a
N0
M0
Low-grade
T2b
N0
M0
Low-grade
Stage IIA*
T1a
N0
M0
High-grade
T1b
N0
N0
High-grade
Stage IIB
T2a
N0
M0
High-grade
Stage III
T2b
N0
M0
High-grade
Stage IV
AnyT
N1
M0
AnyG
AnyT
AnyN
M1
AnyG
*Extraskeletal Ewing and primitive neuroectodermal tumors are classified as
high-grade. If grade cannot be assessed, classify the tumor as low-grade.
(Modified from Sobin LH, Gospodarowicz MK, Wittekind C (eds). TNM Classification of Malignant Tumours (UICC: Union for International Cancer Control), 7th edn.
Chichester: Wiley-Blackwell; 2009; and Wittekind CF, Greene FL, Hutter RVP, et al (eds). TNM Atlas: Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours,
5th edn. Springer; 2004.)

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CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
BOX 28.4  Recommended surgical margins of wide excisions of
nonmelanocytic tumors of the skin and soft tissues
Horizontal margin
Basal cell carcinoma
low risk: 4 mm
high risk: 5–10 mm
Squamous cell carcinoma
low risk: 4–6 mm
high risk: 10 mm
Merkel cell carcinoma
10–20 mm
Sarcoma
low risk: 10 mm
high risk: 20 mm
Vertical margin
With fat layer
Tumors that are limited to the dermis
With deep fascia
Tumors that extend into the fat layer
With skeletal muscle
Tumors that extend into the deep fascia
With the membranes of deeper structures such as cartilage or
bone
Tumors that extend into skeletal muscle
With deeper structures like cartilage or bone
Tumors that extend into membranes of deeper structures like
cartilage or bone
Others
The margins of wide tumor excisions that occur in anatomically
complicated and special regions (e.g., eyelid, vulva, penis, finger/
toe tip, and ear) will vary on a case-by-case basis. This is also true
for soft-tissue tumors. In general, at least one layer of barrier
structure should be excised. For example, for tumors that are limited
to the fat layer, the deep fascia of skeletal muscle is considered as
the barrier structure and should be removed with the tumor upon
wide excision.
chemotherapy that malignant skin tumors are generally
treated with can sometimes be seen as neoadjuvant chemo-
therapy before surgery for advanced stage cancer. Single-agent
chemotherapies include peplomycin sulfate and CPT-1118 for
SCC, paclitaxel for angiosarcoma, and docetaxel for angiosar-
coma and EMPD. Multiagent chemotherapies includes cispla-
tin + doxorubicin and cisplatin + 5-fluorouracil (5-FU) +
bleomycin for SCC; mesna + doxorubicin + ifosfamide +
dacarbazine for angiosarcoma; and 5-FU + mitomycin C, 5-FU
+ carboplatin + leucovorin, and 5-FU + carboplatin + mitomy-
cin C + epirubicin + vincristine for EMPD.
Laser therapy
Dye lasers or neodymium-doped yttrium aluminum garnet
(Nd:YAG) lasers can be used for lesions that are characterized
by neoplastic changes or malformations in capillary vessels or
their overgrowth, such as hemangiomas,19 vascular malforma-
tions,20 and keloid/hypertrophic scars.21 Ruby and alexandrite
lasers can be used to treat superficial pigmented lesions whose
colors range from brown to black, while Q-switched ruby and
alexandrite lasers are useful for intradermal pigmented lesions
such as the nevus of Ota.22 CO2 lasers and erbium yttrium
aluminum garnet (Er:YAG) lasers target the water content of
a lesion,23 which makes them suitable for lesions with various
colors like seborrheic keratosis, telangiectatic granuloma,
xanthoma, and fibroma.
Others (including immunotherapy,
cryotherapy, electrocoagulation therapy, and
sclerotherapy)
At this stage, the only indication for immunotherapy is malig-
nant melanoma. Cryotherapy and electrocoagulation therapy
induce the freezing and melting of the tumor tissues, which
results in their necrosis and/or apoptosis; these methods are
suitable for superficial benign or malignant tumors like sebor-
rheic keratosis, fibroma, and BCC. Sclerotherapy, where a
sclerosant like ethanol, ethanolamine oleate, polidocanol, or
OK-432 is injected into affected vessels, can be used to treat
vascular malformations. Promising technologies that may
become useful in the near future include: hyperthermic infu-
sion therapy, where the tumor is infused with a substance that
makes it more susceptible to locally applied heat; molecular
target therapy, which involves drugs or other substances that
block the growth and spread of the tumor by interfering with
specific tumor growth and progression molecules; and gene
therapy and gene cell therapy, where genes are manipulated
in target healthy cells (to enhance their cancer-fighting prop-
erties) or in target cancer cells (to kill them or inhibit their
growth).
Benign cutaneous and soft-tissue
tumors
Benign epithelial-origin tumors
Epidermal nevus (e.g., verrucous epidermal nevus
and linear epidermal nevus)
This nevus is composed of skin cells that normally occur at
the affected site but show hyperkeratosis and papillomatosis
(Fig. 28.7). It can be considered to be a hamartoma, which is
a benign focal, tumor-like malformation that is composed of
a mixture of the cells that characterize the tissue of its origin;
Fig. 28.7  Epidermal nevus of the upper arm.

539
Benign cutaneous and soft-tissue tumors
occasionally self-heals. If the lesion is on the nose and face,
Mohs micrographic surgery is particularly suitable since it
facilitates good margin control along with minimal tissue
removal.
Epidermoid cyst (also known as epidermal cyst
and atheroma)
Epidermal cyst is a smooth, dome-shaped, freely movable,
somewhat fluctuant subcutaneous swelling that is sometimes
attached to the skin by a central pore (Fig. 28.10). It is covered
with a stratified squamous epithelium that resembles the
epidermis or the follicular infundibulum; thus, there is a
granular cell layer adjacent to the keratin-containing cyst
lumen. Epidermoid cysts can rupture spontaneously or be
ruptured by external mechanical forces. Extremely large epi-
dermoid cysts, also known as giant atheromas (Fig. 28.11),
should undergo pathology to rule out malignant change,27
although such changes are rare. Epidermoid cysts that exhibit
inflammation or recur should be removed by simple excision.
In the case of large cysts, the contents can be removed first,
after which the cyst walls can be removed with minimal
such nodules grow at the same rate as the surrounding tissues.
The dermis below the epithelial nevus is usually normal.
Epithelial nevi sometimes exhibit a diffuse or extensive dis-
tribution that affects a large area of the patient’s body (termed
systematized epidermal nevus); careful observation is neces-
sary in these cases. Systematized epidermal nevus often
occurs together with abnormalities in other organ systems.
This condition is termed epidermal nevus syndrome,24 and
has been described as a sporadic neurocutaneous linkage of
congenital ectodermal defects in the skin, brain, eyes, and/or
skeleton. Laser therapy, cryotherapy, electrocoagulation, sur-
gical abrasion, and excision are suitable for treating epithelial
nevi. If abrasion therapy is used, it should be remembered
that these lesions are usually limited to the epidermis; thus,
to prevent heavy scarring, only the epidermis and the super-
ficial layer of the dermis should be removed.
Seborrheic keratosis (also known as senile wart)
This is a benign skin growth that originates from the basal
and squamous cells in the epidermis (Fig. 28.8). It should be
differentiated from nevus cell nevus, senile keratosis, BCC,
and malignant melanoma. The sign of Leser–Trélat, which is
the dramatic, sudden appearance of multiple seborrheic kera-
toses, can be a paraneoplastic syndrome, namely an ominous
sign of an internal malignancy.25 In such cases, not only do
new lesions suddenly appear, pre-existing lesions also fre-
quently increase in size and become symptomatic. This sign
should not be overlooked and screening for internal malig-
nancy should be recommended to the patient. Laser therapy,
cryotherapy, electrocoagulation, surgical abrasion, and exci-
sion are all suitable treatments for seborrheic keratosis.
However, if the tumor invades the dermis, which can occur,
surgical excision is recommended.
Keratoacanthoma
Keratoacanthoma has been a controversial entity for many
years, mainly because it closely resembles SCC26 (Fig. 28.9). It
grows rapidly and can sometimes self-heal. Upon histopathol-
ogy, atypical squamous cells can be detected, which makes it
difficult to distinguish from SCC. For this reason, excisional
biopsy should be considered despite the fact that this lesion
Fig. 28.8  Seborrheic keratosis on the temporal region.
Fig. 28.9  Keratoacanthoma on the nose.
Fig. 28.10  Epidermoid cyst with a central pore.

540
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
from pilomatricoma on the head and neck region, especially
in pediatric patients. Since it has been reported that dermoid
cysts can exhibit malignant changes, complete surgical
removal is recommended.29
Others
Rare benign epidermal-origin skin tumors include clear
cell acanthoma, large cell acanthoma, acantholytic acan-
thoma, warty dyskeratoma, traumatic inclusion cyst, human
papillomavirus-associated cyst, proliferating epidermal cyst,
and cutaneous keratocyst. The preoperative diagnosis of these
tumors can be difficult, but many can be treated radically with
a simple excision and suture.
Benign appendage-origin tumors
Nevus sebaceus
Nevus sebaceus is a hamartoma rather than a neoplasm (Fig.
28.14). It is essentially confined to the head and neck regions,
and can be found not only in the sebaceous gland but also in
the epidermis, dermis, hair follicles, and sweat glands. Con-
sequently, it is also referred to as organoid nevus. In appear-
ance, it resembles an epidermal nevus. Since other tumors
such as BCC and trichilemmoma can arise from nevus seba-
ceus over time,30 complete surgical excision is recommended.
If it is located in the hair, the hair stream should be carefully
considered while performing the excision and suturing;
moreover, dehairing caused by unnecessary buried or dermal
sutures should be avoided.
Pilomatricoma (also known as calcifying
epithelioma and pilomatrixoma)
This is a cystic nodule that tends to occur on the head and
neck regions of young patients (Fig. 28.15). Multiple pilo­
matricoma may be seen in a familial setting in patients who
also have myotonic dystrophy. A calcified region can be seen
by ultrasound, X-ray, CT and MRI. This region will appear
as a high-intensity signal on ultrasound, while on MRI it
will show up as a low-intensity signal on both T1WI and
T2WI. Since malignant tumors sometimes have a calcified
lesion that is caused by necrosis, it is necessary to exclude this
possibility when making a diagnosis of pilomatricoma. It is
not associated with a clear capsule and thus should be excised
carefully and completely to prevent recurrence. Malignant
incision (Fig. 28.12). In cases where pus and blood are excreted,
the surgeon should consider incising the cyst and draining it
first, and then excising it completely 1–2 weeks later.
Milia
Milia are a smaller version of an epidermoid cyst (less than
4 mm in diameter). They may derive from the outer root sheath
of vellus follicles. There are primary and secondary milia.28
Primary milia include congenital milia, benign primary milia
of children and adults, milia en plaque, nodular grouped
milia, multiple eruptive milia, nevus depigmentosus with
milia, and genodermatosis-associated milia. Secondary milia
are the disease-, medication-, and trauma-associated milia.
Milia can be treated easily by making small holes in the surface
with a needle or CO2 laser and then extruding the contents.
Dermoid cyst
A dermoid cyst is a congenital subcutaneous cyst that devel-
ops along the embryonic lines of closure (Fig. 28.13). It is most
common on the head and neck area, particularly the supraor-
bital region, brow, upper eyelid, glabella, and scalp. These
cysts can be easily removed surgically, but care should be
taken not to injure the temporal branch of the facial nerve.
The cyst lumen contains keratin debris and hair shaft frag-
ments. Preoperative X-rays should be taken to distinguish it
Fig. 28.11  Giant atheroma.
Fig. 28.12  An epidermoid cyst (A) and the removal of the cyst with a minimal incision (B, C).
A
B
C

541
Benign cutaneous and soft-tissue tumors
occurs mainly on the eyelids and presents as a 1–2-mm nodule.
Since the main reason for treating syringoma is cosmetic, the
tumor should be destroyed in such a way that there is minimal
scarring and no recurrence. For this purpose, electrocoagula-
tion, dermabrasion, CO2 lasers, Er:YAG lasers, and fractional
photothermolysis33 can be used, although attention should be
paid to preventing pigmentation and scarring.
Apocrine cystadenoma (also known as apocrine
cysthidroma)
Apocrine cystadenoma is characterized by the dilata-
tion of an apocrine duct and secondary proliferation of
the ductal epithelium that is architecturally bland (Fig.
28.17). Apocrine cystadenomas appear most commonly
as solitary, soft, dome-shaped, and translucent papules or
nodules. They are located most frequently on the eyelids,
especially the inner canthus. They grow slowly and usually
persist indefinitely. They can be incised and drained, but
electrosurgical destruction of the cyst wall is often needed
to prevent recurrence. Punch, scissors, or elliptical excision
pilomatricoma has been reported,31 but there have been less
convincing reports of the carcinomatous transformation of
pre-existing benign pilomatricoma.
Trichilemmal cyst
This is a subcutaneous cyst that is derived from the outer root
sheath of the hair follicle and arises most frequently on the
hairy region on the head (Fig. 28.16). Clinically, it resembles an
epidermoid cyst. Multiple cysts on the head are seen in 70% of
cases. Complete excision is recommended. The conservative
approach involves a small punch biopsy of the cyst that allows
the cyst cavity to be entered. The contents of the cyst can then
be emptied, leaving an empty cyst wall that can be grasped
with a forceps and pulled out of the small incision. This method
often results in a very small scar and very little, if any, bleed-
ing. Proliferating trichilemmal cyst is an uncommon lesion
that is characterized histologically by trichilemmal keratiniza-
tion. It is thought to originate from a trichilemmal cyst and to
have the potential for malignant transformation, at which
point it is termed a malignant proliferating trichilemmal cyst.32
Syringoma
Syringoma is the result of intradermal eccrine proliferation
that is malformative rather than neoplastic in most cases. It
Fig. 28.13  (A) Dermoid cyst on the
supraorbital region. (B) The excised cyst.
A
B
Fig. 28.14  Nevus sebaceus on the scalp.
Fig. 28.15  Pilomatricoma on the upper eyelid.

542
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
can also remove these tumors. Multiple cystadenomas can
be treated with a CO2 laser. Trichloroacetic acid34 has also
been used.
Chondroid syringoma (also known as cutaneous
mixed tumor)
Chondroid syringoma derives from the sweat glands and is
most frequently seen on the head and neck, where it presents
as an unexceptional dermal or subcutaneous nodule (Fig.
28.18). The tumor consists of a gland-like epithelial component
that is set in a chondromyxoid stromal component. It is
believed that there are both eccrine and apocrine variants.
Hirsch and Helwig proposed the following five histologic
criteria for diagnosis: (1) nests of cuboidal or polygonal cells;
(2) intercommunicating tubuloalveolar structures lined with
Fig. 28.16  Solitary trichilemmal cyst on
the scalp (A) and after its excision (B).
A
B
Fig. 28.17  Apocrine cystadenoma on the earlobe.
Fig. 28.18  Chondroid syringoma on the lower eyelid.
two or more rows of cuboidal cells; (3) ductal structures
composed of one or two rows of cuboidal cells; (4) occasional
keratinous cyst; and (5) a matrix of varying composition. Since
malignant forms have been reported, although they are rare,
complete surgical excision is recommended.35
Others
Other benign appendage-origin tumors include steatocystoma
multiplex (Fig. 28.19), trichofolliculoma, trichoepithelioma,
poroma folliculare, trichilemmoma, sebaceous adenoma,
eccrine nevus, and apocrine nevus. Moreover, hair follicles,
sebaceous glands, and sweat glands (apocrine and eccrine
glands) can undergo hyperplasia that results in a hamartoma;
these skin appendages can also develop adenomas, benign
epitheliomas, and primordial epitheliomas.

543
Benign cutaneous and soft-tissue tumors
that has a depigmented area around it is called Sutton’s halo
nevus.38
Congenital pigment cell nevus
The congenital pigment cell nevus is present at the time of
birth and increases in size as the body grows, although its
shape does not change. It is classified according to size into
the small type (less than 1.5 cm in diameter), medium type
(1.5–20 cm in diameter), and large or giant type (over 20 cm
in diameter) (Fig. 28.22). Histology shows that the nevus cells
tend to be diffusely distributed in the deep layer of the dermis.
Careful observation is needed because malignant melanomas
can arise from giant congenital pigmented cell nevi.39 Nevi
that present on both the upper and lower eyelids are called
divided nevi, while hairy giant nevi are called animal-skin
nevi (Fig. 28.23). Giant nevi should be removed and recon-
structed by the serial excision method, skin grafting, local
flaps, or a combination of these.
Dysplastic nevus (also known as Clark’s nevus and
atypical mole)
Clinically, dysplastic nevus resembles an early-stage malig-
nant melanoma.40 It was initially thought to be a prodrome of
Fig. 28.19  Steatocystoma multiplex on the trunk.
Benign neural crest-origin tumors
Pigment cell nevus (also known as pigmented
nevus and nevus cell nevus)
These are acquired and congenital nevi that originate from
melanocytes. It has been suggested that healthy adults have
on average 5–10 nevi. Dome-like elevated nevi sometimes
bear hair. If an acquired nevus has a diameter of more than
7 mm and it is still growing, the possibility of malignant
melanoma should be considered. It seems now that malignant
melanomas do not originate from pigment cell nevus (except
in the case of congenital giant nevus) but rather derive directly
from epidermal melanocytes; this is known as the de novo
carcinogenesis theory.36 There are five types of pigmented
nevi, as follows.
Lentigo simplex
Lentigo simplex is a black–brown pigmented nevus, 2–3 mm
in diameter. It is believed to be an acquired pigment cell nevus
that is at an early stage (Fig. 28.20). Its margins can be either
jagged or smooth. It is the result of the proliferation of mela-
nocytes in the basal layer of epidermis. It is not induced by
sun exposure and is not associated with systemic disease. The
lesions are few in number and may occur anywhere on the
skin or mucous membranes. They usually first appear in early
childhood around 3 years of age, but they can also be present
at birth or develop later. Cryosurgery, lasers,37 and simple
excision can be tried.
Acquired pigment cell nevus
Acquired pigment cell nevi are due to the proliferation of
melanocytes and can be divided into three types according to
the location of the melanocytes. In junction nevi, the melano-
cytes are mainly located at the junction between the epidermis
and dermis. In compound nevi, the melanocytes are located
in the dermis as well as at the junction between the epidermis
and dermis. In intradermal nevi (Fig. 28.21), the melanocytes
are in the dermis only. Laser treatment is ineffective for
melanocytes located in the deeper layer of dermis because
these cells lack the melanin pigment. Thus, simple surgical
excision is recommended to prevent recurrence. The nevus
Fig. 28.20  Lentigo simplex on the forearm.
Fig. 28.21  Intradermal nevus on the lower eyelid.
Fig. 28.22  Medium-type congenital pigment cell nevus on the shoulder.

544
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
to grow rapidly and may reach a size of 1 cm within 6 months.
After this rapid initial growth phase it tends to become static,
although color changes may be observed. Bleeding and pru-
ritus are rare. Complete excision and pathologic examination
should be performed.
Nevus spilus (also known as café-au-lait spot)
This is a benign tumor of melanocytes that is characterized
by the increased accumulation of melanin granules rather
than the proliferation of melanocytes (Fig. 28.25). The whole
nevus has a uniform café-au-lait color. The presence of six
or more nevus spilus lesions that are greater than 5 mm
in diameter in prepuberty and over 15 mm in diameter in
postpuberty is indicative of neurofibromatosis type 1 (NF1),
also known as von Recklinghausen’s disease (Fig. 28.26). NF1
is caused by a mutation of the chromosome band 17q11.2,
which encodes neurofibromin. Neurofibromatosis type 2
(NF2) patients rarely have nevus spilus lesions and do not
demonstrate the cutaneous neurofibromas that typically
result in the early diagnosis of NF1, although they may have
cutaneous schwannomas that resemble skin tags. Moreover,
because symptoms from cranial nerve VIII schwannomas
usually begin in the third decade of life, patients with
NF2 are typically diagnosed later in life than patients
with NF1.43
Becker’s melanosis (also known as Becker’s
pigmented hairy nevus)
This lesion is characterized by the slight proliferation of
melanocytes in the basal layer of the epidermis, the increasing
accumulation of melanin granules, and the presence of hair.
It mainly occurs in males and develops at puberty, which
suggests that androgens may play a role in its development.
This is supported by the fact that it is associated with hyper-
trichosis, the occasional development of acneiform lesions
within the patch, and, albeit rarely, with an accessory scrotum
in the genital region. In addition, it has been reported that
Becker melanosis lesional skin has significantly more andro-
gen receptors than the normal surrounding skin. Ruby lasers,
CO2 lasers, and Er:YAG lasers can be used to treat Becker’s
melanosis.44
malignant melanoma but is now suggested to be a type of
acquired pigment cell nevus. Complete excision and patho-
logic examination should be performed. The US National
Institutes of Health Consensus Conference on the diagnosis
and treatment of early melanoma defined the familial atypical
mole and melanoma syndrome,41 the criteria for which are the
occurrence of malignant melanoma in one or more first- or
second-degree relatives, the presence of numerous (often >50)
melanocytic nevi, some of which are clinically atypical, and
the presence of certain histologic features in many of the
associated nevi.
Juvenile melanoma (also known as Spitz nevus)
This is a dome-like nodule that is about 1 cm in diameter and
occurs on the face or legs of young patients (Fig. 28.24).42 The
surface is smooth and sometimes exhibits telangiectasia. It
may be nonpigmented or have a color that ranges from pink
to orange–red. Some lesions are pigmented, especially those
on the lower extremities. After its appearance, the lesion tends
Fig. 28.23  Animal-skin nevus.
Fig. 28.24  Spitz nevus on the cheek.
Fig. 28.25  Solitary nevus spilus on the knee.
Fig. 28.26  Nevus spilus on the thigh of patient with
neurofibromatosis type 1.

545
Benign cutaneous and soft-tissue tumors
Nevus of Ota (also known as nevus fuscoceruleus
ophthalmomaxillaris and oculodermal
melanocytosis)
This is a blue nevus that arises from the first and second
branches of the trigeminal nerve (Fig. 28.27). It is common in
Asians and rare in Caucasians. Women are nearly five times
more likely to be affected than men. It is not congenital but
appears during early infancy and puberty.45 It is caused by the
proliferation of melanocytes in the dermis. Bilateral nevus of
Ota also exists: this is called acquired bilateral nevus of Ota-
like macules or late-onset dermal melanocytosis. It has been
suggested that nevus of Ota may be derived from melanocytes
that have not migrated completely from the neural crest to the
epidermis during embryogenesis. The variable prevalence
among different populations suggests a genetic influence, but
familial cases of nevus of Ota are exceedingly rare. The two
peak ages of onset in early infancy and early adolescence
suggest that hormones are a factor in the development of this
condition. Q-switched ruby or alexandrite lasers have been
used to treat nevus of Ota.46 After 4–8 treatments, the degree
of skin pigmentation is reduced dramatically. Cryotherapy,
dermabrasion, or peeling can also be used as a multimodal
therapy on a case-by-case basis.
Nevus of Ito
This dermal melanocytosis can be considered as a subtype of
nevus of Ota (Fig. 28.28). It occurs on the acromiodeltoid
region.47 Its pathogenesis is unclear, but the fact that the
dermal melanocytes of the nevus of Ito are in close proximity
with nerve bundles suggests the nervous system may be a
factor in its development. Recommended treatments are the
same as those for nevus of Ota.
Mongolian spot (also known as congenital dermal
melanocytosis)
More than 90% of Native American, 80% of Asian, and 70%
of Hispanic infants have this proliferative disorder of dermal
melanocytes, which presents as bluish-gray spots on the sacral
and coccygeal region (Fig. 28.29). Fewer than 10% of Cauca-
sian infants have Mongolian spots. These spots disappear
before the age of 10 years. The blue–gray color is due to the
melanocytes that are deep in the skin. It usually presents as
multiple spots or one large patch covering the lumbosacral
area (lower back), buttocks, flanks, and/or shoulders (Fig.
28.30). It results from the entrapment of melanocytes in the
dermis during their migration from the neural crest to the
epidermis during embryonic development.48 Treatment is
usually not necessary, but Q-switched alexandrite laser can be
used for severe cases.
Blue nevus
Like the nevus of Ota and the Mongolian spot, this is a dermal
melanocytosis. However, it involves more cells, which means
it has a nodular form. There are three types: common, cel-
lular, and combined.49 The cellular lesion is usually larger than
the common lesion and tends to invade the subcutaneous
tissue. The combined lesion is a blue nevus that is combined
with a pigment cell nevus or a juvenile melanoma. A biopsy
should be performed to determine the proper diagnosis. For
a solitary lesion, simple excision is usually curative. There
are rare cases of persistent blue nevi that manifest as satel-
lite lesions around the original excision site. These must be
distinguished from malignant blue nevus and re-excision is
recommended.
Fig. 28.27  Nevus of Ota.
Fig. 28.28  Nevus of Ito.

546
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
Neurofibroma
A neurofibroma is a benign tumor of the peripheral nerve
sheath. It is usually found in individuals with the genetically
inherited diseases NF1 and NF2, and can result in symptoms
that range from physical disfiguration and pain to cognitive
disability (Figs. 28.32 & 28.33). Neurofibromas arise from
Schwann cells but also incorporate many other types of cells
and structural elements, which makes it difficult to identify
and understand all the pathogenic mechanisms. Neurofibro-
mas should be removed surgically or treated with a CO2 laser.
However, once a plexiform neurofibroma52 has undergone
malignant transformation, radiation and chemotherapy can
be used as adjuvant therapies.
Others
Other benign neural crest-origin tumors include the granular
cell tumor and rudimentary polydactyly. The latter often have
normal Merkel cells in the basal portion of the epidermis in
addition to the proliferation of nerve fibers and encapsulated
corpuscles. The proliferation of various neural components
may be the essential feature of this condition.
Neuroma
Neuromas are hamartomas composed of peripheral nerve
components, namely Schwann cells, fibroblasts, and axons;
they arise as a result of ineffective, unregulated nerve
regeneration that leads to neurofiber hyperplasia. They are
often the result of nerve injury, especially injuries sustained
during surgery; both superficial (skin or subcutaneous fat)
and deep (e.g., cholecystectomy) surgery can induce neuro-
mas. Neuromas are often very painful. It should be noted
that neuroma is often used as a general term to describe
any swelling of a nerve; thus, it does not necessarily mean
neoplastic tumors. An example of this more general usage
of the term is Morton’s neuroma, which is a mononeu-
ropathy of the foot; to avoid confusing it with a tumor,
this condition is now often referred to as Morton’s meta-
tarsalgia.50 Surgical removal is the treatment of choice for
neuromas.
Schwannoma (also known as neurilemmoma)
This is a benign proliferation of Schwann cells in the dermis
or subcutaneous tissues (Fig. 28.31). NF2 is associated with
multiple schwannomas. Pathology shows that there are two
basic histological types of schwannoma called Antoni types A
and B. Type A is characterized by numerous Verocay bodies.
These are acellular, eosinophilic areas that are oval, linear, or
serpiginous in shape and are surrounded by parallel-lying or
palisading bundles of spindled Schwann cells with blunt,
elongated nuclei. In each Verocay body, the long axes of the
cells are all oriented toward the acellular area. Type B lacks
Verocay bodies and consists of a loose, myxomatous stroma
with fewer and more randomly arranged spindle cells. Neither
type appears to have neurites. Schwannomas are typically
encapsulated and the associated peripheral nerve may be
seen in the microscopic section. Occasionally, older lesions
show degenerative changes such as hemorrhage, hemosiderin
deposition, mild chronic inflammatory cell infiltration, dense
fibrosis, and nuclear pleomorphism. Such ancient schwanno-
mas51 are benign but must be differentiated from neurofibro-
sarcoma and malignant schwannoma. Surgical removal is the
first choice of treatment.
Fig. 28.29  Typical Mongolian spot on an Asian infant.
Fig. 28.30  Atypical Mongolian spot on the back.
Fig. 28.31  Schwannoma on the popliteal region.
Fig. 28.32  Mild neurofibroma on a patient with neurofibromatosis type 1.

547
Benign cutaneous and soft-tissue tumors
dermatofibroma, aneurysmal dermatofibroma, myxoid der-
matofibroma, and keloidal dermatofibroma.53 Removal of the
tumor is not necessary unless diagnostic uncertainty exists or
particularly troubling symptoms are present.
Xanthoma
Xanthoma is characterized by the aggregation of foamy his-
tiocytes that have phagocytized lipids (Fig. 28.35). The most
common xanthoma occurs on the upper eyelid and is often
associated with hyperlipidemia. Xanthomas are not always
associated with underlying hyperlipidemia but when they
are, it is necessary to diagnose and treat the underlying lipid
disorders to decrease the xanthoma size and reduce the risk
of atherosclerosis. Treatment of the hyperlipidemia initially
entails dietary changes and the use of lipid-lowering agents
such as statins, fibrates, bile acid-binding resins, probucol, or
nicotinic acid. Eruptive xanthomas usually resolve within
weeks of initiating systemic treatment, while tuberous
xanthomas usually resolve after a few months. However,
tendinous xanthomas take years to resolve or may persist
indefinitely. While the main goal of therapy for hyperlipid-
emia is to reduce the risk of atherosclerotic cardiovascular
disease, in patients with severe hypertriglyceridemia the goal
is to prevent pancreatitis. Surgery or locally destructive
modalities, including lasers, can be used for idiopathic or
unresponsive xanthomas.54
Juvenile xanthogranuloma
This is a single or multiple dome-like tumor that occurs on
the head and neck region, the body, or the limbs of young
patients. Approximately 35% of cases of juvenile xanthogranu-
loma occur at birth, with as many as 70% of cases occurring
in the first year. Most juvenile xanthogranulomas resolve by
the age of 5 years. Despite the term “juvenile” in the disease
name, 10% of cases manifest in adulthood (Fig. 28.36). Histo-
logic analysis can reveal the presence of Touton giant cells
(Fig. 28.37). This tumor can be associated with NF1, Niemann–
Pick disease, urticaria pigmentosa, and juvenile chronic
myelomonocytic leukemia.55 The lesions can be excised for
diagnostic and cosmetic reasons.
Benign mesenchymal-origin tumors
Dermatofibroma (also known as fibrous
histiocytoma)
Dermatofibroma is a common cutaneous nodule that fre-
quently develops on the extremities (mostly the lower legs).
It is usually asymptomatic, although pruritus and tenderness
are not uncommon. It is characterized by the proliferation in
the dermis of both fibroblasts and other cell types, including
histiocytes (skin macrophages) and vascular endothelial cells.
It can be divided into the cellular type, which is mainly charac-
terized by histiocyte proliferation, and the fibrous type, which
predominantly shows fibroblast proliferation. Strong endo-
thelial cell proliferation can sometimes be observed in both
types, in which case a diagnosis of sclerosing hemangioma
is made (Fig. 28.34). Moreover, if the cellular components are
small and the tumor is composed of hyalinized collagenous
fibers, it can be called a sclerotic fibroma. There are many
other special dermatofibroma forms, including hemosider­
otic histiocytoma, xanthomatous histiocytoma, atypical
Fig. 28.33  Severe neurofibroma on a patient with neurofibromatosis type 1.
Fig. 28.34  Sclerosing hemangioma.
Fig. 28.35  Xanthoma on the upper eyelid.
Fig. 28.36  An adult-onset juvenile xanthogranuloma
on the elbow.

548
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
28.41) remains difficult; indeed, it is possible that they are
manifestations of a fibroproliferative disorder of the skin58 that
expresses a continuum of features. Nevertheless, for simplicity
in clinical situations, the terms “hypertrophic scars” and
“keloids” can still be used: hypertrophic scars are considered
to be those that improve naturally and gradually, although the
full maturation process may take up to 2–5 years, whereas
keloids are considered to be those that rarely resolve naturally.
To prevent the development of these scars and to treat them,
multimodal therapy21 that includes steroid ointment/tape/
injection, taping fixation, silicone gel sheeting, surgery, radia-
tion,59 cryotherapy, laser, and 5-FU is recommended.
Lipoma
Lipoma is the most common of the mesenchymal soft-tissue
tumors (Figs. 28.42 & 28.43). There are many subtypes,
Fig. 28.37  Touton giant cell in a juvenile
xanthogranuloma.
Fig. 28.38  Acrochordon.
Fig. 28.39  Fibroma pendulum.
Soft fibroma
There are three types of soft fibroma: (1) acrochordon (also
known as a skin tag) (Fig. 28.38), which occurs on the neck and
axilla and increases after middle age; (2) fibroma pendulum56
(Fig. 28.39), which is a large fibroma over 10 mm in diameter
that has a narrow pedicle; and (3) any but (1) and (2). The color
can vary between normal skin color and brownish-red. Small,
pedunculated soft fibromas can be removed with curved or
serrated blade scissors, while larger skin tags may simply
require excision. For small, soft fibromas, aluminum chloride
applied prior to removal will decrease the amount of bleeding,
which is usually minor anyway. Anesthesia prior to electro-
desiccation is another option. Other methods of removal
include cryotherapy and ligation with a suture or a copper
wire; however, freezing of the surrounding skin during liquid
nitrogen cryotherapy may result in dyschromic lesions. Taking
hold of the acrochordon with forceps and applying cryotherapy
to the forceps may provide superior results.
Keloid and hypertrophic scars
These scars are caused by the hyperproduction of collagen due
to abnormal and prolonged cutaneous wound healing. It has
been suggested that mechanical forces such as skin-stretching
tension and mechanotransduction signaling pathways are
associated with their generation and growth.57 The differential
diagnosis of keloids (Fig. 28.40) and hypertrophic scars (Fig.
Fig. 28.40  Typical keloids on the anterior chest of an Asian patient.
Fig. 28.41  Typical hypertrophic scars on the thigh of an Asian patient.

549
Benign cutaneous and soft-tissue tumors
lipomatosis60 mainly occurs on the upper body (Fig. 28.45).
Steroid-induced lipomatosis can be a side effect of corticoste-
roid administration. A rapidly growing lipoma should be
examined carefully to eliminate the possibility that it is
actually a liposarcoma. Complete surgical excision with the
capsule is advocated to prevent local recurrence.
Leiomyoma
Cutaneous or subcutaneous leiomyoma is a tumor that is
derived from smooth muscles in the skin, including the arrec-
tor muscle of hair and vascular smooth muscle.61 These tumors
are localized and are associated with pain. Leiomyomas can
be categorized into four types: (1) multiple piloleiomyoma;
(2) solitary piloleiomyoma; (3) angioleiomyoma; and (4)
genital leiomyoma. Angioleiomyomas and genital leiomyo-
mas usually occur as solitary lesions. In contrast, piloleiomyo-
mas may be solitary or multiple; in the latter case, there may
be thousands of lesions. This is because the arrector pili
muscle from which piloleiomyomas originate has multiple
points of insertion, such as those located proximal to the hair
follicle, those located distal to the multiple attachment points
within the papillary and reticular dermis, and those located
in the basement membrane. Piloleiomyomas can emerge from
each of these insertion points, thus occurring as multiple
including lipoblastoma, angiolipoma, spindle cell lipoma,
pleomorphic lipoma, and hibernoma. It was shown recently
that these adipocellular tumors are characterized by specific
chromosome and gene abnormalities and that these abnor-
malities can be used for diagnosis. Lipomas can be classified
according to their location into entities such as intramuscular
and intermuscular lipoma. Systemic lipoma is termed lipoma-
tosis (Fig. 28.44). Diffuse lipomatosis sometimes affects the
limbs, head and neck, and intestinal tract. Lipomatosis
on the finger results in megadactyly. Multiple symmetric
Fig. 28.42  Lipoma on the nape (A) and
the lesion after excision (B).
A
B
Fig. 28.43  Lipoma on the face.
Fig. 28.44  Multiple lipomatosis (A) and
the lesions after excision (B).
A
B

550
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
Fig. 28.45  Multiple symmetric lipomatosis.
tumors. Angioleiomyoma often occurs on the distal area of
the limbs, especially under the knee in women. In contrast,
angiolipoma commonly occurs on the head in men and is
often not associated with pain. Surgical excision or ablation
of the leiomyoma may be helpful for some symptomatic
individuals.
Rhabdomyoma
Rhabdomyoma is a benign tumor of striated muscle. It is
most commonly associated with the heart and tongue but
can also occasionally occur as a superficial mesenchymal
tumor. There are adult, fetal, and genital types. The adult-
onset type often occurs on the head and neck area, whereas
the fetal type often occurs on the postauricular area of children
under the age of 3 years. Patients with adult rhabdomyoma
should have surgical resection of head and neck lesions,
especially those lesions that compress or displace the tongue,
or protrude and partially obstruct the pharynx or larynx. Fetal
rhabdomyomas are usually located in the subcutaneous
tissues.62 In most instances, they can be excised without much
difficulty. Local excision is the treatment of choice for genital
rhabdomyomas.
Osteochondrogenic tumors
Chondromas and osteochondromas often occur in adults on
the hand and foot. Osteochondromas are sometimes associ-
ated with calcification. Osteomas are composed of mature
bone but can be considered to be reactive outgrowths. Osteoma
cutis63 refers to the presence of bone within the skin in the
absence of a pre-existing or associated lesion, as opposed to
secondary types of cutaneous ossification that are the result
of metaplastic reactions to inflammation, trauma, and neo-
plastic processes. Osteoma cutis can be removed by excision
or laser resurfacing that ablates the overlying skin. Myositis
ossificans, panniculitis ossificans, and fibrodysplasia ossifi-
cans progressiva are also reactive ossifications. Exostosis is
also considered to be a reactive osteochondrogenic disorder
(Fig. 28.46). This often occurs on the cranial and subungual
regions. Exostosis can be removed easily by a chisel and
hammer, and its recurrence is rare.
Accessory auricle (also known as nevus
cartilagines)
This congenital nevus arises from the area between the tragus
and the lateral neck (Fig. 28.47). Nevi that are near the ear are
largely composed of cartilage, while nevi that are distant from
the ear are mainly composed of hair follicles. Multiple acces-
sory auricles64 are sometimes associated with hemifacial
microsomia. Surgical removal may be possible. If so, sufficient
skin and cartilage should be removed so that flat and linear
scars are the result rather than a dog-ear deformity.
Granuloma
Granulomas can be broadly classified as infectious (Fig. 28.48)
and noninfectious. Almost all noninfectious granulomas are
foreign-body granulomas; some of these are associated with
a type IV allergy. There are a number of causes of foreign-
body granuloma. These can be divided into endogenous
causes such as uric acid salt, cholesterol, and sebum produc-
tion, and exogenous causes such as materials injected for
aesthetic surgery65 (Fig. 28.49), vaccines, surgical sutures, and
materials implanted by trauma (Fig. 28.50). Small pyogenic
granulomas (telangiectatic granulomas) and foreign-body
granulomas can be removed by surgery, but this may not be
possible for large and multiple granulomas. In this case, sys-
temic or local corticosteroid administration to reduce inflam-
mation should be considered.
Fig. 28.46  Exostosis on the frontal bone
(A) and the excised specimen (B).
A
B

551
Benign cutaneous and soft-tissue tumors
Glomus tumor
Glomus tumors arise from the arterial portion of the glomus
body, or the Sucquet–Hoyer canal, which is an arteriovenous
anastomosis in the dermis that participates in temperature
regulation. Patients with solitary glomus tumors usually have
paroxysmal pain that can be severe and exacerbated by pres-
sure or temperature changes, especially cold. Multiple glomus
tumors can also be painful but are less common; the pain is
also usually not severe. Two features that are useful for diag-
nosing glomus tumors, particularly solitary painful glomus
tumors (especially those under a nail), are the Hildreth sign,
which is the disappearance of pain after a tourniquet is placed
on the proximal arm, and the Love test, where pain is elicited
by pressing the skin overlying the tumor with the tip of a
pencil. The treatment of choice for solitary glomus tumors is
surgical excision. For multiple glomus tumors,66 excision may
be more difficult because of their poor circumscription and
the large number of lesions. In this case, excision should be
limited to symptomatic lesions.
Capillary malformation
Hemangioma simplex
This is the result of the abnormal development or differentia-
tion of capillary vessels in the dermis.67 According to its
location, it can be classified into three types: (1) portwine stain
Fig. 28.47  Accessory auricle.
(face, limbs, and upper body) (Figs. 28.51 & 28.52); (2) salmon
patch (medial forehead, glabella, nasal tip, and upper lip);
and (3) nevus Unna (nape). Portwine stains are sometimes
associated with Sturge–Weber syndrome (face) and Klippel–
Trenaunay syndrome (limb). Patients with solitary hemangi-
oma simplex, regardless of whether they have these syndromes,
should be subjected to brain examinations. Of the three types,
only the salmon patch can disappear within a year after birth.
A dye laser or Nd:YAG laser can be used to treat these lesions.
Strawberry hemangioma
This tumor is derived from the endothelial cells of capillary
vessels in the skin. It arises around 3–4 weeks after birth and
its growth peaks at 6–7 months of age (Figs. 28.53 & 28.54).
After this growth period, the volume rarely decreases natu-
rally, although the color can become less livid spontaneously.
Consequently, laser treatments with, for example, dye or
Nd:YAG lasers should be performed at an early stage to
prevent the capillaries from proliferating further.68 On a case-
by-case basis, surgical excision, steroid injection, and com-
pression therapy may also be suitable.
Venous malformation
A representative type of venous malformation is a cavernous
hemangioma, which is a blood-storing lesion with a low
blood flow (Fig. 28.55). Histology shows the absence of
Fig. 28.49  Foreign-body granuloma caused by a
nasal implant.
Fig. 28.48  Pyogenic granuloma on the back.
Fig. 28.50  Foreign-body granuloma
caused by the implantation of a large wood
splinter (A) and view of the patient just
after surgery (B).
A
B

552
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
Fig. 28.51  Portwine stain on the face of an infant.
Fig. 28.52  Portwine stain on the face of an adult.
Fig. 28.53  Strawberry hemangioma on the frontal
head of an infant.
Fig. 28.54  Strawberry hemangioma on the trunk.
Fig. 28.55  Cavernous hemangioma on the lower lip.
endothelial cell proliferation. It is seen in Klippel–Trenaunay
syndrome, which is characterized by various malformations,
including capillary malformation and bony and soft-tissue
hypertrophy. Venous malformation is best treated with scle-
rosing therapy, where sclerosing agents like absolute ethanol,
polidocanol, sodium tetradecyl sulfate, or ethanolamine
oleate are injected into the lesion under ultrasound or digital
subtraction angiography guidance.69
Arteriovenous fistula and arteriovenous
malformation (AVM)
Arteriovenous fistula and AVM are high-flow pulsating
lesions with an arteriovenous shunt; they are either acquired
because of trauma or are congenital (Fig. 28.56). CDI is useful
for detecting the blood flow in the tumor. Patients with
Parkes–Weber syndrome who have a huge limb AVM some-
times exhibit congestive heart failure. The Schobinger classi-
fication allows AVMs to be classified into four clinical stages:
(I) quiescence; (II) expansion; (III) destruction; and (IV)
decompensation. Patients with heart failure are considered to
have stage IV AVMs. Surgical removal is the first choice of
treatment but is often hampered by the diffuse distribution of
the vessels and the specific anatomy in the affected region
(e.g., the local presence of a facial nerve). Incomplete resection
results in the rapid regrowth of the remaining lesion. In cases
where surgical removal is difficult, embolosclerosing therapy
can be used as a palliative therapy.70
Lymphatic malformation
There are two main types of lymphatic malformation:
lymphangioma and cystic hygroma. Clinically, lymphatic
malformation can be classified into macrocyst (cystic hygroma
and lymphangioma cystoides), microcyst (lymphangioma
simplex), and combined (lymphangioma cavenous) types.
The microcysts can be removed surgically, while the mac-
rocysts and combined types should be treated by surgery
or sclerotherapy using OK-43271 or absolute ethanol on a
case-by-case basis.

553
Malignant cutaneous and soft-tissue tumors
hyperkeratotic actinic keratosis. Surgical removal is recom-
mended but cryosurgery, CO2 lasers, 5-FU ointment, and
chemical peeling may also be useful for selected cases.
Bowen’s disease
Bowen’s disease is an intraepidermal carcinoma since it is a
malignant tumor of keratinocytes. It can progress to invasive
SCC. If the invasion is deep, it is termed Bowen’s carcinoma;
this carcinoma can metastasize. The diagnosis of Bowen’s
disease is often delayed because the lesion is asymptomatic
and early skin changes may be subtle and overlap with the
clinical features of many conditions, including tinea corporis,
nummular eczema, seborrheic keratosis, Paget’s disease,
superficial BCC, actinic keratosis, and psoriasis. A classic
feature of the clinical history is the presentation of a
nonsteroid-responsive dermatosis. Surgical removal is recom-
mended but cryosurgery, CO2 lasers, 5-FU ointment, and
imiquimod 5% cream73 may also be suitable for selected cases.
Squamous cell carcinoma
SCC is a common cutaneous malignancy that often presents
as an elevated, indurated lesion with varying degrees of
ulceration and crusting (Fig. 28.59). SCC can arise on any site
but is most common in damaged skin such as actinically
damaged skin, postburn scars (Marjolin’s ulcer), traumatic
Others
There are many other benign mesenchymal-origin tumors.
These include giant cell tumor, histiocystoma, reticulohistiocy-
toma, fibroxanthoma, desmoid tumor, mucous cyst of the oral
mucosa (Fig. 28.57), cutaneous myxoma, Langerhans cell his-
tiocytosis, Kimura disease, plasmacytosis, and mastocytosis.
Malignant cutaneous and soft-tissue
tumors
Malignant epithelial-origin tumors
Actinic keratosis
Actinic keratosis is an intraepidermal early-stage SCC caused
by long-term exposure to ultraviolet light (Fig. 28.58). It is
mostly seen in the elderly, especially fair-skinned people who
have been highly exposed to the sun. The areas that bear the
lesions are those that have been most exposed. Over time,
actinic keratoses develop into invasive SCC. They are epider-
mal lesions that are characterized by aggregates of atypical,
pleomorphic keratinocytes at the basal layer that may extend
upwards to involve the granular and cornified layers.
Cutaneous horns72 sometimes occur in association with a
Fig. 28.56  Congenital mild arteriovenous malformation on the forearm.
Fig. 28.58  Actinic keratosis on the cheek of an elderly patient.
Fig. 28.57  Mucous cyst of the oral mucosa.
Fig. 28.59  Squamous cell carcinoma on the cheek of an elderly patient.

554
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
because it can invade surrounding tissues and cause signifi-
cant destruction and disfigurement. It most commonly affects
the head and neck, and cosmetic disfigurement is not uncom-
mon. It can be classified into 10 types75 (Box 28.5). It should
be removed by surgery. Mohs micrographic surgery is fre-
quently utilized. However, for selected cases of superficial
BCC, CO2 lasers or cryosurgery can be used.
Malignant appendage-origin tumors
Sebaceous carcinoma
Meibomian gland carcinoma (Fig. 28.63), Zeis gland carci-
noma, and Montgomery’s gland carcinoma are all sebaceous
carcinomas. These carcinomas often exhibit erosion and
ulceration. A wide excision with a normal skin margin exceed-
ing 5 mm is recommended. Lymph node dissection should be
considered in T4 cases because of the high rate of lymph node
metastasis associated with sebaceous carcinomas. Chemo-
therapy and radiation therapy may also be useful.76
Trichilemmal carcinoma
The outer hair root sheath consists of cells with clear vacuo-
lated cytoplasm due to the presence of abundant glycogen.
Trichilemmal carcinomas are malignant tumors of these cells.
They include malignant trichilemmoma, malignant pilomatri-
coma, and malignant proliferating trichilemmal cyst (Fig.
28.64). The latter is thought to be derived from proliferating
trichilemmal cyst,32 while malignant pilomatricoma is believed
to be derived from pilomatricoma. Clinically, these tumors
present as pale tan or reddish papules, indurated plaques, or
nodules. Wide excision should be performed as a radical
therapy.
Sweat gland carcinoma
There are many types of eccrine and apocrine carcinomas.
These malignant primary cutaneous tumors exhibit glandular
and/or ductal features that are thought to reflect their origin
scars (Fig. 28.60), stasis ulcers, chronic radiation dermatitis,
lupus erythematosus lesions, lichen planus on the oral mucosa,
and human papillomavirus infection lesions. One type of SCC
is verrucous carcinoma. Since SCC can resemble BCC, it is
important to make a differential diagnosis. One notable char-
acteristic of SCC is the bad smell caused by the macerated
keratin and bacterially infected necrotic tissues (Fig. 28.61).
SCC should be removed by surgery. Mohs micrographic
surgery74 is frequently used to remove SCCs. Radiotherapy
given as external-beam radiotherapy or as brachytherapy
(internal radiotherapy) can also be used.
Basal cell carcinoma
BCC is the most common type of skin cancer (Fig. 28.62). It
rarely metastasizes and kills, but is still considered malignant
Fig. 28.60  Squamous cell carcinoma on the sole
that has arisen from traumatic scars.
Fig. 28.61  Advanced squamous cell carcinoma on
the face that shows necrosis and infection.
Fig. 28.62  Basal cell carcinoma on the scalp.
BOX 28.5 Histological classification of basal cell carcinoma (BCC)
1. Multifocal superficial BCC (superficial multicentric)
2. Nodular BCC (solid, adenoid cystic)
3. Infiltrating BCC
3.1. Nonsclerosing
3.2. Sclerosing (desmoplastic, morpheic)
4. Fibroepithelial BCC
5. BCC with adnexal differentiation
5.1. BCC with follicular differentiation
5.2. BCC with eccrine differentiation
6. Basosquamous carcinoma
7. Keratotic BCC
8. Pigmented BCC
9. BCC in basal cell nevus syndrome
10. Micronodular BCC
(Reproduced from LeBoit PE, Burg G, Weedon D, et al (eds). World Health
Organization Classification of Tumors. Pathology and Genetics of Skin Tumors.
Lyon: IARC Press; 2006:10–33.)

555
Malignant cutaneous and soft-tissue tumors
excision (Fig. 28.65). Sentinel lymph node biopsy is also useful
for deciding whether to remove the lymph nodes.
Merkel cell carcinoma
Merkel cell carcinoma is a rare and highly aggressive cancer
where malignant cancer cells develop on or just beneath the
skin and in hair follicles (Fig. 28.66). The majority of Merkel
cell carcinomas appear to be caused by the newly discovered
Merkel cell polyomavirus. It occurs most often on the face,
head, and neck, and usually appears as firm and painless
nodules or tumors. A normal skin margin of 1–2 cm is needed
for wide excision. Moreover, since this tumor tends to metas-
tasize to lymph nodes, lymph node dissection and adjuvant
radiation therapy may have to be implemented.79 Distant
metastasis cases should also receive chemotherapy.79
Malignant mesenchymal-origin tumors
Dermatofibrosarcoma protuberans (DFSP)
DFSP is also called giant cell fibroblastoma. Over 90% of DFSP
tumors have the chromosomal translocation t(17;22) that
fuses the collagen gene COL1A1 with the platelet-derived
growth factor gene. Typically, DFSP occurs as multiple or
solitary tumors that have a red color, hemispherical elevation,
and papillary vessels on the surface (Fig. 28.67). They have
a keloidal appearance, which has sometimes led to
as eccrine or apocrine ducts and/or glands. The diagnosis of
sweat gland carcinoma requires that the tumor shows sweat
gland features, as shown by extracellular ductal or intracyto-
plasmic lumen formation. This can be indicated by resistance
to diastase, staining with periodic acid–Schiff stain, and
immunohistochemical positivity for epithelial membrane
antigen and carcinoembryonic antigen. The presence of S100
protein may also indicate sweat gland differentiation. Con-
ventional surgical excision has been associated with high
recurrence rates but Mohs micrographic surgery is helpful.77
These carcinomas should be treated according to the guide-
lines for SCC.
Extramammary Paget’s disease
Paget’s disease is an adenocarcinoma that is limited to the
epidermis. Since mammary Paget’s disease is sometimes
associated with invasive breast cancer, it can be considered as
an intraepidermal proliferating breast carcinoma. In contrast,
EMPD is only occasionally associated with an underlying
invasive malignancy. It is usually found in the vulva, penis,
and axilla. Since its invasive speed is relatively high, it can be
difficult to detect early, especially if the lesion has been treated
as eczema. Mohs micrographic surgery78 or mapping biopsy
is helpful for determining the normal skin margin for wide
Fig. 28.63  Meibomian gland carcinoma on the upper eyelid.
Fig. 28.64  Malignant trichilemmal cyst.
Fig. 28.65  Mapping biopsy for extramammary Paget’s
disease.
Fig. 28.66  Merkel cell carcinoma on the eyelid.
Fig. 28.67  Dermatofibrosarcoma protuberans on the
abdomen.

556
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
Leiomyosarcoma
This rare malignancy mainly occurs on the limbs of middle-
aged and older patients (Fig. 28.70). It can be very unpredict-
able as it can remain dormant for long periods of time and
recur after years. It is generally not very responsive to chemo-
therapy or radiation. However, neoadjuvant or adjuvant
chemotherapies,84 or radiation, are recommended.
Rhabdomyosarcoma
Rhabdomyosarcoma is thought to arise from skeletal
muscle progenitors and occurs in many anatomic locations.
misdiagnosis and treatment with corticosteroids. They metas-
tasize rarely, but distant metastasis to the lung can result from
local recurrence. Radical resection should include a normal
skin margin of 5 cm. Mohs micrographic surgery with con-
tinuous histological margin control is needed to reduce local
recurrence rates.80 Adjuvant chemotherapy and radiation
therapy may be useful.
Pleomorphic undifferentiated sarcoma (PUS)
There are four types of malignant fibrous histiocytoma
(which is more recently being classified as pleomorphic
undifferentiated sarcoma81): (1) storiform-pleomorphic type;
(2) myxoid type; (3) giant cell type; and (4) inflammatory
type. Moreover, atypical fibroxanthoma is considered to be a
superficial type (Fig. 28.68). Despite being called histiocyto-
mas, these tumors are not believed to be derived from histio-
cytes. In fact, it is currently being argued on the basis of
immunohistochemistry and electron microscopic observa-
tions82 that most of the storiform-pleomorphic type should
be reclassified as liposarcomas, leiomyosarcomas, or rhabdo-
myosarcomas. Radical therapy involving wide excision is
needed. Adjuvant chemotherapy and radiation therapy may
also be useful.
Liposarcoma
Liposarcoma is derived from the fat cells in deep soft tissues
such inside the thigh or the retroperitoneum (Fig. 28.69). They
are generally large and bulky tumors with multiple smaller
satellites located outside the main tumor. Diagnosis requires
the detection of lipoblasts, which usually have an abundant,
clear, multivacuolated cytoplasm and an acentric, darkly
staining, vacuole-compressed nucleus. Dedifferentiated lipo-
sarcomas exhibit a dedifferentiated area in the tumor that
sometimes results in osseous metaplasia.83 Radical therapy
involving wide excision is needed. Adjuvant chemotherapy
and radiation therapy may be useful.
Fig. 28.68  Malignant fibrous histiocytoma on the axilla.
Fig. 28.69  Liposarcoma on the thigh.
Fig. 28.70  Leiomyosarcoma on the face.

557
Malignant cutaneous and soft-tissue tumors
lymphangiosarcoma and hemangiosarcoma when more clini-
cal precision is required. Haemangiosarcomas and lymphan-
giosarcomas of the skin are not uncommon. Given the location
of angiosarcomas, metastasis to distant sites occurs often.
Surgery, radiation therapy, chemotherapy, and immunother-
apy using interleukin-288 should be used, but the prognosis of
these tumors is poor. However, the prognosis of neoplasia of
superficial vessel tissues such as those in the skin is generally
better because the risk of malignancy is lower; moreover,
these tumors are generally more accessible to treatment.
Kaposi’s sarcoma
Kaposi’s sarcoma is caused by the Kaposi’s sarcoma-associated
herpesvirus (KSHV), also known as human herpesvirus 8. It
became widely known after its frequent appearance in acquired
immune deficiency syndrome patients was noted in the 1980s.
Although the viral cause of this cancer was discovered in 1994,
this causal link remains poorly understood by the general
populace, including by the groups that are at particular risk of
contracting KSHV. Kaposi’s sarcoma lesions present as red,
purple, brown, or black nodules or blotches that are usually
papular (i.e., palpable or raised). They are typically found on
the skin but can often spread elsewhere, especially to the
mouth, gastrointestinal tract, and respiratory tract. Their
growth can range from very slow to explosively fast, and they
are associated with significant mortality and morbidity. Radia-
tion therapy, cryotherapy, and chemotherapy may be useful.
Surgery is not the primary choice of treatment, although it may
be useful as supportive therapy. Highly active antiretroviral
therapy should be combined with these therapies.89
Others
Other malignant mesenchymal-origin tumors include epithe-
lioid sarcoma, synovial sarcoma, extraskeletal Ewing’s
sarcoma, histiocytic sarcoma, and Langerhans cell sarcoma. In
general, treatment consists of induction chemotherapy, wide
surgical excision, and then maintenance chemotherapy. Multi-
agent chemotherapy has improved survival rates.
Sometimes it is found attached to muscle tissue or wrapped
around intestines. Mostly it occurs in areas that naturally lack
skeletal muscle, such as the head, neck, and genitourinary
tract. Its three most common forms are embryonal rhabdo-
myosarcoma, alveolar rhabdomyosarcoma, and pleomorphic
rhabdomyosarcoma. Embryonal rhabdomyosarcoma is more
common in younger children, where the cancer cells resemble
those of a typical 6–8-week embryo. Alveolar rhabdomyosar-
coma occurs more commonly in older children and teenagers,
and the cells resemble those of a typical 10–12-week embryo.
Pleomorphic rhabdomyosarcoma is a rare sarcoma that occurs
most often in older patients. Radical therapy involving wide
excision is needed. There is also evidence that rhabdomyosar-
comas are the target of host immune responses.85
Osteosarcoma
This aggressive cancerous neoplasm arises from primitive
transformed cells of mesenchymal origin that exhibit osteo-
blastic differentiation and produce malignant osteoids (Fig.
28.71). Complete radical surgical en bloc resection is the treat-
ment of choice.86 Some recent studies have suggested that
osteoclast inhibitors such as alendronate and pamidronate
may improve the quality of life by reducing osteolysis, which
decreases the pain as well as the risk of pathological fractures.
Chondrosarcoma
At presentation, nearly all chondrosarcoma patients appear to
be in good health as this form of cancer usually does not affect
the whole body. Indeed, the patients are generally not aware
of the growing tumor until there is a noticeable lump or pain.
An earlier diagnosis is generally accidental, such as when a
patient undergoes testing for another problem. Occasionally,
the first symptom will be a broken bone at the cancerous site.
Therefore, broken bones due to mild trauma warrant further
investigation, even though there are many conditions that can
lead to weak bones and this form of cancer is not a common
cause of such breaks. Chemotherapy or traditional radio-
therapy is not very effective for most chondrosarcomas,
although proton beam radiation therapy is showing promise
with regard to local tumor control.87 Complete surgical abla-
tion is the most effective treatment but can be difficult to
achieve. Proton beam radiation can facilitate the surgical
removal of chondrosarcomas in awkward locations.
Angiosarcoma
Angiosarcoma is the common name for malignant neoplasms
of endothelial cells (Fig. 28.72) but it is replaced with the terms
Fig. 28.71  Computed tomography of an osteosarcoma on the frontal bone.
Fig. 28.72  Angiosarcoma on the axilla.

558
CHAPTER 28 • Benign and malignant nonmelanocytic tumors of the skin and soft tissue
2. Jemec GB, Gniadecka M, Ulrich J. Ultrasound in dermatology. Part
I. High frequency ultrasound. Eur J Dermatol. 2000;10:492–497. Basic
ultrasound terminology and mechanics are discussed. A discussion of
applications of this technology to dermatologic diagnosis is offered.
3. Blumer SL, Scalcione LR, Ring BN, et al. Cutaneous and
subcutaneous imaging on FDG-PET: benign and malignant
findings. Clin Nucl Med. 2009;34:675–683. This atlas-style article
describes the appearance of cutaneous and subcutaneous lesions on
FDG-PET. The authors stress that, with clinical correlation, FDG-PET
can be a useful diagnostic adjunct for these lesions.
5. Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM Classification
of Malignant Tumours (UICC: International Union Against Cancer). 7th
ed. Chichester: Wiley-Blackwell; 2009.
6. Wittekind CF, Greene FL, Hutter RVP, et al. TNM Atlas: Illustrated
Guide to the TNM/pTNM Classification of Malignant Tumours. 5th ed.
Berlin: Springer; 2004.
10. Tierney EP, Hanke CW. Cost effectiveness of Mohs micrographic
surgery: review of the literature. J Drugs Dermatol. 2009;8:914–922.
This review compares the efficacy of Mohs micrographic surgery (MMS)
to alternative treatment modalities for nonmelanoma skin cancer in terms
of cost, initial cure rate, and recurrence rate. The authors conclude that
MMS is superior in terms of these metrics.
11. Erba P, Ogawa R, Vyas R, et al. The reconstructive matrix – a
new paradigm in reconstructive plastic surgery. Plast Reconstr Surg.
2010;126:492–498. The “reconstructive ladder” is a classic paradigm in
which the simplest effective treatment modality for a given defect is
identified as the most appropriate. The authors offer the “reconstructive
matrix” as a new treatment model that accounts for socioeconomic issues
as well as evolving medical knowledge and technology in determining the
optimal reconstructive option for a given patient and defect.
12. Bath FJ, Bong J, Perkins W, et al. Interventions for basal cell
carcinoma of the skin. Cochrane Database Syst Rev.
2003;(2):CD003412.
21. Ogawa R. The most current algorithms for the treatment and
prevention of hypertrophic scars and keloids. Plast Reconstr Surg.
2010;125:557–568. The author presents an algorithm for the treatment of
hypertrophic scars and keloids based on a review of the literature.
Differential diagnosis and prevention are also addressed.
41. The US National Institutes of Health Consensus Conference on the
diagnosis and treatment of early melanoma. consensus.nih.gov/1992/1992Melanoma088html.htm>.
Access the complete reference list online at

558.e1
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29 
Melanoma
Stephan Ariyan and Aaron Berger
SYNOPSIS
■ The definitive diagnosis of melanoma is based on histologic analysis.
Clinical features suggestive of malignancy include: asymmetry, border
irregularity, color changes, diameter >
14 inch, and evolving changes;
the ABCDE criteria.
■ The four major histopathologic subtypes of melanoma are: lentigo
maligna, superficial spreading, nodular, and acral lentiginous.
Desmoplastic melanoma is a less common subtype of melanoma that
lacks pigment and may demonstrate perineural invasion.
■ Initial work up of the pigmented lesion should include excisional biopsy
with a 1–2-mm margin of normal-appearing skin. If functional or
cosmetic concerns prohibit removal of the entire lesion, incisional or
punch biopsy may be performed.
■ Histologic evaluation of the primary lesion must include: Breslow depth
in millimeters, presence/absence of ulceration, mitotic rate per mm2,
peripheral and deep margin status, and Clark level (especially for
lesions ≤1 mm in depth).
■ Recommended excision margins are determined by Breslow depth. In
situ melanoma requires a 0.5-cm margin of normal-appearing skin. For
invasive melanoma, a 1-cm margin is recommended for lesions
≤1 mm in depth, a 1–2-cm margin is recommended for lesions
1.01–2.0 mm in depth (dependent upon functional/cosmetic
concerns), and a margin of at least 2.0 cm is recommended for
lesions >2.0 mm in depth.
■ Subungual melanoma of the hand should be resected at the distal
interphalangeal joint to preserve function.
■ Sentinel lymph node biopsy (SNLB) is offered to patients with
melanomas >1 mm in thickness, and patients with thin melanomas (≤
1 mm thick) that demonstrate high-risk features, including ulceration
and/or high mitotic rate. The likelihood of detecting metastatic deposits
in an SLNB increases with the thickness of the primary lesion.
■ For patients with stage I and II disease, chest X-ray and liver function
tests compose the recommended workup. Patients with regional
(stage III) or systemic metastases (stage IV) should undergo a
comprehensive staging workup that may include CT scans with PET
imaging.
■ Serum LDH (lactate dehydrogenase) is used in the AJCC staging system
as it portends a worse prognosis in patients with metastatic disease.
■ Patients with high-risk primary tumors or metastatic disease should be
considered for adjuvant treatment with interferon-alfa or enrollment in
a clinical trial.
Introduction
Few diseases are as fascinating and as troublesome to physi-
cians as malignant melanoma, and perhaps no other disease
elicits as much fear in the patient as does this diagnosis.
Although it accounts for only 4% of all malignant neoplasms,
its very diagnosis suggests to some patients an aggressive,
rapid progression to death. The name alone may leave some
patients with a sense of hopelessness that is often unjustified.
Despite some reported descriptions of rapid spread, the natural
history of melanoma and its overall cure rate of 80% compare
favorably with those of cancers of the breast, colon, rectum,
and oropharynx and are far better than for cancer of the lung.
Epidemiologic studies demonstrate that the incidence of
melanoma has been increasing faster than that of any other
cancer in the United States.1 It is estimated that there were
76 100 new diagnoses of melanoma and 9710 deaths in the
United States in 2014.2 Melanoma incidence rates doubled
from 1982 to 2011.3 An individual dying from melanoma loses
an average of 20.4 years of potential life.4
Our understanding of melanoma continues to improve,
and we can now differentiate low-risk from high-risk patients
on the basis of multifactorial analyses from several series of
large numbers of patients. However, despite our best attempts
to understand the molecular basis of this disease, limited
success has been demonstrated in terms of new medical treat-
ments, and successful treatment of this disease relies heavily
upon the surgeon.
Access the Historical Perspective section, Table 29.1
and Figs. 29.1 & 29.2 online at

559.e1
Historical perspective
Historical perspective
Although Hippocrates is credited with the first reported
observation of what appears to be a melanoma, Handley5
attributes the first clinical case of malignant melanoma
reported in England to Dr. William Norris. In 1820, Norris felt
compelled to report this case because of the rapid spread of
the tumor, which led to his patient’s death. He reported that
at the autopsy, every organ except the spleen and the bladder
was riddled with “black specks”.6 The patient’s father had
died of similar disease, and the patient’s brothers and his
children had “many moles on various parts of their bodies”.
Handley had never himself treated a patient with a mela-
noma, but he made considerable observations after perform-
ing an autopsy on a 34-year-old woman who had died of
disseminated metastatic melanoma. He was interested in the
mechanisms of spread of melanoma. Halsted had already
described the spread of breast cancer along the lymphatics
surrounding the primary tumor.7,8 In his two Hunterian lec-
tures, Handley proposed that the primary spread of melanoma
was through the lymphatics and not by blood vessels. In his
first lecture, he described his autopsy findings; the 34-year-old
woman previously had a primary melanoma excised from her
right foot over the Achilles tendon. At autopsy, Handley
observed a large collection of tumor growths in the right groin
and virtually every part of the body except the entire left leg
(Fig. 29.1). Arguing incorrectly that every organ would have
been involved if tumor spread were hematogenous, he stated
that sparing of the spleen, bladder, stomach, and left leg could
be explained by “lymphatic permeation”. Although Handley
did not discount the concept of hematogenous spread, he
believed that early dissemination was by lymphatics and that
invasion of the blood stream occurred later “either by local
infiltration of veins from concomitant permeated lymphatics,
or by malignant cells carried into the blood along the thoracic
duct from invaded lymphatic glands”.5
In his second lecture, Handley proposed that lymphatics
were amenable to surgical removal with the primary mela-
noma. He based his treatment recommendations on histologic
examination not of the primary site but of the regional groin
recurrence. Indeed, Handley had confessed that “no opportu-
nity of investigating the spread of permeation round a primary
focus of melanotic growth has fallen to me”.9
Nevertheless, because the site of the groin recurrence had
shown “permeation spreading centrifugally in the lymphatic
plexus of the deep fascia and invading skin and muscle sec-
ondarily over a smaller area”, he advocated a wide radical
resection for a primary melanoma (Fig. 29.2): “A circular inci-
sion should be made through the skin round the tumour …
situated as a rule about an inch from the edge of the tumour,
should be just deep enough to expose the subcutaneous fat…
The skin with a thin attached layer of subcutaneous fat is now
to be separated from the deeper structures for about two
inches in all directions round the skin incision…. Finally, the
whole mass with the growth at its centre is removed by scoop-
ing out with a knife a circular area of the muscle immediately
subjacent to the growth.”9
This approach presented a minimal excision of 2.5 cm of
skin and 5 cm of subcutaneous tissue surrounding the mela-
noma, down to and including the muscle fascia, as well as
incorporating a portion of the underlying muscle. Therefore,
it is this report by Handley, in which he recommended a 5-cm
margin of skin and soft tissues around a melanoma, that
appears to be the first such proposal for a wide margin of
resection.
Fig. 29.1  Autopsy findings of patient with melanoma of right ankle spreading in a
centripetal manner to right groin and remainder of body while sparing the left leg.
(Redrawn from Handley WS. The pathology of melanotic growths in relation to their
operative treatment. Lecture I. Lancet. 1907;1:927.)
A
B
C
Fig. 29.2  Handley recommended removal of melanoma
(a) together with 1 inch (f) of skin (b) and 2 inches (g) of
underlying subcutaneous fat (c), muscle fascia (d), and
muscle (e). h, skin incision. (Redrawn from Handley WS.
The pathology of melanotic growths in relation to their
operative treatment. Lecture I. Lancet. 1907;1:927.)
a
f
h
g
b
c
d
e

559.e2
CHAPTER 29 • Melanoma
Handley believed that the regional lymph nodes also
should be removed as part of the first operation. Furthermore,
he advised that the excision of these glands be complete, “that
is to say, a larger circular area of the surrounding deep fascia
must be exposed, dissected up from its circumference towards
the infected glands, and removed in one piece with them”. He
then reported the treatment of a melanoma of the thigh by a
senior colleague, A.P. Gould, by resection of the primary
tumor and femoral nodes in this manner, but the patient had
iliac node recurrence within 2 months.
In the year after Handley’s lecture, Pringle10 described
three patients with melanoma whom he treated during the
previous 10 years. However, Pringle further advocated
removal of all subcutaneous tissue, including the lymphatics,
between the primary site and the regional nodes together with
the specimen. This was the first paper to describe the tech-
nique of an in-continuity dissection. He reported that one of
his patients – a young woman who was alive 9 years after
surgery at the time of the report – had moved to Canada,
married, and had children. Pringle concluded in his report
that “all that is removed should be in one continuous strip as
far as possible”.
These early papers established the trends toward aggres-
sive treatment of primary melanoma by wide excision of the
tumor together with the underlying muscle and its fascia and
by in-continuity lymph node dissection in an effort to achieve
better cures. As Handley stated in his Hunterian lecture:
“Nowadays the improved operation for breast cancer pro-
duces prolonged or permanent immunity in about 50 percent
of cases. And upon the evidence I have laid before you I
venture to predict that the application of more thorough and
scientific methods to the surgery of cutaneous melanomata
will produce a corresponding, though perhaps a smaller,
improvement in the results of operation.”9
However, the methods of treating melanoma changed very
little during the first half of the 20th century. The various
reports of cure rates after aggressive surgical treatment of
melanoma remained the same: a better prognosis if the patient
did not have clinically palpable nodes (80% 5-year cure rate
for stage I disease) than if the nodes were palpable (40% cure
rate for stage II disease).11
Subsequently, surgeons gained some information on prog-
nostic factors of this tumor. Within each clinical stage, the
prognosis is improved by the pathologic findings of no evi-
dence of metastatic tumor cells on microscopic examination
of the removed lymph nodes. However, the advantage of
in-continuity removal of all tissues between the primary site
and the regional lymph nodes, as advocated by Pringle10 and
as widely employed for decades, was challenged by Goldsmith
et al.11 who demonstrated no difference between this technique
and that of discontinuous dissection of the primary tumor and
the lymph nodes (Table 29.1). They, too, found no difference
between immediate and delayed lymphadenectomy.
Finally, the issue regarding excision of underlying muscle
and fascia was evaluated and resolved. Olsen12 reviewed a
series of 67 patients treated for melanoma in Denmark between
1949 and 1957. She found a 45% incidence of subsequent
regional nodal metastases among the 31 patients who had the
fascia removed during excision of the primary tumor and a
14% incidence of metastases among the 36 patients in whom
this fascia was left intact. Because the patients who underwent
a fasciectomy may have had more aggressive tumors, Olsen
reviewed the next 51 patients treated from 1958 to 1961 who
did not undergo excision of the fascia and observed only a
10% incidence of regional metastases. Kenady et al.13 reviewed
their data of 202 patients treated at the M.D. Anderson Hos-
pital, Houston, from 1961 to 1974 and found that local recur-
rence, regional nodal recurrence, distant metastases, and
survival were not statistically different between the 107
patients who had the fascia excised and the 95 patients who
did not. There appears to be no indication for removal of
underlying muscle fascia unless the fascia becomes involved
by contiguous tumor growth. In fact, the risk of lymphedema
may be decreased by preserving the muscle fascia. In a series
of 209 consecutive patients, 119 undergoing complete axillary
lymphadenectomy, permanent upper extremity lymphedema
occurred in 5% of the patients; and in 93 patients undergoing
ilioinguinofemoral lymphadenectomy, permanent lower
extremity edema occurred in 14% of the patients.14
Table 29.1  Outcome based on interval of timing of node
dissection
5-year cure rate
Clinical
stage
No. of
patients
Nodal
dissection
Simultaneous
Delayed
I
296
In continuity
63 (76%)
165 (78%)
Discontinuous
15 (75%)
53 (75%)
II
435
In continuity
53 (42%)
167 (42%)
Discontinuous
20 (35%)
195 (41%)
(Modified from Goldsmith HS, Shah JP, Kim DH. Prognostic significance of
lymph node dissection in the treatment of malignant melanoma. Cancer.
1970;26:606.)

560
CHAPTER 29 • Melanoma
pass through the less pigmented epidermis and are reflected
back to the eye as a blue nevus (Fig. 29.3D).
Congenital nevus
Congenital nevi differ from others in that they already produce
pigment at birth (Fig. 29.4A). There is some controversy about
Fig. 29.3  (A) Junctional nevus is flat, smooth, and nonpalpable. (B) Compound nevus is developing into mature, thicker intradermal nevus in center within a flat junctional
nevus in periphery. (C) Intradermal nevus is mature mole with elevation of the surface elements due to thickening of the layer of nevus cells. (D) Blue nevus presents with
melanin deposits deep in the dermis reflecting the blue wavelength of light.
A
B
C
D
Fig. 29.4  (A) Congenital nevus is a large flat pigmented mole that has produced
pigmentation in utero and is present as a pigmented lesion on the day of birth. It
may be hairy (as in this case) or not. (B) Invasive (1.4 mm) melanoma developed
within a congenital nevus on the trunk of a 57-year-old male.
A
B
Clinical evaluation
Clinical diagnosis
The definitive diagnosis is not made until the specimen is
examined histologically. Therefore, a review of the various
pigmented lesions is essential for making a differential
diagnosis.
All infants are born with nevi, but the lesions are usually
not apparent at birth because they do not produce pigment.
During the following few weeks or months, melanocytes
produce pigment as a response to circulating hormones. As
the nevi develop, they undergo maturation, which leads to
the classification of the following various forms.
Junctional nevus
Junctional nevi are small flat lesions that first appear after
birth and are smooth, nonpalpable, and light to dark brown
or black (Fig. 29.3A). They are called junctional because the
nevus cells are located at the interface of the epidermis and
dermis. As the person develops and matures, the nevus cells
grow and push into the dermis to develop into the common
adult intradermal nevus.
Compound nevus
As the nevus matures, the central portion pushes into the
dermis, causing this central portion to elevate and appear
thicker (Fig. 29.3B). This nevus is called compound because
the central portion is intradermal and thick, whereas the
periphery is still junctional and flat. Compound nevi often are
seen during adolescence, and the changes in such moles
may cause concern to the patient, family, or primary care
physician.
Intradermal nevus
The intradermal nevus is the common adult mole of the face
or trunk that is elevated because of the maturation and pro-
liferation of the nevus in the dermis, which now pushes up
the overlying epidermis (Fig. 29.3C). It may be light or dark,
usually is elevated, and may be sessile or pedunculated.
Blue nevus
Most nevi appear brown or black because the melanin is
superficial and absorbs light. When the nevus contains
melanin that is located more deeply, blue wavelengths of light

561
Clinical evaluation
On the basis of available information about the potential
for malignant transformation, it is a good policy to remove
congenital nevi if it can be done without much difficulty or
disfigurement (see Fig. 29.5). Malignant transformation does
not usually occur before adolescence, thus, if the lesion is to
be excised, it should be done before adolescence. Because it is
difficult to excise nevi from the skin of children under local
anesthesia and general anesthesia is often necessary for chil-
dren younger than 12 years, the risk of complications from
general anesthesia should be weighed against the risk of
malignant transformation before adolescence. On the other
hand, patients may request removal of the lesion to improve
their appearance. Despite concerns for appearance, some
lesions cannot be completely removed because in doing so we
may cause a greater deformity. These lesions may require
staged excisions.
Atypical (dysplastic) nevus
The atypical nevus is a clinical diagnosis of a nevus with
melanocytes involving the epidermis and dermis that have
features suggestive of malignancy. Clinically, it is large
(>6 mm), with a macular surface, irregular margin, and
whether congenital nevi are precursors of melanoma. Kaplan’s
review15 of the literature reported the transformation to mela-
noma to occur in 2% to 42% of congenital nevi (Fig. 29.4B). In
a retrospective study of 234 melanomas by Rhodes and
Melski,16 some of the histologic features of congenital nevi
were found among 8% of the melanoma specimens. A system-
atic review of all studies evaluating the risk of melanoma in
congenital nevi was performed by Krengel.17 A total of 6571
patients with congenital nevi were followed for at least 3.4
years, and 46 patients (0.7%; range 0.05% to 10.7%) developed
49 melanomas. Of note, primary melanomas arose inside the
nevi in 67% of cases. Using age-adjusted data from the Surveil-
lance, Epidemiology and End Results (SEER) database, they
calculated that patients with congenital nevi carry an approxi-
mately 465-fold increased relative risk of developing mela-
noma during childhood and adolescence. Patients with large
congenital nevi (Fig. 29.5), greater than 40 cm in diameter,
were associated with the highest risk of developing melanoma,
as well as dying from melanoma.17,18 However, the true inci-
dence of the development of melanoma within congenital nevi
is difficult to determine as the number of patients in the general
population who have congenital nevi but never consult a
physician, or eventually undergo excision, is unknown.
Fig. 29.5  Staged excision. A large truncal congenital nevus (A) was excised from the central portion of the lesion (B) to reduce the size of the lesion to half after one
operation (C). A second procedure a year later (D) removed the remainder of the lesion (E).
A
B
C
D
E

562
CHAPTER 29 • Melanoma
presence of multiple atypical nevi and no personal or family
history of melanoma, to the familial atypical multiple mole
and melanoma syndrome.24
B-K mole syndrome
Some prospective studies have shown that melanoma may be
associated with a familial distribution in 10% to 11% of cases.25
These familial melanomas tend to appear earlier and are
distributed among dysplastic nevi over the body, with an
excess over the trunk and a deficit over the upper extremities.
Clark et al.26 and Reimer et al.27 suggested the role of atypical
moles and dysplastic nevi in the development of hereditary
melanoma when they described these moles in association
with melanomas in seven families. They applied the initials
of the first family, which were B.K., to name this clinical entity
the B-K mole syndrome.
Differential diagnosis
The clinician is faced with the task of differentiating the
malignant melanoma from a number of other lesions that may
clinically resemble melanoma, such as seborrheic keratosis
(Fig. 29.7A), pyogenic granuloma (Fig. 29.7B), and pigmented
basal cell carcinoma (Fig. 29.7C). This differentiation may
sometimes be difficult because of recent growth, bleeding into
a lesion, or peripheral inflammation. In these instances, only
microscopic examination of the tissue provides the proper
diagnosis.
Extensive or radical surgical procedures should not be per-
formed without the proper diagnosis of a melanoma because
clinical impressions are not uniformly correct. Epstein et al.28
reviewed 559 patients with black lesions that they believed
might be melanomas. They found that their diagnosis of mela-
noma was correct only a third (38.7%) of the time. The most
common diagnoses were benign nevi (35%), pigmented basal
cell cancer (30%), and benign angiomas or vascular lesions
(13%). Only 2% of the lesions were found to be melanoma.
Dermoscopy, the use of a hand-held lens in combination with
oil immersion, has been shown to improve diagnostic accuracy
in skilled hands.29,30 However, it is used routinely by only 23%
of dermatologists.31 In general, the diagnostic work-up of
melanocytic lesions will precede the surgeon’s involvement,
unless the lesion is in a region of cosmetic concern.
Hutchinson freckle
A Hutchinson freckle is a flat, brown, macular lesion that may
grow at various rates and achieve different shades of pigmen-
tation (Fig. 29.8). This lesion occurs most commonly on the
face, neck, and other sun-exposed surfaces of adults in middle
age or later. On histologic examination, this lesion appears as
an overgrowth of melanocytes at the epidermis–dermis junc-
tion. Although lentigo maligna is an in situ melanoma, invasive
melanoma may develop within a Hutchinson freckle and is
then called lentigo maligna melanoma.
Melanoma
Melanoma lesions may be flat or nodular, with significant
darkening, erythema, or bleeding. On histologic examination,
the earliest lesions demonstrate atypical melanocytes migrat-
ing above the dermis–epidermis junction and appearing
variegated color. It may have a background of erythema (Fig.
29.6). These are benign lesions with histologic features that
are abnormal. At various times, they have been called atypical
nevi or dysplastic nevi. A National Institutes of Health Con-
sensus Conference in 1992 recommended the descriptive term
atypical nevus for the clinical diagnosis and the histologic term
dysplastic nevus to describe the histologic degree of atypia and
architectural disorder.19
To ensure accurate diagnosis, histologic examination of the
lesion is required. Microscopically, the dysplastic nevus has
melanocytic hyperplasia, with the melanocytes arranged as
solitary units or small elongated nests oriented parallel to the
long axes of the rete ridges. The melanocytes have nuclear
atypia and abundant cytoplasm with a fine “dusty pattern”
of melanin deposits.20 Dysplastic nevi are often associated
with atypical melanocytic hyperplasia, lymphocytic infiltra-
tion, and some evidence of regression. As such, patients with
these lesions are believed to be at greater risk for transforma-
tion to melanomas.
Atypical (dysplastic) nevus syndrome
Studies at several institutions have found atypical nevi in
association with melanoma that has no familial pattern. At the
University of Pennsylvania, Elder et al.21 first described this as
the dysplastic nevus syndrome in their 1980 report. In the
same year, the Yale Melanoma Unit visited the Sydney Mela-
noma Unit in Australia and documented the presence of
atypical nevi in 37% of 296 patients with melanoma who had
no known family history.22 Similar atypical nevi were discov-
ered in only 7% of a control population of male prison inmates
without any history of melanoma.22 Clinically, these moles
were large and resembled the dysplastic nevi of familial mela-
noma. Biopsies showed a 90% correlation between the histo-
logic diagnosis of dysplastic nevi and the clinical appearance
of these atypical moles. The tendency to develop atypical nevi
is presumed to have a genetic basis, and the diagnosis of
“atypical nevus syndrome” has been applied to patients with
a range of phenotypic expressions,23 including just the
Fig. 29.6  Dysplastic nevus is a histologic confirmation of the clinical entity called
atypical nevus. This is a large (>6 mm) flat mole of varying coloration.

563
Clinical evaluation
In addition to the above ABCD criteria, a review of the litera-
ture recommended the addition of E for “evolution”, in order
to emphasize the significance of evolving pigmented lesions
in the natural history of melanoma, especially given the
existence of small-diameter (≤6 mm) melanomas.34 In treating
patients with suspicious pigmented lesions, physicians should
be attentive to changes (evolving) of size, shape, symptoms
(itching, tenderness), surface (especially bleeding), and shades
of color. An investigation of the recognition process of mela-
noma by 135 dermatologists revealed that most dermatolo-
gists rely more on the lesion’s overall pattern, the “ugly
duckling sign” (i.e., unique appearance relative to the patient’s
other nevi), and recent change according to the patient, rather
than the more well-known ABCD algorithm.35 This observa-
tion lends support to the addition of an E category for evalu-
ation of melanocytic lesions by the non-dermatologist.
Based on existing literature, most patients who present
to their dermatologist are unaware of an existing melanoma.
Most melanomas (56.3%) detected in the general dermatology
practice are found by the dermatologist during routine
physical examination, and are not part of the presenting
within the upper portions of hair follicles and eccrine ducts.
These changes are typical of melanoma in situ.32 Special stain-
ing with S100 and HMB45 may be necessary to confirm the
diagnosis in cases with histologic features that may be equivo-
cal. However, when even a single atypical melanocyte invades
from the dermis–epidermis junction down into the dermis,
the diagnosis is melanoma.33
There are clinical features of pigmented lesions that are
characteristic for melanoma. These criteria have been pro-
moted by the American Cancer Society as the ABCD Guide-
lines (Fig. 29.9).
A  Asymmetry of the lesion as it grows from a round or
oval lesion
B  Border irregularity, which is a result of irregular growth
rates of different parts of the lesion
C  Color changes representing pigment granules deposited
at varying depths in the dermis, depending on the rate of
invasion
D  Diameter of the lesion becoming more than
14 inch
(>6 mm)
Fig. 29.7  Pigmented lesions that need to be differentiated from a melanoma.
(A) Seborrheic keratosis of cheek is a velvety smooth keratosis that may turn dark
brown to black with drying of the keratin layer. (B) Pyogenic granuloma with
exophytic granulation tissue and darkening due to desiccation of the blood and
coagulum. (C) Pigmented basal cell carcinoma with heaped up “pearly” margins.
Pigment may represent hemosiderin or melanin granules from melanocytes that may
be incorporated into the lesion.
A
B
C

564
CHAPTER 29 • Melanoma
a probability approaching 100% in time.44 Although multiple
primary melanomas may be found among 10% of the patients,
Ariyan et al.45 reported that half of these subsequent melano-
mas are in situ, and the vast majority of the rest are less than
1.0 mm thick; thus, they did not seem to affect cure rates.
Classification/staging of disease
Melanoma is most commonly located in the skin, although it
may also occur rarely in the mucosa of the oral cavity, naso-
pharynx, esophagus, vagina, and rectum. The staging system
developed for melanoma applies to lesions arising in the skin,
and thus, the discussion in this chapter is primarily limited to
cutaneous melanoma.
The purpose of a classification system in malignant disease
is to separate varying stages of severity to predict prognosis
and to propose treatment options based on those predictions.
Therefore, all classification systems have evolved from data
collected over time. As such, each of these classifications
needs to be re-evaluated periodically to refine the separation
of stages on the basis of changes in outcome. Melanoma
staging has evolved to include important data acquired from
pathologic analysis of the initial biopsy (and potential biopsy
of regional lymph nodes).
The most recent (2017), eighth edition of the American Joint
Committee on Cancer (AJCC) staging system relies upon data
related to the primary tumor (T), regional lymph nodes (N), and
metastases (M). Also known as the TNM system, this staging
system was developed based upon analysis of over 38 900
patients with cutaneous malignant melanoma46 (Tables 29.2
& 29.3).
Histologic subtypes of melanoma
While morphology, or histologic subtype, does not necessarily
correlate with clinical behavior, subclassification is important
for pathologic recognition and diagnosis. Melanoma may be
classified morphologically into four major growth patterns:
lentigo maligna, superficial spreading, nodular, and acral
lentiginous types (Fig. 29.12). Superficial spreading melanoma
(Fig. 29.12B) represents 50% to 80% of all the types and is
characterized by growth in the radial (horizontal) phase for a
period of years before evolution into the vertical growth
phase. Nodular melanoma (Fig. 29.12C), on the other hand,
evolves into the vertical growth phase early in its develop-
ment and represents 20% to 30% of the group but in some
series may compose the majority of the lesions.48 Lentigo
maligna melanoma (Fig. 29.12A) is differentiated from super-
ficial spreading melanoma and nodular melanoma by its
location on sun-exposed surfaces of the body and within pre-
existing lentigo maligna (Hutchinson freckle). This morpho-
logic type of melanoma was believed to have a better prognosis
than other types by virtue of a different biologic behavior, but
it has been shown to have a prognosis identical with that for
superficial spreading melanoma with comparable depths of
invasion.49 It has been shown that lentigo maligna melanoma
merely grows in a horizontal fashion more than in a vertical
fashion, resulting in thinner lesions than superficial spreading
melanoma or nodular melanoma, which is the reason for its
purported better prognosis.
Acral lentiginous melanoma appears on the palms of the
hands, soles of the feet (Fig. 29.12D), subungual areas of the
complaint.36 Numerous studies37–39 demonstrate that physi-
cians are more likely to detect melanomas at a thinner stage
than non-physicians. In these studies, there was a significant
difference between the thickness of physician-detected mela-
nomas (0.23–0.68 mm) and those detected by patients or their
spouses (0.9–1.43 mm).
An occasional, and potentially reassuring, feature of mela-
noma is intralesional depigmentation (Fig. 29.10). This is a
manifestation of immunologic regression of the tumor as a
result of the destruction of the melanoma cells by the host’s
immune system. The histologic examination of only a section
through the depigmented portion may be misread as an
inflammatory reaction. However, deposits of residual melanin
granules may exist in the depigmented portion (Fig. 29.10B),
and histologic examination of sections through the adjacent
pigmented portion may reveal the true diagnosis of the
melanoma.
Nevertheless, depigmentation does not always indicate
melanoma; a halo nevus (Fig. 29.11A) is a benign lesion with
a peripheral ring of depigmentation.40 Histologic examination
of the halo portion shows lymphocytic infiltration without
pigment granules (Fig. 29.11B). Further evaluation of the
lesion and surrounding tissue shows no evidence of cells of
malignant melanoma (Fig. 29.11C).
Multiple primary melanomas
Multiple primary melanomas have been reported to occur
among 3% of melanoma patients.41 The risk for a second mela-
noma in a patient with one melanoma approaches 4% to 5%.42
However, with a positive family history of melanoma, the risk
for multiple primary melanomas rises to 10% or more.43 The
highest risk of all appears to be in individuals who have a
family history of melanoma in one or two first-degree relatives
and who have clinical evidence of dysplastic nevi, suggesting
Fig. 29.8  Hutchinson freckle is a flat lesion with various shades of pigmentation.

565
Clinical evaluation
Fig. 29.9  Melanoma with characteristic changes. (A) Asymmetry of lesion shape. (B) Border irregularity. (C) Color variegation. (D) Diameter greater than 6 mm.
A
B
C
D
A
B
Fig. 29.10  (A) Melanoma with areas of depigmentation within the lesion. (B) Histologic examination of the specimen cut through the area of depigmentation shows
significant lymphocytic infiltration with disrupted pigment granules leading to the colorless patches within.

566
CHAPTER 29 • Melanoma
of amelanotic melanoma was found to be 1.8%.57 Desmoplastic
melanoma (DM) is subtyped to those that are pure DM (100%
are spindle cells) and those that are mixed DM (not all are
spindle cells), because of the lower risk of nodal metastases
reported in the pure DM.58
Histopathologic factors of prognostic
significance
With respect to analysis of the primary lesion alone, the depth
of invasion of melanoma into the dermis has been shown to
be the most powerful determinant of outcome. In 1965,
Mehnert and Heard59 reported the earliest correlation of depth
with prognosis. A few years later, Clark et al.60 described the
following system of levels for the classification of depth of
invasion into the dermis (Fig. 29.15):
Level I: In situ melanoma; limited to the dermis–epidermis
junction
Level II: Invading the papillary dermis but without
expansion of this layer
Level III: Invading and expanding into the papillary dermis
but not into the reticular dermis (to the interface of the
papillary–reticular dermis)
Level IV: Invading the reticular dermis, but not into the
subcutaneous fat
Level V: Invading the subcutaneous fat or the associated
subreticular tissues
fingers and toes (Fig. 29.12E), and web spaces.50 The importance
of subungual melanoma is that it is often erroneously believed
to be a fungal infection, and appropriate treatment may be
inadvertently delayed because of a delay in obtaining diagnos-
tic biopsy. Presumably due to delayed diagnosis, this type of
melanoma has the lowest 5-year survival rates of all histologic
variants, generally found to be in the range of 10% to 20%.25,51
While older studies suggested that prognosis may be
associated with histologic subtype (e.g., patients with nodular
melanomas were thought to have a worse prognosis than
patients with superficial spreading melanomas),52 more recent
multivariate analyses demonstrate that these prognostic dif-
ferences are more likely due to other histologic features (i.e.,
tumor thickness and ulceration).53
Another less common clinical variant of melanoma, desmo-
plastic melanoma, usually does not produce pigment, and
grows on the external surfaces of the skin. It may have the
appearance of a hypertrophic scar (Fig. 29.13A) at a location
where the patient does not recall having had an injury to the
skin. It must be differentiated clinically from a dermatofi-
broma and other benign or malignant tumors of the dermis.
Histologic examination reveals a cicatricial growth of the
lesion with spindle cell variants of malignant melanocytes
(Fig. 29.13B,C).54–56 This histologic subtype must be differenti-
ated from amelanotic melanoma (Fig. 29.14), which is simply
a variant of nodular or superficial spreading melanoma that
is not producing sufficient pigment granules to appear as a
pigmented lesion. In one series of melanomas, the incidence
Fig. 29.11  (A) Halo nevus with a ring of depigmentation surrounding the lesion.
(B) Histologic examination of the depigmented portion shows infiltration with
lymphocytes, but there is no evidence of pigment granules or malignant cells (C).
A
B
C

567
Classification/staging of disease
Table 29.2  Cutaneous melanoma TNM staging (AJCC 8th
Edition)
T classification
Thickness
Ulceration status
Tis
not applicable
not applicable
T1
≤1.0 mm
a: <0.8 mm w/o
ulceration
b: <0.8 mm with
ulceration
0.8–1.0 mm with or
w/o ulceration
T2
1.01–2.0 mm
a: w/o ulceration
b: with ulceration
T3
2.01–4.0 mm
a: w/o ulceration
b: with ulceration
T4
>4.0 mm
a: w/o ulceration
b: with ulceration
N classification
No. of metastatic
nodes
Nodal metastatic
mass
N1
1 node
a: clinically occult
micrometastasis*
b: clinically detected
macrometastasis**
c: in transit met(s)/
satellite(s) without
metastatic nodes
N2
2–3 nodes
a: clinically occult
micrometastasis*
b: clinically detected
macrometastasis**
c: in-transit met(s)/
satellite(s) with 1
metastatic node
N3
4 or more metastatic
nodes, or matted
nodes, or
in-transit met(s)/
satellite(s) with
metastatic
node(s)
a: clinically occult
micrometastases*
b: 1 clinically detected
micrometastasis**
c: 2 or more clinically
detected
micrometastases
M classification
Site
Serum LDH
M1a
Distant skin,
subcutaneous or
nodal metastases
(0): normal
(1): elevated
M1b
Lung metastases
(0): normal
(1): elevated
M1c
Other visceral (non
CNS) metastases
(0): normal
(1): elevated
M1d
Distant CNS
metastasis
(0): normal
(1): elevated
*Micrometastases are clinically occult nodes diagnosed after sentinel node
biopsy.
**Macrometastases are defined as clinically detectable nodal metastases
confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits
gross extracapsular extension.
(Source: Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma of the Skin.
AJCC Cancer Staging Manual. 8th Edition. Springer; 2017, pp. 563–585.)
Table 29.3  Melanoma stage/prognostic groups
Stage 0
Tis
N0
M0
Stage IA
T1a
N0
M0
Stage IB
T1b
N0
M0
T2a
N0
M0
Stage IIA
T2b
N0
M0
T3a
N0
M0
Stage IIB
T3b
N0
M0
T4a
N0
M0
Stage IIC
T4b
N0
M0
Stage IIIA
T1ab-2a
N1a
M0
T1ab-2a
N2a
M0
Stage IIIB
T1ab-2a
N1b/c
M0
T2b-3a
N1a-2b
M0
Stage IIIC
T1a-3a
N2c
M0
T1a-3a
N3a-c
M0
T3b/T4a
N1 or +
M0
T4b
N1a-2c
M0
Stage IIID
T4b
N3a-c
M0
Stage IV
Any T
Any N
M1
(Source: Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma of the Skin.
AJCC Cancer Staging Manual. 8th Edition. Springer; 2017, pp. 563–585.)
The difficulty with this classification system is the qualitative
and somewhat subjective nature of determining the depth of
invasion. Various pathologists examining a histologic slide of
mid-dermal invasion often disagree on the Clark level of inva-
sion; some may call it a level III, while others call it a deep level
II, and still others call it an early level IV invasion. As a result
of this difficulty, Breslow61 reported a method of quantitative
measurement that employs a simple and readily reproducible
system of microstaging. According to Breslow, the melanoma’s
depth of invasion is measured in tenths of millimeters as a
thickness from the surface of the tumor in the epidermis to the
deepest tumor cell identified by means of an ocular micrometer
on the microscope. In a number of studies using multivariate
analyses,46,48 Breslow’s method has been shown to be the most
powerful prognostic indicator for survival in early stage mela-
noma (i.e., disease limited to primary tumor). Additional
factors shown, in appropriate multivariate analyses of several
thousand patients, to be associated with recurrence and sur-
vival include: ulceration in the lesion, the mitotic rate within
the lesion, the patient’s age and sex, the site of the primary
lesion, and the morphologic type of melanoma.46,62
T category of TNM staging system
The histopathologic factors incorporated into the T category
of the 2017 TNM staging system are the thickness of the
primary tumor, i.e., the Breslow depth,61 and the presence or
absence of ulceration of the overlying epithelium.46
The thickness of the primary tumor (T) defines four catego-
ries (see Table 29.2):
T1: ≤1.0 mm
T2: 1.01–2.0 mm
T3: 2.01–4.0 mm
T4: >4.0 mm

568
CHAPTER 29 • Melanoma
A
B
C
D
Fig. 29.12  Various morphologic types of melanoma. (A) Lentigo maligna melanoma
– thin, flat lesion within patchy discoloration of Hutchinson freckle. (B) Superficial
spreading melanoma – flat lesion with cells proliferating in the horizontal plane.
(C) Nodular melanoma – thicker lesion growing in a vertical plane. (D,E) Acral
lentiginous melanoma of the foot and nail bed.
E
Increasing tumor thickness is closely correlated with poorer
prognosis. The 10-year survival decreases progressively, from
96% for patients with primary lesions <0.5 mm thick to 54%
for patients with lesions 4.01 to 6.0 mm thick.46
The T categories are further subdivided into “a” or “b”
based upon the presence or absence of ulceration (see Table
29.2). Ulceration is defined as the absence of an intact
epithelium over the melanoma. Outcomes in patients with
ulcerated primary tumors are worse than in patients with
primary melanomas of the same thickness but without ulcer-
ation. The mitotic rate was incorporated into the previous
2010 TNM staging system based upon the observation that it
was the second most important prognostic factor in over
11 000 patients with localized melanoma analyzed in the

569
Classification/staging of disease
A
B
Fig. 29.13  (A) Desmoplastic melanoma is often nonpigmented and has the
appearance of hypertrophic scar. (B) Low-power magnification of the desmoplastic
melanoma shows the proliferation of the tumor in a cicatricial fashion.
(C) High-power magnification of the lesion shows the spindle cell variant of the
malignant melanocytes with the production of some pigment granules.
C
Fig. 29.14  The lack of pigment production in this amelanotic melanoma is
deceptive in a lesion that is otherwise suggestive of malignancy.
AJCC Melanoma Staging Database. In that series, there was
a highly significant correlation between increasing mitotic
rate and declining survival rates (p <0.0001). For instance,
for melanomas less than 1.0 mm thick, the 10-year survival
rate was 93% for those with <1 mitosis/mm2 and 48% for
those with >20 mitoses/mm2.46,47 The previously recom-
mended approach to determining the mitotic rate was to
identify the area of dermis containing the most mitoses (the
“hot spot”), and average the number of mitoses within a
1-mm2 area of the hot spot.47 The substaging according to
mitotic rates applied only to T1 lesions.
With respect to prognostic classification (see Table 29.3),
Stage I melanoma defines patients with low-risk melanomas
(T1a–T2a) without evidence of regional or distant metastases.
Further subdivision (Stages IA and IB) is based upon character-
istics of the primary tumor. Stage II melanoma includes primary
tumors at a higher risk of recurrence or metastasis (T2b–T4b)
without evidence of surgical or distant metastases. Similarly,
stage II subdivision (IIA, IIB, IIC) is based upon characteristics
of the primary tumor.46 Details of more advanced stages of
melanoma will be covered in the next section.
In-transit and regional lymph node disease
Local metastatic spread of cutaneous melanoma is known to
occur through lymphatic channels in the majority – approxi-
mately 90% – of cases.63 Direct hematogenous dissemination
of melanoma, more difficult to assess and treat, is another less
common route of metastasis. There are a number of clinical
and pathologic characteristics of regional spread of metastatic
melanoma that have become incorporated into the prognostic
staging system for primary melanoma, namely satellite/
in-transit metastases and sentinel lymph node status.64
Intralymphatic spread of melanoma in the skin can present/
manifest as satellite lesions, also known as microscopic satel-
litosis, or in-transit metastases, which are skin or subcutaneous
metastases more than 2 cm from the primary lesion.53 Micro-
scopic satellitosis is seen in up to one-third of primary mela-
noma lesions greater than 3 mm thick, compared to less than

570
CHAPTER 29 • Melanoma
the interstitial tissue to nourish the cells. The breakdown
products of metabolism are then picked up by the veins and
taken back into the systemic system. Because the pressure in
the arteries is greater than in the veins, more of this vascular
fluid is diffused into the tissue than is taken away by the vein.
To avoid the consequences of edema, lymphatic vessels (the
micro sump pumps of the system) draw away this excess fluid
and take it to the regional lymph nodes to filter the product
before returning it to the systemic vascular system. This filter-
ing function of the lymph nodes allows detection and attack
of foreign bacteria, antigens, and cancer cells. It was this
principle that permitted Sappey68 to show the lymphatic pat-
terns of the human body in 1874 by injecting mercury into the
skin. Sappey’s lines are a helpful guide to determine the likely
directions of lymphatic spread. Subsequent experience has
shown that lesions located more than 2 cm above or below a
“belt line” drawn through the umbilicus usually drain to the
axillary or groin nodes, respectively. Lesions more than 2 cm
on either side of the midline drain to the lymph nodes on that
respective side. Lesions within 4 cm of the vertical and hori-
zontal bands may go to any one of the pairs of options (Fig.
29.16).
As a result of potentially unclear lymphatic drainage pat-
terns, Sherman and Ter-Pogossian69 introduced lymphoscin-
tigraphy in 1953. They injected radiocolloid gold (198Au)
intradermally and used a gamma counter to detect the con-
centrated colloidal isotope in the filtering lymph nodes. This
technique has since been modified with various other isotopes
and colloids of various particle sizes for specific diagnostic
purposes. The intent of each of these modifications is to
identify the lymphatic vascular pattern in the tissue being
evaluated.
The technique of lymphatic mapping is helpful for predict-
ing the pattern of spread for cutaneous melanoma metastases
to regional draining lymph node basins, and it may be helpful
in actually detecting metastases in melanoma of the extremi-
ties.70 In particular, the test may be useful in patients with T2
or thicker lesions of the lower extremity for evaluation of the
iliac and pelvic lymph nodes to determine the extent of
5% of thinner lesions.64 The presence of microscopic satellitosis
and in-transit metastases has been shown to carry a poorer
prognosis, similar to the presence of regional lymph node
metastases.46 Thus, in the current AJCC system, patients with
microscopic satellitosis or in-transit metastases are upstaged
to the level of a patient with established lymph node metas-
tases (see Tables 29.2 and 29.3).
Spread of melanoma to the regional lymph nodes portends
a poorer prognosis. As melanoma is known to mostly metas-
tasize through lymphatic channels (and the first sites of
metastasis are typically regional lymph node basins), evalua-
tion of the regional lymph node basins has become critical in
the staging of melanoma. Unfortunately, clinical evaluation of
the regional lymph nodes is often inaccurate; as many as 20%
of clinically node-negative patients have metastatic involve-
ment on pathologic evaluation, and up to 20% of those with
clinically positive nodes are pathologically negative.65
Mostly of historical significance, elective lymph node
dissection (ELND) has largely been supplanted by SLNB.
However, brief mention is warranted. In the setting of clinically
node-negative disease, ELND involves removal of all lymph
nodes in a suspected draining basin. The rationale is that
removal of subclinical regional disease may provide a survival
benefit over a therapeutic node resection performed after
regional disease becomes clinically evident. Performance of
this procedure is now controversial, in the era of lymphoscin-
tigraphy and sentinel lymph node biopsy, especially as most
melanomas are being diagnosed early (thinner and less inva-
sive), and the morbidity associated with a completion lymph-
adenectomy can be quite significant. Additionally, while a few
retrospective analyses suggested ELND might improve sur-
vival by 25–40 percent,66 most prospective randomized trials
have not demonstrated a survival benefit from ELND.67
Lymphoscintigraphy (lymphatic mapping) and
sentinel lymph node biopsy
In the skin, as in all parts of the body, arterial blood pressure
diffuses serum and nutrient material out of the vessels into
Fig. 29.15  The Clark classification of melanoma is
dependent on the qualitative determination of the extent of
invasion into the various areas of the dermis or
subcutaneous fat. The Breslow classification is determined
by the micrometer reading of the depth of invasion into the
dermis, measured in tenths of millimeters.
Breslow
depth
Clark level
Subcutaneous fat
Reticular
dermis
Papillary
dermis
Epidermis
I
II
III
IV
V

571
Classification/staging of disease
Fig. 29.16  (A,B) Lymphatic drainage as predicted by Sappey’s lines. (Redrawn from Sugarbaker EV, McBride CM. Melanoma of the trunk: the results of surgical excision
and anatomic guidelines for predicting nodal metastasis. Surgery. 1976;80:22.)
A
5 cm
5 cm
B
L2
5 cm
lymphadenectomy that may be indicated. The iliac nodes
should certainly be removed if they appear to be involved,
but a pelvic lymphadenectomy is not indicated if the para-
aortic lymph nodes are involved because cure is unlikely in
these cases.
The sites of lymphatic spread from melanoma at other loca-
tions, including the trunk and head and neck regions, may be
also evaluated by radionuclide lymphoscintigraphy.71 Several
radiocolloids have been employed for lymphoscintigraphy,
including gold, sulfur, and antimony. Antimony sulfide colloid
and technetium sulfur colloid have been found to be safe, and
both give reliable information for determining appropriate
lymph nodes for elective dissection among patients with
truncal or head and neck melanomas (Fig. 29.17).
A lymphoscintigram can demonstrate predicted as well as
unexpected patterns of lymph node drainage from lesions at
primary sites. The test has been demonstrated as a reliable
predictor of the sites of nodal involvement. In a prospective
study of 51 consecutive patients with primary melanomas
greater than 1 mm thick and observed for a mean of 45
months, 23% of the 35 patients who chose to undergo elective
lymphadenectomy were found to have micrometastases to
these lymph nodes; all were in the node groups detected by
the lymphoscintigram.72 During the several years of their
follow-up, 5 of the 16 patients (31%) who chose to be observed
eventually developed clinical evidence of nodal metastases;
in each case, the nodes that were involved with tumor were
at the very sites of drainage predicted by the lymphoscinti-
grams that were performed at the time of initial diagnosis
(Table 29.4). During the 7-year interval of follow-up, no
patient in either group developed metastases to any nodes not
predicted by lymphoscintigraphy.
Sentinel lymph node biopsy
As stated previously, the availability of lymphatic mapping
with SLNB has obviated a possible role for ELND in the treat-
ment of cutaneous melanoma. The concept of the sentinel
lymph node is based on the principle that all lymphatic fluid
from specific tissues is filtered by lymph nodes, and as such
the first (or sentinel) lymph node filtering a specific site can
be removed and evaluated for metastasis of malignant cells.
The validity of this entire principle is predicated on the tenets
that: finite regions drain to a specific node; the sentinel node
can be found; a negative biopsy finding means no other
metastases exist; and a negative sentinel node is truly
negative.
Morton63 introduced the technique of detecting the senti-
nel lymph node with the intraoperative injection of vital
blue dyes in the dermis surrounding the site of the primary
melanoma. He identified the sentinel lymph node in more
than 80% of the patients and reported that the false-negative

572
CHAPTER 29 • Melanoma
rates had been about 5%. Subsequent investigators73–75
reported the use of preoperative lymphatic mapping and the
intraoperative use of radiocolloids together with vital blue
dyes with increased identification and successful removal of
the sentinel lymph node to the range of 98% to 99% of
patients with melanoma (Fig. 29.18). Based on studies of
melanoma patients who underwent SLNB and subsequent
completion lymphadenectomy of the respective lymph node
basin, it can be assumed that if the sentinel lymph nodes are
not involved, the entire basin should be free of tumor, in
96% of cases.63,73,76
N category of TNM system
Sentinel lymph node biopsy has largely become the standard
of care in the initial evaluation of cutaneous melanoma, par-
ticularly for patients with melanoma thicker than 1 mm in
depth. The likelihood of finding nodal metastases in patients
with tumors less than 1 mm in thickness is quite low (less than
10%).77–79 However, the presence of certain high-risk features,
including ulceration and/or a high mitotic rate, may justify
SLNB in thin melanomas.80–83 The likelihood of detecting
metastatic deposits in an SLNB increases with the thickness
of the primary lesion; for lesions <1.0 mm, 1.01 mm to 2.0 mm,
2.01 mm to 4.0 mm, and >4 mm, the risk is approximately
4–7%, 12–20%, 28–33%, and 40–44%, respectively (Table
29.5).84,85 The test is particularly useful for patients with inter-
mediate thickness melanomas, 1–4 mm. However, it should
still be considered in the treatment algorithm of patients with
Fig. 29.17  Lymphoscintigram of a right scapular melanoma (A) demonstrates
drainage to the right axillary lymph nodes (B), as well as the right lower cervical
nodes (C).
A
B
C
Table 29.4  Reliability of lymphoscintigrams
ELND
Observe
Number of patients*
35 (70%)
16 (30%)
Lymph node metastases
8 (23%)
—
Subsequent lymph node metastases
—
5 (31%)
*51 patients with melanoma greater than 1 mm thick; 7-year follow-up (mean of
45 months).
ELND, elective lymph node dissection.
(Data from Stephens PI, Ariyan S, Ocampo RJ, et al. The predictive value of
lymphoscintigraphy for nodal metastases of cutaneous melanoma. Conn Med.
1999;63:387.)
Table 29.5  Risk of detecting a positive sentinel lymph node
Breslow depth
Risk of + SLN
<1.0 mm
4–7%
1.01–2.0 mm
12–20%
2.01–4.0 mm
28–33%
>4.0 mm
40–44%
(Data from Rousseau DL Jr, Ross MI, Johnson MM, et al. Revised American
Joint Committee on Cancer staging criteria accurately predict sentinel lymph
node positivity in clinically node-negative melanoma patients. Ann Surg Oncol.
2003;10:569–574 and Morton DL, Hoon DS, Cochran AJ, et al. Lymphatic
mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic
utility and implications of nodal microanatomy and molecular staging for
improving the accuracy of detection of nodal micrometastases. Ann Surg.
2003;238:538–549.)

573
Classification/staging of disease
from the early removal of these metastatic nodes before the
disease can spread any further, and to consider these patients
for adjuvant therapy. In patients with nodal disease (includ-
ing those with nodal disease limited to micrometastases), it
has been demonstrated that the most important prognostic
factor is the number of involved nodes.90
The node (N) category of the 2017 edition of the AJCC
Melanoma TNM system (see Table 29.2), includes the follow-
ing designations:
Nx: Nodes are not assessable (e.g., previously resected for
other reasons)
N0: No regional lymphatic metastases.
N1: One involved lymph node.
N1a: clinically occult micrometastasis;
N1b: clinically detected macrometastasis
Fig. 29.18  Sentinel node dissection. Blue dye injected into the dermis (A) at the site of
the primary melanoma can be detected in the lymphatic vessels (B). The radiocolloid
injected in the dermis is detected by the hand-held gamma counter (C) to localize the
sentinel lymph node (D). A second node (E) was also identified adjacent to the first.
A
B
C
D
Sentinel
Secondary
E
very thick tumors (greater than 4 mm) because even though
this group of patients has a 65–70% risk of distant metastases,
the SLNB may still provide important prognostic information,
and obviate a subsequent lymphadenectomy in a number of
patients who would subsequently develop enlarged nodes.86
Based on analyses of the AJCC Melanoma Staging Data-
base, nodal status has been demonstrated as the overriding
factor predicting disease outcome.87–89 For patients with clini-
cally detectable nodal disease (macrometastases), the charac-
teristics of the primary tumor essentially become irrelevant
with respect to predicting five-year survival. That is, thick-
ness, ulceration, and mitotic rate do not maintain statistical
significance on multivariate analysis.90 As the majority of
patients present without clinically apparent nodal involve-
ment, the goal of SLNB is to identify patients with microscopic
nodal metastases as early as possible so they might benefit

574
CHAPTER 29 • Melanoma
Table 29.6  Staging evaluation: tests recommended for
determination of presence and extent of tumor spread
Primary tumor (no clinical evidence of other involvement)
Physical examination
Chest radiography
Liver function tests
Lymphoscintigraphy to detect sites of sentinel nodes (if primary
tumor is 1 mm or more thick)
Local and regional disease (in-transit lesions or nodal
involvement)
Physical examination
Liver function tests
CT scans
  of chest and abdomen (to examine lungs and liver)
  of pelvis if tumor involves lower extremities
  of neck if tumor involves the head and neck
Lymphoscintigraphy to detect sites of sentinel nodes
Additional scans as indicated by clinical signs or symptoms
Distant organ metastases
Physical examination
Liver function tests and serum lactate dehydrogenase level
CT scans as indicated above
MRI scans if required to detect extent of soft tissue invasion
PET scans to detect extent of tumor involvement of vital organs
(lung, liver, brain)
Fig. 29.19  CT scans of the brain can detect small lesions. In this patient, several
lesions are identified in both hemispheres.
N1c: in transit or satellite metastasis without metastatic
nodes
N2: Two to three involved nodes
N2a: clinically occult micrometastases
N2b: at least one node with clinically detected
macrometastasis
N2c: in-transit or satellite metastasis with one metastatic
lymph node
N3: Four or more positive nodes, matted nodes, or in-transit/
satellite metastases with one or more positive nodes
N3a: clinically occult micrometastases
N3b: one clinically detected micrometastasis
N3c: two or more clinically detected micrometastases
The presence of in-transit metastases, or nodal involvement,
classifies the patient as Stage III, with subclassification (IIIA,
IIIB, IIIC, or IIID) dependent upon the extent of lymphatic
disease (see Table 29.3).
Evaluation of systemic disease
The evaluation of the patient with malignant melanoma
requires a complete physical examination of the primary site
and regional draining lymph nodes to detect any clinical
evidence of satellite or in-transit lesions (metastases) in the
skin or of metastases to lymph nodes. The abdomen needs to
be examined for evidence of an enlarged liver, enlarged
spleen, or abdominal masses that would suggest intra-
abdominal metastases. The extent of examination and the
tests ordered for such evaluations are predicated on the
stage of the primary diagnosis (Table 29.6). A chest radio-
graph may be indicated to look for pulmonary metastases,
and computed chest tomograms may add to the detection of
small and early lesions. Liver enzyme function tests are
simple, sensitive, and reliable for detecting liver metastases
and, when results are negative, may serve as a baseline
for later annual follow-up examinations. Serum lactate dehy-
drogenase (LDH) has been identified as an important, inde-
pendent prognostic factor in patients with disseminated
melanoma. The AJCC Melanoma Staging Database included
7972 patients with distant metastases, and one- and two-year
survival rates were significantly lower in patients with ele-
vated serum LDH (32% versus 65% and 18% versus 40%).46
Therefore, serum LDH must be measured at the time stage
IV disease is documented, as it provides important prognos-
tic information.
Computerized scans
Although tomographic radiographs of the lungs are helpful
in detecting pulmonary metastases, computed tomographic
(CT) scanning of the chest and abdomen does not offer a
significant advantage as an initial screening test over chest
radiographs and liver function tests.91 Even though this
imaging technique requires skillful interpretation for optimal
use, analyses have shown that screening chest radiographs, a
much less expensive modality, are just as useful as CT scans
in detecting metastatic lesions at the time of the initial diag-
nosis. However, CT scans do offer the potential for superior
detection of metastatic lesions in various organs, and they are
quite useful for evaluating the brain (Fig. 29.19).
Whereas patients with primary melanomas thicker than
1 mm may be considered at moderate risk, those with lesions
greater than 2 mm are considered at high risk for metastases.
Patients with stage III disease are certainly candidates for
intensive surveillance. These higher risk patients should
be evaluated for distant organ metastases with chest and
abdominal CT scans, which enable the physician to examine
the lungs, the liver, and the spleen in one test. Enhanced brain
CT scans should also be considered.

575
Evaluation of systemic disease
LDH. M1b denotes patients with lung metastases and a
normal (0), or elevated (1) serum LDH. The patients with the
worst prognosis are M1c, with metastases to other visceral
(non CNS) sites, and M1d, with distant CNS metastasis (both
also with a normal (0) or an elevated (1) serum LDH). With
respect to staging (see Table 29.3), any M designation (i.e., the
presence of any metastatic disease beyond the regional lymph
nodes) places the patient in the Stage IV category.
While rare, patients will occasionally present with meta-
static melanoma without an identifiable primary tumor. In
these situations, if the patient has isolated metastases in the
lymph nodes, skin, or subcutaneous tissues and an unknown
primary, they are considered Stage III, as studies suggest they
have a similar (or slightly better) survival rate compared to
those with involved lymph nodes and a known primary
tumor.94–98
Members of the AJCC Melanoma Task Force recently
developed an electronic prediction tool for patients present-
ing with localized disease (
net). The prediction tool can be used to predict the 1, 2, 5 and
10-year survival rates from initial diagnosis (with a 95%
confidence interval) for an individual patient based on his/
her relevant clinical and pathologic information. The predic-
tive models were developed and validated using a combined
On the other hand, CT scans can be helpful for staging the
disease in patients who present with local or regional exten-
sion of the disease. In some patients, the extent of the disease
detected from the CT scans can be elaborated by the use of
magnetic resonance imaging scans (Fig. 29.20). Positron emis-
sion tomography (PET) scan has been found to be valuable
for evaluating patients for extension of their disease and
assigning stage.92,93 The increased metabolism of the tumor
is reflected in the increased uptake of radioactive-labeled
glucose, which is represented by the brighter activity at the
site of the metastases (Fig. 29.21). In the absence of infectious
processes, the false-positive rate has been reported to be less
than 5% with PET scans. The restrictions to the use of PET
scans are the limited availability of the scanners and the
greater expense for these studies.
M category of TNM system
The AJCC staging system categorizes patients with distant
metastases according to the site(s) of disease involvement
and the serum lactate dehydrogenase (LDH) level (see Table
29.2).46 M1a, associated with the best prognosis, identifies
patients with metastases limited to distant skin, subcutaneous
or lymph node sites, and a normal (0), or elevated (1) serum
Fig. 29.20  Magnetic resonance imaging, in this case
of the brain, demonstrates involvement of soft tissue
by melanoma.
Fig. 29.21  PET scan of the chest and abdomen
(right) confirms the increased activity of metastatic
lesions seen on CT scan in the lung (upper left) and
liver (lower left).