SQUAMOUS CELL CARCINOMA

Introduction
• SCC is a neoplasm of keratinizing cells  shows malignant characteristics, including : anaplasia,
rapid growth, local invasion and metastatic potential.

• > 200,000 cases of SCC are diagnosed in the US/year  second most common human cancer
after BCC.

• SCC in blacks arises most often on sites of preexisting inflammatory conditions such as burn
injuries, scars or trauma.

• Patients treated with PUVA or undergoing immunosuppressive therapy following solid-organ

transplantation are at increased risk of SCC.
Pathogenesis of squamous Cell
Carcinoma
• Major factors involved  include cumulative exposure to UVR, genetic mutations,
immunosuppression and viral infections.

• UVR acts as both a tumor-initiating and a tumor-promoting factor.

• UV-induced mutations in TSG lead to uncontrolled cell-cycle progression and subsequent

transformation of keratinocytes.

• UVA and UVB contribute to mutagenesis of DNA by inducing UV landmark mutations.

• UVB leads to decreased density and antigen-processing capability of Langerhans cells and
may suppress production of the T-helper cell type 1 cytokines IL-2 and INF-γ.
• Although these genome-wide studies highlight the mutational complexity and heterogeneity of
SCC, two underlying features emerge.

• First  Inactivating mutations in TSGs and activating mutations in oncogenes (often multiple)
are required for malignant progression.

• Second  loss of functional p53 is a central feature of SCC pathogenesis observed in a

majority of tumors.
• Other agents  SCC include :

• chemical agents (petroleum, coal tar, soot, arsenic)

• physical agents (ionizing radiation)

• exposure to PUVA calculated adjusted relative risk

• HPV, especially important for SCC in the anogenital and periungual regions, in the setting of
immunosuppression with HIV and solid-organ transplantation and in patients with
epidermodysplasia verruciformis

• smoking
• Development of SCC with chronic nonhealing wounds, burn scars, and chronic inflammatory
dermatoses (discoid lupus, ulcers, osteomyelitis).

• Cervicofacial regions, the ear and the lower lip  prone to developing SCC than BCC.

• Heritable conditions associated with higher incidence of SCC include xeroderma pigmentosum,
dystrophic epidermolysis bullosa, and oculocutaneous albinism.
Clinical Features of Squamous Cell Carcinoma
and Its Variants
• SCCIS appears as a discrete solitary, sharply demarcated, scaly pink to red papule or thin plaque
(Fig. 92.7).

• Erythroplasia of Queyrat (SCCIS on the glans of penis of uncircumcised male related to HPV
infection) presents as a verrucous or polypoid papule or plaque, often eroded.

• Invasive SCC appears as a slightly raised papule plaque or nodule that is skin-colored, pink, or red
(Fig. 92.8).
• The surface of the tumor may be smooth, keratotic or ulcerated.

• The lesion may also be exophytic or indurated.

• Symptomatic with pain or pruritus, bleeding with minimal trauma is common.

• It can be clinically difficult to distinguish an invasive SCC from a hypertrophic AK, a benign
seborrheic keratosis, or a benign inflammatory lesion.

• Biopsy  performed.
• Keratoacanthoma (KA) is a variant of SCC defined by a symmetric crateriform architecture and a
clinical presentation marked by rapid growth (up to several centimeters) over a period of several
weeks.

• Typically stabilizes in size and often spontaneously regresses.

• KAs  in a benign fashion.

• Recommended to treat Kas as a subtype of SCC with appropriate surgical therapy.

• Verrucous carcinoma, a variant of SCC, includes oral florid papillomatosis, giant condyloma of
Buschke-Lowenstein (on the genitalia) and epithelioma cuniculatum (on the plantar foot).

• a low-grade carcinoma.

• It grows slowly and metastasizes, but is frequently deeply invasive into underlying tissue and
therefore is difficult to eradicate.

• Following treatment with RT, may become aggressive or even metastasize.

Clinical Behavior of Squamous Cell
Carcinoma
• Cutaneous SCCIS is a full-thickness intraepidermal carcinoma.

• Most lesions are indolent and enlarge slowly over years, progressing to invasive carcinoma.

• Retrospective studies  the risk of progression to invasive SCC is approximately 3% to 5%.

• The risk of progression into invasive disease for genital erythroplasia of Queyrat is approximately 10%.

• Bowenoid papulosis classically presents as a reddish brown verrucous papule and HPV-16 and -18,
involves the genitals.
• Based studies and other retrospective case series, the National Comprehensive Cancer Network
identified key clinical and histologic risk factors for recurrence of NMSC and the American Joint
Committee on Cancer (AJCC) developed staging criteria for cutaneous SCC based upon these
characteristics in 2011.

• The AJCC criteria specifically identify four high-risk features: depth >2 mm thickness or Clark level
IV or greater, perineural invasion, location on ear or nonglabrous lip, and poor histologic
differentiation.

• Tumors ≤2 cm in diameter with less than two of these high-risk features are classified as T1

• Tumors >2 cm or any tumor with two or more high-risk features are classified as T2.

• Tumors with invasion of bone are classified as T3 and T4, depending on whether there is
invasion of facial bones (T3) or other skeletal sites (T4).
Treatment
• Many treatments for BCC are also appropriate for SCC.

• The type of therapy should be selected on the basis of size of the lesion, anatomic location, depth
of invasion, degree of cellular differentiation, history of previous treatment, and immune status of
the host.

• general approaches to treatment of SCC:

• (1) destruction by C&D

• (2) removal by excisional surgery or MMS and

• (3) radiation therapy

Cautery/Electrodesiccation

• C&D is a simple, cost-effective technique for treating low-risk SCCs.

• Study, two recurrences were noted in lesions <2 cm in diameter.

• C&D is frequently used for SCCIS.

• SCCIS may be treated by cryotherapy.

Surgical Modalities

• treatment modality for SCC.

• demonstrated that lesions of <2 cm in diameter can be safely treated by excision, with a 95%
confidence interval using margins of 4 mm and 6 mm for low-risk and high-risk tumors,
respectively.

• High risk as a size of ≥2 cm, histologic grade higher than 2, invasion of the subcutaneous tissue,
and location in high-risk areas (primarily periorifical central face).

• Carcinomas of the penis, vulva, and anus are usually treated by excision or MMS.

• Surgical excision  treatment for verrucous carcinoma.

• MMS is indicated for high-risk SCCs including invasive, poorly differentiated SCCs, and lesions occurring
in high-risk anatomic sites or sites in which conservation of normal tissue is essential for preservation
of function and/or cosmesis.

• Recurrence rates with MMS are superior to those obtained with traditional excisional surgery in
• primary SCC of the ear (3.1% versus 10.9%)
• primary SCC of the lip (5.8% versus 18.7%)

• recurrent SCC (10% versus 23.3%),

• SCC with PNI (0% versus 47%), SCC >2 cm (25.2% versus 41.7%), and poorly differentiated SCC (32.6%
versus 53.6%).

• MMS has proven useful in SCC involving the nail unit  a limb-sparing procedure in cases of SCCarising
in osteomyelitis.
Radiation Therapy

• Indications for RT for patients with SCC are similar to those for patients with BCC.

• For early stage lesions is similar for both surgery and RT.

• The decision on which modality to employ depends on other factors, including a patient’s
underlying medical status, age, expected post treatment cosmesis, cost and treatment availability.
• Advanced cutaneous cancers may be treated with surgery and adjuvant RT.

• In a retrospective study of patients with SCC of the lip a 53% local RR in patients who underwent
surgery alone (37% of positive, borderline, or unreported surgical margins) compared with a 6% local
RR in the minority of patients treated with surgery and adjuvant RT.

• Indications for postsurgical RT include positive margins, PNI (symptomatic), multiple recurrences and
underlying tissue invasion.

• Advanced unresectable cancers, with marked PNI or with gross disease in the cavernous sinus, treated
with RT.
Management of Regional Lymph Node
Metastases
• Treatment of nodal disease  involve local RT, lymph node dissection or a combination of both.

• Skin cancer metastatic to the parotid nodes is commonly managed with superficial or surgical
total parotidectomy followed by adjuvant RT (60 Gy in 30 fractions).

• Surgery and adjuvant RT, 5-year disease-free survival ranges from 70% to 75%.

• The risk of subclinical disease in the clinically negative nodes is ≥20%, the ipsilateral neck 
electively irradiated when the parotid is treated postoperatively.

• RT alone is used  unresectable disease and for medically inoperable.

Medical Therapy for Advanced Subcutaneous
Cell Carcinoma
• Apart from surgical therapy or RT, treatment options for SCC are limited.

• Local, intralesional chemotherapy with methotrexate (one to three injections of 5 to 40 mg each)

and 5-FU (up to eight injections of 10 to 150 mg each)  up to 100% effective for treatment of
KA-type SCC in small case series.

• Typical SCC, intralesional treatment with IFN  effective treatment, and may be particularly
useful as salvage therapy for advanced or multiply recurrent disease.

• The study to date treated 27 invasive SCC and 7 SCCIS with intralesional IFN-alpha-2b, 1.5 million
units three times a week for 3 weeks and found a 97% cure rate at 3 months.
• The long-term prognosis for metastatic SCC is extremely poor.

• Treatment of metastatic disease  systemic chemotherapy or treatment with biologic response

modifiers.

• Cetuximab is a chimeri monoclonal antibody directed against EGFR that inhibits EGFR signaling 
treatment of head and neck (mucosal) SCC and has been used off label for cutaneous SCC.

• The first phase 2 study of monotherapy with weekly cetuximab infusions for unresectable or
metastatic cutaneous SCC showed a complete response rate of 6% and a partial response (at least
30% decrease in tumor size) of 22%.
Angiosarcoma
Introduction
• Angiosarcoma  malignant hemangioendothelioma, hemangiosarcoma, and lymphangiosarcoma
is an uncommon, aggressive.

• Neoplasm of vascular endothelium origin accounting for <2% of all sarcomas.

• Incidence of this tumor is approximately 0.1 per million per year.

• Four variants of cutaneous AS  recognized and include AS of the “head and neck” (also known
as idiopathic AS) accounting for 50% to 60% of all cases, AS in the context of lymphedema
(lymphedema-associated AS (LAS) Stewart-Treves syndrome), radiation-induced AS and
epithelioid AS.
Clinical Presentation and Prognosis
• Cutaneous AS of the head and scalp usually affects older adults.

• 70% of AS occurs in patients over the age of 40 years and the highest incidence of the disease is
reported in 70 years of age.

• Men are more commonly affected than women with 1.6 to 3:1 ratio.
• Cutaneous AS presents :
• violaceous to red.
• illdefined patch on the central face.
• forehead or scalp.
• resembling a bruise.
• Facial swelling and edema.
• Satellite lesions are common.
• Ulceration
• Differential diagnosis 
• Benign vascular tumor.
• Hematoma secondary to trauma.
• Inflammatory dermatosis.

• Prognosis of cutaneous AS is poor,

• mortality rate of 50% at 15 months after diagnosis

• survival rates ranging from 10% to 30% over a 5-year period, median survival 18 to 28 months.

• Metastatic potential of AS is high  lung, liver, lymph nodes, spleen, and brain are common.
Histology
• Highly variable in the degree of cellular endothelial differentiation between and within individual
tumors.

• In well-differentiated lesions, an anastomosing network of sinusoidal irregularly dilated vascular

channels lined by a single layer of flattened endothelial cells with mild to moderate nuclear atypia is
commonly seen.

• Highly infiltrative pattern, splitting collagen bundles and subcutaneous adipose tissue.

• Less-differentiated tumors  proliferation of atypical, polygonal or spindle-shaped, pleomorphic

endothelial cells with increased mitotic activity and anastomosing vascular channels.
• In poorly differentiated AS, luminal formation may be no longer apparent and mitotic activity is high.

• Poorly differentiated AS may mimic other high-grade sarcomas, carcinoma, or even melanoma.

• Immunohistochemical analysis  diagnosis of AS, as cells stain positively for Ulex europaeus I lectin
and factor VIII–related antigen.

• Ulex I is considered to be more sensitive marker for AS.

• AS cells express stem cell antigen CD34 and endothelial cell surface antigen CD31.

• The majority of AS cases stain positively for vimetin, D2-40, and VEGFR-3.
Treatment
• Treatment options for AS are limited.

• Surgical excision with wide margins is the treatment of choice.

• Amputation with shoulder disarticulation or hemipelvectomy is recommended for tumors

involving the extremities.

• Patients with isolated lymphatic spread treated with taxol-based chemotherapeutic regimens
have a favorable outcome.

• Chemotherapy and radical RT are palliative only for metastatic disease and do not improve overall
survival.
Dermatofibrosarcoma Protuberans
Introduction
• DFSP  rare soft tissue sarcoma with aggressive local but low metastatic potential with an annual
incidence of approximately 4 per million.

• DFSP constitutes approximately 1% of all sarcomas and <0.1% of all malignancies.

• The vast majority, 90% of DFSPs, low-grade sarcomas, classified as intermediate or high grade
because of the presence of a high-grade fibrosarcomatous component (DFSP-FS).

• DFSP  affects patients in their mid- to late 30s

• Childhood and congenital cases of DFSP reported.

• Blacks have slightly higher incidence than whites.

• Both men and women are equally affected.

Pathogenesis
• DFSP is incompletely understood but may involve factors as diverse as aberrant TSG or a history of
local trauma/scarring.

• > 90% of DFSP feature a translocation between chromosomes 17 and 22, resulting in the fusion
between the collagen type Iα1 gene (COL1A1) and the plateletderived growth factor (PDGF) β-
chain gene (PDGFB).

• Growth of DFSP is a result of the deregulation of PDGF β-chain expression and activation of PDGF
receptor (PDGFR) protein tyrosine kinase.

• DFSP classically presents as a solitary, frequently asymptomatic, plaque with violaceous to blue
hue.
Treatment
• Treatment options for DFSP include WLE and MMS.

• Most authors advocate WLE with a minimal margin of at least 3 cm of surrounding skin, including
the underlying fascia, without elective lymph node dissection.

• Conservative resection can lead to RRs of 33% to 60%, whereas wider excision margins (≥2.5 cm)
to reduce the RR to 10%.

• Extirpation of tumor by MMS, using frozen sections with or without confirmation by examination
of paraffin-embedded sections, beneficial in sites where maximum conservation of normal tissue
is required.
• In study, compared literature-reported observational data on 41 patients who underwent MMS
and 38 who underwent WLE.

• Recurrence rates were 13.2% and 0% for WLE and MMS at 4.8 and 5.4 years follow-up.

• In the cases of congenital DFSP treated with MMS  100% during an average follow-up period of
4.3 years.

• Alternative treatment options for DFSP include RT and chemotherapy.

Merkel Cell Carcinoma
Definition

• Merkel Cell Carcinoma (MCC) is a rare and aggressive tumor of neuroendocrine cell
origin.

• Merkel cells derive from the neural crest and differentiate as a part of the amine precursor
uptake and decarboxylation system.

• Merkel cells function as slowly adapting type I mechanoreceptor

Epidemiology
• The incidence in the United States is estimated at 3 per million people.

• Incidence of MCC is estimated at more than twice in men that in women, and whites are
more than 20 times more likely to develop the disease than blacks.

• The average age at diagnosis is 70 years.

• The risk is higher among whites of European ancestry, incidence is inversely related to latitude,
and the majority of tumors present on the face (36%), head, extremities, and trunk
PATHOGENESIS
• The pathogenesis of MCC is incompletely characterized.

• Age and UVR has been indirectly implicated in the development of MCC.

• The risk of MCC is particularly high with prior PUVA treatment (100 times higher than
expected in the general population)

• Immunosuppression, HIV infection, or neoplasia, may play a role in the development of

MCC.
CLINICAL PRESENTATION
• MCC presents as a rapidly growing, firm, fleshcolored or red-violaceous, dome-shaped papule
or plaque on sunexposed skin.

• Most lesions are <2 cm in diameter at the time of diagnosis.

• Clinical differential diagnosis often includes leukemia cutis, amelanotic melanoma, metastatic
carcinoma, pyogenic granuloma, BCC, and SCC.

• Regional lymph nodes are involved in up to 30% of patients, and approximately 50% of
patients develop systemic disease.

• Secondary sites of MCC spread include skin (28%), lymph nodes (27%), liver (13%), lung
(10%), bone (10%), and brain (6%).
HISTOLOGY
• Histologic examination of MCC reveals sheets and cords of atypical cells in the dermis
extending to the subcutaneous layer that sometimes form an interlacing trabecular or
pseudoglandular pattern
TREATMENT
• MCC warrants aggressive therapy.
• It has a high propensity for local recurrence (20% to 75%), regional
(31% to 80%), and distant metastases (26% to 75%).
• Evaluation must include full-body skin examination with lymph node
evaluation, a complete blood cell count, and liver function tests. CT
scanning of the chest, pelvis, and abdomen may be indicated to
detect distal metastasis
STAGING
• stage I (primary tumor alone, <2 cm in diameter),
• stage II (primary tumor alone, >2 cm in diameter),
• stage III (regional nodal disease),
• stage IV (distant metastatic disease).
RECURRENCE AND METASTATIC RISK
• MCC has a propensity to recur locally (sometimes with satellite lesions and/or in-transit
metastases) following surgical excision.

• MCC spreads to regional lymph nodes within 2 years in up to 70% of cases.

• Radiation to the primary site has been considered for patients with larger (>2 cm) tumors
and locally unresectable tumors, while adjuvant nodal radiation is considered for those
with positive regional nodes (stage II)

• Chemotherapy is used for nodal, metastatic, and recurrent MCC, but an optimal treatment
regimen is yet to be established
PROGNOSIS
• The prognosis of MCC is directly correlated with the stage of disease.

• Reported 5-year survival according to MSKCC classification is 81% for stage I, 67% for
stage II, 52% for stage III, and 11% for stage IV.

• More than 50% of patients experience recurrence with the median time to recurrence of 9
months (range, 2 to 70 months).

• Ninety-one percent of recurrences occurred within 2 years of diagnosis.

Microcystic adnexal carcinoma
• Literature described MAC as sclerosing sweat duct carcinoma, malignant syringoma,
sweat gland carcinoma with syringomatous features, aggressive trichofolliculoma, and
combined adnexal tumor of the skin.

• MAC originates from pluripotent adnexal keratinocytes capable of both eccrine and
follicular differentiation.

• The pathogenesis of MAC is not completely understood but may involve exposure to
ionizing and UVR that may precede development of MAC by as long as 40 years

• Primarily affects white, middle-aged individuals, and female predominance.

CLINICAL AND HISTOLOGIC FEATURES
• MAC classically presents as a smooth-surfaced, nonulcerated, flesh-colored to yellowish
asymptomatic nodule, papule, or plaque.

• Common symptom : numbness, tenderness, anesthesia, paresthesia, burning, discomfort,

and/ or rarely pruritus of the affected site.

• MAC has a clear predilection for the head and neck (86% to 88%), particularly the central
face (73%). Other sites include eyelid, scalp, breast/chest, axillae, buttocks, vulva,
extremities, and tongue.
• Histologically, MAC is a tumor of pilar and eccrine differentiation.

• The tumor frequently exhibits a stratified appearance with larger keratin horn cysts and
epithelial nests, strands, or cords in the superficial dermis and desmoplastic features in
the deeper dermis with smaller cysts and more pronounced ductal structures.
TREATMENT AND PROGNOSIS
• Current standard of care for MAC is to surgically remove the tumor in its entirety
whenever feasible.

• Margins reported in the literature for WLE vary from a few millimeters to 3 to 5 cm.

• Extirpation of tumor by MMS may prove beneficial in the management of MAC.

• Recurrence rates vary significantly between the two surgical techniques with rates after
WLE and MMS ranging from 40% to 60%204 and 0 to 12%.
Sebaceous carcinoma
• Sebaceous carcinoma (SC) is a malignant adnexal tumor with variable sites of origin,
histologic growth patterns, and clinical presentations.

• About 75% of SCs are periocular in location.

• Periocular SC may arise from Meibomian glands and, less frequently, from the glands of Zeis.
The upper eyelids are most frequently involved.

• Worldwide, SC affects all races, but Asians are particularly prone to the disease.

• Women are affected more commonly than men, at a ratio of approximately 2:1.

• SC classically presents in the seventh to ninth decades.

CLINICAL AND HISTOLOGIC FEATURES
• The most frequent clinical presentation is a slowly growing, painless, subcutaneous nodule.

• Other presentations include diffuse thickening of the skin, pedunculated papules, or an

irregular subcutaneous mass.

• On the eyelid, SC is most often misdiagnosed as chalazion

• Histologically, SCs are classified as well, moderately, or poorly differentiated.

• Most commonly, lesions have an irregular lobular growth pattern with sebaceous and
undifferentiated cells.
TREATMENT AND PROGNOSIS
• Treatment options for SC include WLE with 5- to 6-mm margins and extirpation by MMS.

• SCs have high rates of local recurrence and metastasis, particularly when occurring on
he eyelid.

• SC can spread by lymphatic or hematogenous routes or by direct extension.

• Distant metastases are reported in up to 20% of cases and may involve the lungs, liver,
brain, bones, and lymph nodes.

• Mortality of SC ranges from 9% to 50%.

Extramammary Paget disease
• Extramammary Paget disease (EMPD) is a rare cutaneous malignancy of older adults,
often on the genitalia, with a mean age of onset of approximately 70 years.

• While there is a slight female predominance in Caucasian patients, there is a strong 4:1
male predominance in Asians.

• EMPD is most often a primary intraepidermal malignancy thought to derive from eccrine
or apocrine glands.
CLINICAL AND HISTOLOGIC FEATURES
• EMPD most often presents as a pink to bright red plaque of the genitalia. Scaling,
erosion, and maceration are common features.

• Biopsy of EMPD reveals acanthosis with an intraepidermal proliferation of large, pale

staining cells with prominent vesicular nuclei.

• These cells are spread throughout all layers of the epidermis, often forming large clusters
just above the basal layer.

• Mitotic figures may be present.

TREATMENT AND PROGNOSIS
• Complete surgical excision of EMPD has classically been the standard of care, although
local RRs may be as high as 30% to 40%.

• Overall, the prognosis for primary EMPD is good, with a reported 85% overall survival at 5
years.
Malignant Fibrous Histiocytoma
• Under the new classification, the term malignant fibrous histiocytoma is a synonym for
undifferentiated pleomorphic sarcoma (UPS) not otherwise specified.

• UPS is a deep-seated subcutaneous nodule rarely encountered in the skin; it is most

often seen on the limbs of elderly patients.

• UPS is an aggressive tumor with a poor prognosis.

• Although complete surgical excision is the preferred treatment (often with adjuvant RT),
up to 50% of patients may have distant metastasis at the time of initial presentation, with
the lung being the most common site.
Atypical Fibroxanthoma
• AFX is a spindle cell tumor that occurs on the head and neck of sun-exposed individuals
and on the trunk and extremities of younger patients.

• Tumors of the head and neck characteristically present during the eighth decade,
whereas tumors involving the extremities often present during the fourth decade.

• The ratio of affected men to women appears to be equal.

• The pathogenesis of AFX involves exposure to UVR, ionizing radiation, and/ or aberrant
immune host response.
CLINICAL AND HISTOLOGIC FEATURES
• AFX usually presents as an asymptomatic, often rapidly growing, dome-shaped papule or
nodule covered by thin epidermis on actinically damaged skin of individuals with a fair
complexion.

• Average size at presentation is 1 to 2 cm.

• The clinical appearance is not distinctive, and the clinical differential diagnosis of the
lesion often includes pyogenic granuloma, SCC, BCC, amelanotic melanoma, MCC, and
cutaneous metastasis.

• AFX may be found in the setting of other NMSCs.

TREATMENT AND PROGNOSIS
• Treatment of AFX is surgical removal by WLE or MMS.

• The authors favor the use of MMS for AFX because of the superior margin control and
conservation of normal tissue.

• Although AFX rarely metastasizes, it is a locally aggressive tumor with metastatic

potential.

• Metastases to the parotid gland, lymph nodes, and lung have been reported.
Carcinoma Metastatic to Skin
• The most frequently observed cutaneous metastatic cancers are breast, colon, and melanoma in
women, and lung, colon, and melanoma in men.

• Cutaneous involvement is also seen in the leukemias, with a wide variation in the morphology of
lesions.

• The scalp is a common site for cutaneous metastatic disease. Immunohistochemical stains may be
helpful in determining the site of the primary tumor.

• The discovery of cutaneous metastatic disease should prompt consultation with an oncologist for
staging and management.
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