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Penis and scrotum

Squamous cell carcinoma and variants

Squamous cell carcinoma-general

Reviewers:

Revised: 30 April 2010

Last major update: April 2010

See also specific variants described separately

Definition

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● Malignant epithelial tumor composed of squamous cells

Epidemiology

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● Most penile neoplasms are squamous cell carcinoma

● Rare in US: <1% of carcinomas in men (Cancer 2008;113:2883) vs. 10-20% in Asia [excluding Japan], Africa, South America

● Usually age 40-70 years, median age 58 years

● Incidence is 0.29 per 100K in US whites vs. 4.2 per 100K in Paraguay vs. 4.4 per 100K in Uganda

● Rare if circumcision at birth, more common if late circumcision (after age 10)

● More prevalent in populations with lower education and higher poverty (Cancer 2008;113:2910)

● More common in Hispanic and black men

● Familial cases have occasionally been reported

● Patients from high-risk areas tend to be younger and present with a higher stage disease

● Rarely associated with genital piercing (J Sex Med 2010 Apr 20 [Epub ahead of print])

Risk factors

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● Phimosis and long foreskin, paraphimosis (Am J Surg Pathol 2003;27:994)

● HPV, particularly HPV 16, and related risk factors (Cancer Epidemiol Biomarkers Prev 2008;17:2683)

● 1/3 of non-HPV cases are associated with lichen sclerosus (balanitis xerotica obliterans, Am J Surg Pathol 2003;27:1448)

● Penile injury, tears and chronic balanitis

● Genital warts (6x increased risk) (J Natl Cancer Inst 1993;85:19)

● Smoking, psoriasis patients treated with UV B radiation, penile rash > 1 month, immunosuppression, radiation therapy

HPV related squamous cell carcinoma

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● HPV present in 40-50% of penile carcinomas (lower rate in Japanese, Pathol Int 2008;58:477), but frequency varies by histologic type (Am J Surg Pathol 2010;34:104)

● Usually HPV 16 or 18 (J Clin Pathol 2009;62:870)

● HPV-related tumors include basaloid, warty and warty-basaloid carcinomas

● HPV is rarely found in papillary and sarcomatoid carcinomas

● Verrucous, pseudohyperplastic and cuniculatum carcinomas are consistently HPV negative

Sites

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● Most tumors arise from glans or inner foreskin near coronal sulcus as a slow growing, irregular mass

● In high incidence areas, tumors involve multiple anatomical compartments in up to 50% of cases

Clinical features and outcome

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● Patients occasionally present with inguinal nodal metastases with occult penile cancer due to severe phimosis or very small primary tumor

● Local recurrence in 1/3 is due to insufficient surgery or positive margins; increases risk of regional inguinal and pelvic nodal metastases

● 10 year survival rate of 82% (J Urol 2009;182:528)

● Histologic subtypes have similar frequency in Paraguay and US (Int J Surg Pathol 2009 Jul 3 [Epub ahead of print])

Metastases:

● 5% have metastases at diagnosis

● Common sites are inguinal and pelvic lymph nodes, liver, lung, heart or bone (Int J Surg Pathol 2009 May 1 [Epub ahead of print])

● Nodes are often enlarged at clinical presentation due to infection, not metastases

● 5 year survival is related to nodal involvement: 66% (not involved) vs. 27% (involved)

Low grade:

● Usually no regional metastases if only superficial invasion of 6 mm or less (Mod Pathol 2001;14:963)

High grade:

● Deep invasion (8-10 mm) into corpus spongiosum, dartos or corpora cavernosa is associated with 80% rate of metastases

● Intermediate/high grade with invasion of 5-10 mm have 15% risk of metastases

Poor prognostic factors

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● High stage

● High histologic grade (Am J Surg Pathol 2008;32:974, J Surg Oncol 2008;97:487)

● Deeper invasion (anatomic levels are epithelium, lamina propria, corpus spongiosum and corpus cavernosum), but anatomic variations exist (corpus cavernosum may not be located in glans in 25% of cases, Am J Surg Pathol 2001; 25:1091)

● Angiolymphatic invasion (J Urol 2008;180:1354)

● Perineural invasion (World J Urol 2009;27:169)

● Anaplastic, basaloid, pseudoglandular, sarcomatoid or solid subtypes

● Lymph node density in one study (J Urol 2009;182:2721)

The Prognostic Index Score

● Combines histologic grade, anatomical level of tumor infiltration and perineural invasion to predict the likelihood of inguinal nodal involvement (Am J Surg Pathol 2009;33:1049)

● Useful for risk-group stratification and clinical management

● Appropriate for surgical specimens, not for biopsies

● Score is sum of points for histologic grade (grade 1: 1, grade 2: 2, grade 3: 3), anatomical level of maximum tumor infiltration (lamina propria: 1, corpus spongiosum/dartos: 2, corpus cavernosum/preputial skin: 3) and perineural invasion (absent: 0, present: 1)

● Low risk: score of 2-3, intermediate risk: score of 4, high risk: score of 5-7

Diagrams

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Schematic representation of effect of anatomic level of invasion on risk of lymph node metastasis in carcinoma of the glans: Each dot represents an individual case in a series of 51 cases, the green representing cases without lymph node metastasis and the red, cases with lymph node metastasis. Note the propensity for the latter cases to spread into the deep corpus spongiosum or corpus cavernosum. The converse is true for the cases represented by the green dots. (lp-lamina propria, scs-superficial corpus spongiosum, dcs-deep corpus spongiosum, cc-corpus cavernosum.)

Schematic representation of effect of anatomic depth of invasion on risk of lymph node metastasis in carcinoma arising from the mucosa of the foreskin: Each dot represents an individual case in a series of 20 cases, the green dots representing cases without lymph node metastasis and the red dots, cases with lymph node metastasis. Note the tendency for most of the former to invade no deeper than the superficial dartos and the spread to deep dartos or beyond of all cases with lymph node metastasis. (m-mucosa, lp-lamina propria, sd-superficial dartos, dd-deep dartos, dm-dermis, e-epidermis.)

Treatment

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● Local resection, partial/total penectomy (US National Cancer Institute)

● Local excision and partial penectomy are inadequate for sarcomatoid and basaloid carcinomas (Am J Surg Pathol 2009;33:1299); poor outcomes with metastatic disease (Ann Surg Oncol 2007;14:3614)

● Higher risk for recurrence if node positive or partial penectomy (Eur Urol 2008;54:161)

● Possibly brachytherapy for tumors confined to glans (Int J Radiat Oncol Biol Phys 2009;74:1150)

● Criteria for inguinal lymphadenopathy are controversial, as palpable nodes may be reactive (Can Urol Assoc J 2008;2:525)

● Patients with Prognostic Index scores of 2-3 may not need inguinal nodal dissection

● Patients with Prognostic Index scores of 5-7 may benefit from prophylactic groin dissection

Gross description (Macroscopy)

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● Grossly noted growth patterns may have prognostic implications (Am J Surg Pathol 1993;17:753-63, World J Urol 2009;27:169)

● Superficial spreading: tumors are limited to lamina propria or superficial corpus spongiosum and usually extend horizontally through multiple anatomical compartments

● Vertical growth: tumors invade deep anatomical levels, surface is non-verruciform and frequently ulcerated

● Verruciform: tumors are exophytic and papillomatous, with a cauliflower-like aspect, may be limited to surface (verrucous) or invade deep anatomical levels (cuniculatum)

● Mixed patterns: observed in 10-15% of all cases

● In some cases, multicentric tumors (two or more independent foci of carcinomas) are identified

Gross images

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Glans

An exophytic cauliflower-like mass The glans is extensively involved by

has effaced the glans a multinodular mass with focal ulceration

Foreskin

A circumcision specimen shows a flat, Massive involvement has caused multiple foci

granular, beige neoplasm involving the of ulceration of foreskin

mucosa of the foreskin but not the skin

Coronal sulcus

Nodular white tumor extensively Cut section shows two discrete nodules of tumor

involves the sulcus The glans is to the left and the foreskin to the

right. The nodule to the left is in the sulcus, the

one on the right involves the foreskin

Multiple compartments

Massive involvement of glans, coronal sulcus Massive involvement has resulted in

and foreskin with complete effacement of the autoamputation. Patient had penile lesion for

corpus spongiosum, sparing the urethra 11 years but declined treatment until

penis had been destroyed by the cancer,

necessitating an emasculating procedure.

Four separate foci of carcinoma are present

(red in diagram on right). The larger neoplasm

is located in the ventral glans (g) and is

exophytic; three smaller, flat lesions involve

the glans, coronal sulcus (cos), and mucosa

of the foreskin (f)

Superficial spreading squamous cell carcinoma

Tumor involves the glans with extension to The tumor is white, involves the mucosa of the

coronal sulcus; there is an abnormal foreskin and coronal sulcus, and completely

white to erythematous abnormality of the glans covers the glans. There is focal superficial

mucosa which is extensive squamous cell infiltration of the corpus spongiosum. The

carcinoma in situ with a minor foci of invasion diagram shows (red) widespread involvement

of epithelial compartments: mucosa of

foreskin (f), glans (g) and coronal sulcus (cos).

The urethra (u), meatus (m), and skin of shaft (s)

are not involved.

Vertical growth squamous cell carcinoma

A solid yellow-tan neoplasm in the dorsal

half of the glans (top). The diagram shows

that the neoplasm (in red) replaces the

corpus spongiosum of the dorsal glans

and is present at the interface with the

tunica albuginea (a). Foreskin (f),

meatus (m), urethra (u), and corpus

cavernosum (cc) are not compromised.

Verruciform lesions

A: Verrucous carcinoma: regular papillae with broad bulbous bases and prominent hyperkeratosis (red). Keratinized cysts are present (seen on cross section at base). B: Papillary carcinoma, not otherwise specified: papillae that are more irregular than in A, many with fibrovascular cores. Infiltration is present at the base and koilocytosis is absent. C: Giant condyloma: arborescent hyperkeratotic papillae with broad bases and koilocytosis (indicated by the white dots) at the surface. D: Warty (condylomatous) carcinoma: papillae are more irregular than in C, koilocytosis is diffuse, and the interface between tumor and stroma is irregular.

Verrucous carcinoma: A large, destructive,

cauliflower-like mass has extensively

replaced the penis.

Mixed low- and high-grade squamous cell carcinoma

Neoplasm shows superficial, white, serrated papillary and tan, solid, deeply invasive components. In the diagram, the glans surface is completely covered dorsally by a thickened solid tissue (dark blue), which corresponds to the squamous hyperplasia (sh); a papillary exophytic appearance just below the meatus (in mixed blue-red-black colors) corresponds to a low-grade papillary carcinoma (pca) and a serrated benign papillary hyperplasia (ph) (lower part). Most of the corpus spongiosum, including its periurethral and meatal (m) components, is replaced b a high-grade carcinoma (red). Surgical margins are positive ventral to the urethra (u).

Assessment of depth of invasion

Penile carcinoma has been transversely Assessment of depth of invasion of tumor

sectioned showing differing depths of in resected specimen: A close-up of the

invasion of crucial anatomic compartments. bottom portion of the top specimen is seen.

Note involvement of corpora cavernosa

(central two slices), urethra and

periurethral corpus spongiosum (top), and

Buck’s fascia (top and bottom).

Margin involvement

Partial penectomy specimen

Left: There is extensive involvement by carcinoma, including Buck’s fascia, at the resection margin (top right)

Right: This is seen diagrammatically in this figure (top right). (bf-Buck’s fascia, f-foreskin, lp-lamina propria, cs-corpus spongiosum, cc-corpus cavernosum)

Frozen section evaluation of surgical margins

A: Diagrammatic representation of periurethral corpus spongiosum involvement by carcinoma (ca-yellow, u-urethra, cc-corpos cavernosa, fas-Buck’s fascia)

B: Squamous cell carcinoma involves the corpora cavernosa, with the left more involved than the right. The urethra (bottom) is uninvolved

C: Diagram of B showing tumor involvement in yellow (ca-carcinoma, a-tunica albuginea, cc-corpus cavernosum, cs-corpus spongiosum, u-urethra)

Micro description (Histopathology)

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● Most histologic subtypes resemble those in vulva, anus or buccal mucosa

● 48-65% are usual squamous cell carcinoma

● Verruciform tumors are verrucous, warty, papillary or cuniculatum carcinomas

● Basaloid and sarcomatoid carcinomas usually have a vertical growth pattern

● Often undifferentiated (bowenoid) penile intraepithelial neoplasia and lichen sclerosis (J Am Acad Dermatol 2010;62:284)

● Features to report: depth of invasion measured from deepest malignant cells to highest overlying dermal papilla; resection margins

Grading (Am J Surg Pathol 2009;33:1042):

Grade 1: well-differentiated cells, almost undistinguishable from normal squamous cells except for the presence of minimal basal/parabasal cell atypia

Grade 3: any anaplastic cells

Grade 2: all tumors not fitting into criteria for grade 1 or 3

Micro images

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Depth of invasion is measured from the Mucosa is involved by carcinoma at the

deepest malignant cells to the highest top but epidermis (bottom) is spared

overlying dermal papilla

Various histologic subtypes

Grade 1 superficially invasive Grade 2 carcinoma with incomplete

squamous cell carcinoma squamous differentiation and only

focal keratinization

Grade 3 carcinoma with minimal squamous Tumor embolus within vascular space

differentiation, numerous mitotic figures

and bizarre nuclei

Invasion of the lamina propria with

sparing of the corpus spongiosum (left)

Possible sites of resection margin involvement at time of frozen section. Left: Diagrammatic representation of possible sites of involvement. The purple dots indicate the usual sites of positive margins (u-urethra, lp-lamina propria, cs-corpus spongiosum, bf-Buck’s fascia). Right: Urethral mucosal involvement is illustrated microscopically.

EGFR+

Positive stains

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● EGFR (Curr Oncol 2010;17:4)

Molecular / cytogenetics description

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● Mutations in PIK3CA, HRAS or KRAS genes in 39% (J Urol 2008;179:2030)

● Epigenetic silencing (by methylation) of FHIT gene in 92% (Virchows Arch 2008;452:377)

Additional references

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● eMedicine

End of Penis and scrotum > Squamous cell carcinoma-general

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