Squamous Cell Carcinoma, General Concepts

Squamous Cell Carcinoma, General Concepts

Antonio L. Cubilla, MD

Alcides Chaux, MD

Elsa F. Velazquez, MD

Distal penis includes the glans image (mostly composed of corpus spongiosum and containing the penile urethra image), coronal sulcus image, and foreskin image with an inner mucosal and an outer skin surface.

Transverse section of penile shaft depicts both dorsal corpora cavernosa image, ventral corpus spongiosum image with penile urethra image, tunica albuginea image, penile fascia image, and skin image.



  • Squamous cell carcinoma (SCC)


  • Malignant epithelial neoplasia showing keratinocytic differentiation


Anatomical Considerations

  • Penile anatomical regions are glans, foreskin, and shaft

  • Glans is distal, most cone-shaped region, formed by corpus spongiosum (CS) covered by squamous mucosa

    • Distal urethra opens up into meatus, a ventrally located slit-like orifice in glans

    • Glans corona separates glans from coronal sulcus

  • Coronal sulcus is cul-de-sac between glans and foreskin

  • Foreskin covers glans and presents mucosal (inner) and cutaneous (outer) surface

    • Frenulum connects foreskin to ventral portion of glans corona

  • Penile shaft is composed mainly by ventral column of corpus spongiosum and 2 dorsal columns of corpora cavernosa

  • Penile root anchors penis to perineal membrane and pubic arc

Histological Features

  • Glans, coronal sulcus, and inner foreskin are covered by nonkeratinized squamous epithelium overlying loose lamina propria

  • Penile erectile tissues comprising 2 corpora cavernosa (CC) and CS surrounding penile urethra form body of penile shaft

    • Irregular vascular spaces with intermingling elastic connective tissue form penile erectile tissues

    • Vascular spaces of CS are more widely spaced and irregular when compared with CC

    • CC present more densely packed vascular spaces with less intervening stroma

    • Tunica albuginea composed of dense connective tissue encompasses both CC and separates them from CS

    • CS is also covered by tunica albuginea

  • Outer foreskin and shaft are covered by skin

  • Bundles of dartos muscle extend underneath dermis throughout shaft and foreskin


Age Range

  • Most frequent in 6th to 7th decades

  • Average age is 58 years


  • SCC represents most common malignant tumor of penis

  • Wide range of geographical variation

    • Low incidence in USA and Europe

    • High incidence in South America, Africa, Asia

Natural History

  • Local invasion of penile anatomical levels

  • Extension to adjacent tissues

    • Scrotum, perineum, prostate

  • Metastasis to inguinal lymph nodes

    • Sentinel node(s), superficial and deep nodes

  • Metastasis to pelvic lymph nodes

  • Systemic dissemination (nonregional lymph nodes, visceral, and bone involvement)

  • Liver is most common site of metastatic dissemination followed by lungs and heart

  • Systemic dissemination presents in up to 1/3 of patients in high-risk regions



  • 30-40% of all SCC are HPV-related

  • High-risk HPV predominates

    • HPV-16 is most common genotype encountered

    • HPV-18 is 2nd most common type

    • Other reported genotypes include 45, 52, and 74

  • Low-risk HPV infection is uncommon

    • Low-risk HPV reported are genotypes 6 and 11

  • Striking correlation of HPV presence and tumor morphology

    • Basaloid and condylomatous (warty) SCC are HPV-related in most cases

    • HPV incidence is low in usual, sarcomatoid, and papillary SCC


  • Verrucous, pseudohyperplastic, and cuniculatum SCC are typically HPV-negative tumors

  • Chronic inflammatory conditions (such as lichen sclerosus) are common in these cases

Risk Factors

  • Phimosis is major risk factor for penile cancer

  • Lack of neonatal circumcision

  • HPV infection (especially by high-risk genotypes)

  • History of genital warts

  • Poor hygiene

  • Smoking

  • Treatment with psoralen and ultraviolet A (PUVA) therapy


Clinical Presentation

  • Most penile SCCs originate from squamous mucosal surface of distal penis (glans, coronal sulcus, &/or foreskin)

    • Glans is most common affected site followed by inner foreskin and coronal sulcus

    • About 1/2 of penile carcinomas affect multiple anatomic compartments

  • SCC of penile shaft are exceedingly rare

  • Presence of painless tumoral mass is most frequent clinical presentation

  • Ulceration may be present

  • Urinary obstruction secondary to urethral tumoral extension is uncommon

  • Phimosis is found in 50% of cases


General Features

  • Patterns of growth include superficial spreading, vertical, verruciform, and multicentric

    • Superficial spreading

      • Broad horizontal/superficial extension with involvement of 1 or more anatomical compartments

      • Extensive in situ component with tumoral invasion usually confined to lamina propria

    • Vertical growth

      • Deeply infiltrative tumor with frank invasion of corpus spongiosum or corpus cavernosum

    • Verruciform

      • Exophytic cauliflower-like tumor mass usually invading only superficial anatomical levels

    • Multicentric

      • Presence of 2 or more independent foci of SCC

  • Mixed/combinations of any of aforementioned patterns may be seen

  • Superficial spreading tumors show intermediate risk for inguinal metastasis

  • Vertical growth tumors show higher rate of nodal involvement and poor outcome

  • Verruciform tumors may reach large sizes but tend to be localized and metastatic rate is low

  • In multicentric tumors, foci should be separately evaluated

Specimen Handling

  • Wide local excision specimen

    • Fix in 10% buffered formalin, preferably overnight

    • Measure and describe specimen, identifying and describing tumor

    • Photograph or diagram specimen

    • Ink entire surgical margin of specimen

    • Section specimen transverse to longest axis

    • Submit tumor entirely if < 3-4 cm and section at least 1 per cm, including grossly apparent deepest penetration and all margins (if not entirely submitted)

  • Circumcision specimen for tumor

    • Lightly stretch and pin specimen to flat surface

    • Fix in 10% buffered formalin, preferably overnight

    • Measure and describe specimen, identifying and describing tumor

    • Photograph or diagram specimen

    • Ink mucosal and cutaneous margins of resection with different colors

    • Section specimen transversally to its longest axis

    • Label each section from 1-12 clockwise

    • Submit entirely if < 3-4 cm, section at least 1 per cm, including grossly apparent deepest penetration and all margins (if not entirely submitted)

  • Partial/total penectomy specimen

    • Fix entire specimen in 10% buffered formalin, preferably overnight

    • When fixed, section specimen in 2 halves using meatus and anterior urethra as a guide

    • Do not probe urethra

    • If foreskin is not affected by tumor, separate leaving 3 mm margin from coronal sulcus and include as circumcision specimen

    • If foreskin is affected by tumor, do not remove

    • Photograph or diagram specimen, focusing on tumor invasion of anatomic levels

    • Section each 1/2 longitudinally to longest axis, at 3-5 mm intervals

    • Photograph (or diagram) and submit entirely section, depicting deepest anatomic level infiltrated by tumor

    • If tumor affects multiple anatomic compartments, at least 3 sections of each affected compartment should be submitted

    • Sections should always include adjacent nontumoral mucosa

    • Resection margins in partial penectomies are urethra and periurethral tissues; corpora cavernosa and skin of shaft should be appropriately submitted

  • Lymphadenectomy specimen

    • Fix in 10% buffered formalin, preferably overnight

    • Identify number and size of all lymph nodes

    • If feasible, record anatomic location of lymph nodes as upper inner quadrant, superficial and deep inguinal nodes

    • Submit all lymph nodes for histologic examination


General Features

  • Most penile cancers are SCCs, but there are several histological subtypes/variants

  • Each subtype is usually associated with defined clinical outcome and prognosis

  • Subtyping helps in management of therapy

    • Some variants are often treated more aggressively than others

Histological Subtypes

  • Subtyping should always be done following strict morphological criteria

  • Histological subtypes of penile SCC include

    • Usual

    • Verrucous

    • Papillary, not otherwise specified (NOS)

    • Warty (condylomatous)

    • Basaloid

    • Adenosquamous

    • Pseudoglandular (acantholytic, adenoid)

    • Cuniculatum

    • Pseudohyperplastic

    • Sarcomatoid

    • Mixed

  • Each histologic subtype often clinically behaves in distinctive fashion

  • Verruciform tumors and pseudohyperplastic carcinomas are associated with low risk for nodal metastasis

  • Tumors with high risk for nodal involvement include basaloid, sarcomatoid, adenosquamous, and poorly differentiated usual SCC

  • Low-grade usual SCC, some mixed tumors, and pleomorphic variants of warty carcinoma are in intermediate category

Correlation of Pattern of Growth and Histological Subtype

  • Verruciform tumors include warty (condylomatous), verrucous, papillary NOS, and cuniculatum carcinomas

  • Basaloid, high-grade usual type, and sarcomatoid SCCs (aggressive variants) usually present with vertical pattern of growth

  • Superficial spreading growth pattern is characteristic of low-grade variants of SCC

  • Multicentricity is more common in low-grade highly differentiated SCC variants, especially those located in foreskin (e.g., pseudohyperplastic SCC)

  • Mixed patterns of growth are usually observed in mixed low- and high-grade variants of SCC

Histological Grade

  • Important predictive factor of inguinal lymph node metastasis and outcome

    • Grading should always be done following strict morphologic criteria

  • Criteria for grading

    • Grade 1

      • Almost normal to slightly enlarged nuclei and abundant eosinophilic cytoplasm

      • Minimal basal/parabasal atypia and prominent keratinization

    • Grade 2

      • More disorganized growth compared to grade 1 lesions

      • Higher nuclear:cytoplasmic ratio, evident mitoses, and less prominent keratinization

    • Grade 3

      • Tumors composed of any proportion of anaplastic cells with evident nuclear pleomorphism

  • Heterogeneous tumors showing areas with different histologic grades are seen in up to 1/2 of all cases

    • Tumor grading should be performed considering highest grade component, regardless of its proportion

Depth of Invasion/Tumor Thickness

  • Depth of invasion measured from basal cell layer of adjacent normal epithelia to deepest point of infiltration

  • Thickness measured from nonnecrotic nonkeratinized tumor surface to its deepest point of infiltration

  • Depth and thickness are equally useful, except for verruciform tumors, for which depth of invasion should be preferred

    • In tumors measuring < 5 mm, there is minimal risk for nodal metastasis

    • In tumors measuring > 10 mm, there is high risk for nodal involvement

    • In tumors measuring 5-10 mm, histological grade and perineural invasion are helpful to estimate potential for nodal metastasis

Anatomic Level of Invasion and Pathologic Stage

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Squamous Cell Carcinoma, General Concepts

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