Penis & scrotum

Squamous cell carcinoma and variants

HPV associated squamous cell carcinoma

Last author update: 1 April 2010
Last staff update: 19 January 2024

Copyright: 2002-2024,, Inc.

PubMed Search: HPV associated squamous cell carcinoma penis

Alcides Chaux, M.D.
Antonio L. Cubilla, M.D.
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Cite this page: Chaux A, Cubilla AL. HPV associated squamous cell carcinoma. website. Accessed May 19th, 2024.
Basaloid carcinoma
Definition / general
  • Squamous cell carcinoma composed of uniform, small to intermediate cells in solid sheets or nests and often with central comedo-like necrosis

ICD coding
  • ICD-O: 8083/3 - basaloid squamous cell carcinoma


  • Glans is the preferred site but extension to coronal sulcus and inner foreskin is common


Diagrams / tables

AFIP images

Yellow with focal necrosis

Clinical features
  • Aggressive, high grade and deeply invasive penile tumor
  • Inguinal nodal metastases in 50 - 100% and local recurrence in 36% (J Urol 2006;176:1431)
  • High mortality rate (21 - 67%)

Prognostic factors
  • Regional metastasis and mortality associated with tumor thickness > 10 mm and infiltration of corpus cavernosum (Am J Surg Pathol 1998;22:755)


Gross description
  • Flat, ulcerated, irregular mass with solid tan tissue replacing corpus spongiosum and invading tunica albuginea and corpus cavernosa
  • Mean tumor size of 3 - 4.5 cm

Gross images

AFIP images

Yellow-white tumor

Microscopic (histologic) description
  • Closely attached nests of tumor cells, often with central comedo-like necrosis
  • Vertical growth pattern is typical
  • Composed of small to intermediate basophilic cells with scant cytoplasm, indistinctive cell borders and high mitotic / apoptotic rate
  • Occasionally peripheral palisading and focal central abrupt keratinization
  • May have peripheral clefts due to retraction artifact
  • Frequently associated with basaloid or warty penile intraepithelial neoplasia (Int J Surg Pathol 2004;12:351)
  • Prominent perineural and vascular invasion

Microscopic (histologic) images

Contributed by Alcides Chaux, M.D., Antonio Cubilla, M.D. and AFIP

Tumor nests

Pleomorphic cells

Basaloid differentiation

Closely packed nests

Starry sky appearance

Hyperchromatic nuclei

Focal necrosis

Positive stains

Differential diagnosis
  • Basal cell carcinoma:
    • Neoplastic cells have less atypia, tumor occurs usually in skin of shaft, nests have prominent peripheral palisading and characteristic myxoid stromal changes
  • Neuroendocrine carcinoma:
    • Similar morphology
    • Immunohistochemistry for neuroendocrine differentiation may be useful
  • Poorly differentiated usual squamous cell carcinoma:
    • More irregular nests
    • Neoplastic cells with eosinophilic cytoplasm and distinct cellular boundaries
    • Gradual (not abrupt) keratinization and clear tendency towards squamous differentiation
  • Urothelial carcinoma:
    • More pleomorphism, features of urothelial differentiation usually evident in the invasive or in situ component
    • Positive for uroplakin III and thrombomodulin
Clear cell carcinoma
Definition / general
  • Recently described aggressive variant of penile carcinoma

  • Middle aged men

  • Foreskin inner mucosa

  • Most likely of sweat gland origin
  • HPV 16 DNA found in all reported cases

Clinical features
  • All reported patients presented with inguinal nodal metastases with clear cells and sclerotic basement membrane material

Case reports

  • Excision with wide surgical margin

Gross description
  • Large, exophytic and partially ulcerated
  • Size 2.5 - 5.5 cm

Microscopic (histologic) description
  • Solid proliferation of large neoplastic clear cells
  • Marked nuclear atypia
  • Extensive geographical necrosis
  • Angiolymphatic invasion is common
  • Warty PeIN may be found at surface

Positive stains

Differential diagnosis
Warty carcinoma
Definition / general

  • Also called condylomatous carcinoma


  • Affected sites include glans, foreskin and coronal sulcus
  • Usually affects multiple anatomical compartments
  • Tends to multicentricity

Clinical features
  • Slow growing
  • Lymph node metastasis in 17 - 18% of cases; associated with deep invasion
  • Intermediate behavior between low grade verrucous or papillary carcinomas and usual squamous cell carcinomas of penis
  • May recur due to inadequate excision or multicentric disease not identified at time of surgery
  • Low mortality rate (0 - 9%) (Am J Surg Pathol 2001;25:673, Am J Surg Pathol 2000;24:505)

Prognostic factors
  • Poor: invasion of corpora cavernosa; high grade areas; presence of vascular / perineural invasion

  • Partial or total penectomy; circumcision
  • Groin dissection according to risk group stratification

Gross description
  • Typical lesion is exophytic mass arising from glans; also coronal sulcus or foreskin
  • Verruciform, white-tan, cauliflower-like and up to 5 cm
  • May have cobblestone surface
  • Endophytic cut surface
  • May penetrate deep into corpus spongiosum or corpora cavernosa with broad or irregular contours

Gross images

AFIP images

Exophytic, cauliflower-like white to tan tissue

Exophytic neoplasm

Microscopic (histologic) description
  • Low grade verruciform tumor with acanthosis, hyperkeratosis and parakeratosis
  • Identical to warty carcinomas of vulva, uterine cervix or anus
  • Arborescent papillary pattern with long, rounded or spiky papillae with prominent fibrovascular cores
  • Conspicuous koilocytosis (increased nuclear size with hyperchromasia, wrinkling and bi or multinucleation, perinuclear halos and individual cell necrosis) throughout entire tumor (not just surface)
  • May have intraepithelial abscesses
  • Early: sharply delineated interface between tumor and stroma with no invasion (noninvasive warty carcinoma)
  • Later: jagged boundary between tumor and stroma (invasive warty carcinoma)

Microscopic (histologic) images

Contributed by Alcides Chaux, M.D., Antonio Cubilla, M.D. and AFIP

Conspicuous koilocytosis

Undulating, complex and hyperkeratotic papillae

High power view of papillae

Positive stains

Molecular / cytogenetics description

Differential diagnosis
  • Carcinoma cuniculatum:
    • Deep tumoral invaginations forming irregular, narrow and elongated neoplastic sinus tracts connecting surface to deep anatomic structures
  • Giant condyloma:
    • Benign, HPV changes only in superficial layers, no pleomorphism and no invasion
  • Papillary carcinoma:
    • No HPV changes, irregular fibrovascular cores with complex papillae and invasive jagged border
    • More likely to have inguinal metastases
  • Verrucous carcinoma:
    • No HPV changes
    • Inconspicuous fibrovascular cores
    • Broad based invasive front
    • No regional or distant metastases
  • Warty basaloid carcinoma:
    • Warty carcinoma mixed with basaloid squamous cell carcinoma
    • Basaloid cells present in bottom layers of papillae or in deeply infiltrative nests
    • More aggressive than pure warty carcinoma
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