Penis & scrotum

Squamous cell carcinoma and variants

HPV independent squamous cell carcinoma (usual, verrucous, papillary, sarcomatoid)



Last staff update: 13 October 2023

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PubMed Search: HPV independent squamous cell carcinoma penile

Alcides Chaux, M.D.
Antonio L. Cubilla, M.D.
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Cite this page: Chaux A, Cubilla AL. HPV independent squamous cell carcinoma (usual, verrucous, papillary, sarcomatoid). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/penscrotumHPVindependentSCC.html. Accessed February 23rd, 2024.
Usual
[Pending]
Usual - pseudohyperplastic carcinoma
Definition / general
  • Nonverruciform, highly differentiated invasive tumor resembling pseudoepitheliomatous hyperplasia

Epidemiology
  • Affects elderly patients (mean age 69 years)
  • ~12 cases have been reported

Sites
  • Preferentially involves inner mucosa of foreskin
  • Tends to be multicentric

Clinical features
  • Good prognosis
  • Usually no recurrence after excision
  • Negative inguinal nodes

Treatment
  • Circumcision or partial penectomy
  • Groin dissection is not needed in absence of clinically evident metastatic disease

Gross description
  • Often multicentric
  • Typically flat or slightly elevated, white and granular, 2 cm

Microscopic (histologic) description
  • Nonverruciform, highly differentiated and downward proliferation of keratinizing nests of squamous cells with minimal atypia
  • Squamous pearls in almost all cases
  • Most nests are orderly and surrounded by reactive fibrous stroma with variable inflammatory cells
  • Tumor cells have eosinophilic cytoplasm with distinct intercellular bridges
  • Definite invasion with irregular stromal interface is present but may need additional sections to identify
  • Frequent extension beyond lamina propria
  • Adjacent squamous epithelium exhibits squamous hyperplasia and differentiated penile intraepithelial lesion
  • Well developed lichen sclerosus is almost always present (Am J Surg Pathol 2004;28:895)
  • Peripheral palisading is not evident

Microscopic (histologic) images

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

Well differentiated
squamous cells
with minimal atypia



Molecular / cytogenetics description
  • HPV- in analyzed cases

Differential diagnosis
  • Pseudoepitheliomatous hyperplasia:
    • Regular nests, conspicuous peripheral palisading, scant stromal reaction, no extension beyond lamina propria and no cytological atypia
  • Squamous cell carcinoma, usual type:
    • Glans penis is preferential location, has irregular nests with moderately differentiated neoplastic cells
    • The presence of broad areas of highly differentiated tumor is uncommon
  • Verrucous carcinoma:
    • Exophytic pattern of growth, broad pushing tumor base
Verrucous
Definition / general
  • Verruciform, slow growing, extremely well differentiated variant of squamous cell carcinoma with low malignant potential

Terminology
  • Also called Buschke-Löwenstein tumor

ICD coding
  • ICD-O: 8051/3 - verrucous carcinoma, NOS

Epidemiology

Sites
  • Glans is the preferred site but there is occasionally extension to other compartments
  • Tends to be multicentric in foreskin

Etiology

Clinical features
  • Many cases classified as verrucous carcinoma could be reclassified as other verruciform neoplasms
  • Slow growing but may recur locally
  • No inguinal nodal metastases and no death due to disease in pure verrucous carcinoma

Treatment

Gross description
  • Broad based white to gray exophytic neoplasm with a verruciform pattern of growth
  • Invasion is usually limited to lamina propria or superficial corpus spongiosum

Gross images

AFIP images

Large, destructive, cauliflower-like mass

Papillary lesion involving the glans



Microscopic (histologic) description
  • Very well differentiated with prominent intercellular bridges, minimal atypia and rare mitotic figures
  • Penetrates through lamina propria with broad base and pushing borders
  • Hyperkeratotic and acanthotic papillae with keratin cysts
  • Orthokeratosis more prominent than parakeratosis
  • Tumor cells are polygonal squamous cells with glassy cytoplasm, central vesicular nuclei and intercellular edema; may have superficial vacuolated clear cells but no koilocytosis
  • Dense inflammatory infiltrate may obscure tumor stroma boundary
  • Intraepithelial abscess and crust formation is common
  • Frequently associated with squamous hyperplasia and differentiated penile intraepithelial neoplasia
  • Central fibrovascular cores are uncommon

Microscopic (histologic) images

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

Mixed (hybrid) usual verrucous carcinoma

Exophytic growth

Acanthosis

Pronounced exophytic tumor

Sharp interface

Tumor cells have bland cytologic features



Negative stains

Differential diagnosis
  • Giant condyloma:
    • Conspicuous koilocytosis, prominent fibrovascular cores
  • Hybrid verrucous carcinoma:
    • Foci of usual squamous cell carcinoma intermingled with a typical verrucous carcinoma
  • Papillary carcinoma:
    • Invasive and jagged border, more atypia, irregular but usually evident fibrovascular cores
  • Squamous hyperplasia:
    • No atypia, no stromal reaction and no extension beyond lamina propria (in some cases distinction is not possible)
  • Warty carcinoma:
    • Koilocytotic change present, jagged tumor front, neoplastic cells with more pleomorphism, prominent fibrovascular cores and usually deeper invasion
Verrucous - carcinoma cuniculatum
Definition / general
  • Rare, low grade variant of verruciform penile carcinoma with deeply penetrating and burrowing pattern of growth
  • More common in plantar surface of foot, first described in 1954 (Br J Surg 1954;42:245)

Terminology
  • Cuniculatum: from cuniculus, rabbit's burrow (hole)

Epidemiology
  • Elderly men
  • Mean age 77 years (range 73 - 83 years)

Sites
  • Glans and coronal sulcus frequently involved
  • Multiple anatomical compartments usually affected

Etiology
  • No evidence of HPV infection

Clinical features
  • Slow growing
  • Tumors may begin as small warts and slowly progress to larger tumors
  • No reported cases with regional nodal metastasis or cancer related death

Case reports

Gross description
  • Verruciform pattern of growth
  • Average size 6.3 cm (range 5 - 9 cm)
  • Tumor invade deep erectile tissues with a burrowing pattern of growth on cut section
  • Stroma tumor interface sharply delimited
  • Presence of cyst-like and sinus structures
  • Fistulae to preputial or shaft skin are common

Gross images

Images hosted on other servers:

Ulcerated verrucous carcinoma



Microscopic (histologic) description
  • Low grade keratinizing neoplastic nests resembling verrucous carcinoma
  • Hyperkeratosis, papillomatosis and marked acanthosis
  • Bulbous front of invasion
  • Cyst-like and sinus lumina filled with hyperkeratotic material
  • No / rare vascular and perineural invasion; no fibrovascular cores; no koilocytes

Microscopic (histologic) images

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

Cyst-like sinuses and tracts

Progressive
squamous maturation
and extensive
acantholysis



Differential diagnosis
  • Mixed (hybrid) usual verrucous carcinoma:
    • Verrucous carcinoma with foci of usual squamous cell carcinoma typically located at tumor front, absence of a burrowing pattern of growth
  • Verrucous carcinoma:
    • Similar in the exophytic component, usually limited to lamina propria or superficial corpus spongiosum and absence of a burrowing pattern of growth
  • Warty carcinoma:
    • Condylomatous papillae with prominent fibrovascular cores, conspicuous koilocytosis and jagged tumor front
Papillary
Definition / general
  • Slow growing, low grade verruciform variant of squamous cell carcinoma representing 5 - 15% of all penile carcinomas and 27 - 53% of all verruciform tumors (Anal Quant Cytol Histol 2007;29:185)
  • Diagnosis is made after exclusion of other verruciform tumors

ICD coding
  • ICD-O: 8050/3 - papillary carcinoma, NOS

Epidemiology
  • Mean age 57 years (range 26 - 84 years)

Sites
  • Usually involves glans, possibly with foreskin and coronal sulcus

Etiology

Clinical features

Gross description
  • Usually in glans but extension to coronal sulcus and inner foreskin is common
  • Large gray-white exophytic destructive lesion
  • Mean tumor size 5.5 cm (range 1 - 9 cm)
  • Cut surface shows pearly white papillomatous tissue, poor demarcation between tumor and stroma

Gross images

AFIP images

Tumor of foreskin

Longitudinal section after removal of foreskin



Microscopic (histologic) description
  • Well differentiated papillary squamous neoplasm
  • Prominent hyperkeratosis and acanthosis
  • Complex papillae with irregular fibrovascular cores
  • Irregular / infiltrative tumor base
  • Frequent association with squamous hyperplasia (74%), differentiated penile intraepithelial neoplasia (46%) and lichen sclerosus (34%)
  • May have keratin cysts and intraepithelial abscesses
  • High grade foci are unusual
  • No koilocytotic changes

Microscopic (histologic) images

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

Complex papillae

Papilla

Surface papillarity and focal invasion

Well differentiated papillae but no koilocytosis

Invasion at the base



Negative stains

Differential diagnosis
Sarcomatoid
Definition / general

Terminology
  • Also called spindle cell carcinoma
  • Rare tumors with distinct sarcoma and carcinoma components are called carcinosarcoma

ICD coding
  • ICD-O: 8074/3 - squamous cell carcinoma, sarcomatoid

Epidemiology
  • Median age 59 years (range 28 - 81 years)

Sites
  • Preferred site is glans but extension to coronal sulcus and foreskin is not unusual

Etiology
  • May occur after radiation therapy; low HPV detection rate

Clinical features
  • Represents 1 - 3% of all penile carcinomas (J Urol 2004;172:932)
  • High mortality rate (40 - 75%)
  • Inguinal nodal metastases in 75 - 89% and local recurrence in 67% of all cases

Case reports

Gross description
  • Large gray-white or red polypoid or fungating mass with frequent ulceration and hemorrhage
  • Mean tumor size 3 - 5 cm (up to 7 cm)
  • Cut surface shows deep invasion of corpus spongiosum or corpora cavernosa
  • Superficial or deep tumor satellite nodules

Gross images

AFIP images
Missing Image

Polypoid solid mass



Microscopic (histologic) description
  • Predominantly anaplastic spindle cells resembling fibrosarcoma or leiomyosarcoma
  • Occasional giant or multinucleated malignant fibrohistocytoma-like cells
  • Foci of usual squamous cell carcinoma present in most cases
  • Prominent necrosis and mitotic activity
  • Areas of myxoid, chondroid, osteosarcomatous or angiosarcomatous-like changes may be observed
  • Penile intraepithelial neoplasia in adjacent mucosa is not uncommon

Microscopic (histologic) images

Contributed by Alcides Chaux, M.D., Antonio Cubilla, M.D., Ajeeth Kumar, M.D., Eliz Thomas, M.D., Mythreye Karthikeyan, Ph.D. and AFIP
Missing Image

Marked nuclear atypia and pleomorphic giant cells

Missing Image

Resembles angiosarcoma

Missing Image

Aggregate of rounded carcinoma cells


Missing Image Missing Image Missing Image

55 year old man with ulcerated lesion on glans penis

Missing Image

CK10



Positive stains

Negative stains

Differential diagnosis
  • Melanoma:
    • Melanin, intraepidermal melanocytic proliferation, nevoid component
    • Positive for S100, MelanA and HMB45, negative for keratin
  • Primary penile sarcoma:
    • Usually in penile shaft, no squamous differentiation, no penile intraepithelial neoplasia
    • Negative for p63 and keratin 34bE12
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