Penis and scrotum - Printer Friendly Version
Last revised 12 April 2007
Copyright © 2002-2007, PathologyOutlines.com, Inc.
Reviewed by Antonio L. Cubilla, M.D., January 2004 (see Reviewers page)
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Penis
Anatomy, congenital anomalies, circumcision, priapism
Inflammatory lesions: accessory urethral canals, balanoposthitis, cellulitis, chancroid, cutaneous verruciform xanthoma, fungal infections, Fournier’s gangrene, gangrenous balanitis, granuloma inguinale, herpes simplex virus, HIV, inflammatory pseudotumor, lentiginous melanosis, lichen sclerosus (BXO), lymphogranuloma venereum, molluscum contagiosum, Mondor’s phlebitis, mucoid cyst, os penis, papillomatosis of glans corona, paraphimosis, Peyronie’s disease, phimosis, plasma cell balanitis, scabies, syphilis, Tancho’s nodules and paraffinomas
Benign tumors: condyloma acuminatum, epithelioid hemangioma, giant condyloma, leiomyoma, myointimoma, squamous hyperplasia, transitional papilloma
Dysplasia/carcinoma in situ: penile intraepithelial neoplasia, carcinoma in situ, Bowen’s disease, bowenoid papulosis, erythroplasia of Queryat
Squamous cell carcinoma and variants: general, squamous cell carcinoma NOS, adenosquamous, basaloid, papillary, sarcomatoid, verruciform, verrucous, warty
Other malignancies: basal cell carcinoma, clear cell sarcoma, Kaposi’s sarcoma, leiomyosarcoma, malignant mesothelioma, melanoma, metastases, mucoepidermoid carcinoma, proximal type epithelioid sarcoma, sclerosing epithelioid fibrosarcoma
Miscellaneous: staging, features to report, grossing penectomy specimens, grossing circumcision specimens
Scrotum
Non-neoplastic lesions: fat necrosis, Fournier’s gangrene, idiopathic calcinosis, massive localized lymphedema in morbidly obese, peritesticular fibrosis, sclerosing lipogranuloma, tunica albuginea cysts
Neoplastic lesions: aggressive angiomyxoma, angiomyofibroblastoma, calcifying fibrous pseudotumor, cutaneous verruciform xanthoma, desmoplastic round cell tumor, leiomyoma, leiomyoma with bizarre nuclei, liposarcoma, malignant mesothelioma, Paget’s disease, posttraumatic spindle cell nodules, squamous cell carcinoma
AJCC Cancer Staging Manual (6th Ed)
American Journal of Clinical Pathology (AJCP), Jan 1975 to Jan 2004 [no images]
American Journal of Pathology, (AJPath), Jan 1975 to Feb 2004
American Journal of Surgical Pathology (AJSP), Mar 1977 to Jan 2004
Archives of Pathology and Lab Medicine (Archives), Jan 1976 to Feb 2004
Human Pathology (Hum Path), Mar 1970 to Jan 2004
Modern Pathology (Mod Path), Jan 1988 to Feb 2004
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
www.Webpathology.com - source of numerous beautiful GU images used in these outlines
Please refer to these primary references for more detailed discussions and photographs
Penis
Suspended from front and sides of pubic arch, contains majority of urethra
There are 3 main parts: the distal glans (head), the middle body (corpus or shaft) and the proximal root
Body is composed of three cylindrical masses of cavernous erectile tissue (specialized venous sinuses of variable diameter and widely interconnected) bound together by fibrous tunica albuginea
Orientation: the upper surface is termed dorsal, the undersurface is termed ventral
Buck’s fascia
Fibroelastic and vascular membrane encasing and separating dorsal corpora cavernosa and ventral corpus spongiosum
Coronal sulcus
Narrow and circumferential cul de sac (in non-circumcised) behind glans corona; area of insertion of dartos and Buck’s fascia
Corpora cavernosa
Two lateral masses of erectile tissue that form bulk of penis; posterior portions are called crura, are connect to pubic arch
Corpus spongiosum
Median mass of erectile tissue that contains most of urethra
Dartos
Smooth discontinuous muscle layer covering corpora and mid part of foreskin
Foreskin (prepuce)
Skin folded on itself covering the glans (clitoris in females)
In normal males, long foreskins cover the meatus and the glans is not visible
Layers are outer skin (squamous epithelium, lamina propria), dartos, inner mucosa
Fossa navicularis
Terminal dilated portion of penile urethra, contains stratified, non-keratinized, squamous epithelium
Frenulum
Fibrous band of tissue attaching foreskin to ventral glans
Glans
Portion distal to coronal sulcus
Conical cup covering distal end of penile shaft
Layers are squamous epithelium, lamina propria, corpus spongiosum, tunica albuginea and corpora cavernosa
Glans corona
At base of glans, slightly elevated circumferential rim
Urethral meatus (meatus urethralis)
Urethral opening
Usually at central ventral glans penis
Vertical cleft, related to frenulum
Urethra
Divided into 3 portions in male: prostatic urethra (proximal, surrounded by prostate, contains urothelium), membranous urethra (from lower pole of prostate to bulb of corpus spongiosum, stratified or ciliated pseudostratified columnar epithelium), penile urethra (passes through corpus spongiosum, stratified or ciliated pseudostratified columnar epithelium)
Layers are surface columnar epithelium and basal stratified or pseudostratified epithelium
Occasional PSA positive glands are present, Hum Path 2002:33;905
Penile urethra contains plasma cells, T lymphocytes and macrophages, epithelium contains IgA secretory component and dendritic cells; protect against ascending infections, AJPath 1995;147:155
Regional lymph nodes
Superficial inguinal nodes (site of 1-3 sentinel nodes), deep inguinal, external iliac, internal iliac (pelvic nodes)
Periurethral glands
Cowper’s (bulbourethral) glands: mucinous acinar structures deep at level of membranous urethra
Intraepithelial glands (Morgagni’s lacunae): one-layer cylindrical intraepithelial glands
Littre’s glands: tubuloacinar mucinous glands present along entire length of corpus spongiosum
Miscellaneous:
Penile glycogenated epithelial cells indicate recent vaginal intercourse, AJCP 1985;84:524
Penile swabs after recent vaginal intercourse almost always contain female cells identifiable by FISH, Archives 2000;124:1080
Skin covering of penis is thin, stratified squamous epithelium, loosely connected to deeper parts of organ; non-keratinizing at glans penis; keratinized after circumcision
Skin at root of penis is continuous with skin over scrotum and perineum
Aphallia
Agenesis of penis
Only 70 cases reported; associated with other GU abnormalities
Chordae
Fibrous band associated with hypospadias or epispadias
Concealed penis
Penis is normally developed but hidden under fat in suprapubic region, scrotum, perineum, thigh
Diphallia
Duplication of penis
Associated with hypospadias, bifid scrotum, bladder duplication, renal agenesis
Epispadias
Urethra opens onto dorsal surface of penis
Penopubic epispadias (opening in penopubic junction) is most common, associated with urinary incontinence
Hypoplasia
Almost always associated with abnormalities of GU tract
Hypospadias
Urethra opens onto ventral surface of penis or scrotum
1/300 live male births
Due to failure of fusion of urethral folds
Hypospadias and epispadias are associated with abnormal descent of testes, urinary tract malformations, obstruction, urinary tract infections, possibly infertility if orifices are near base of penis
Lateral curvature
Due to hypo/hyperplasia of one corpora cavernosa
Median raphe cysts
Due to anomalies in development of urethral groove, trapped epithelial cells or migration of epithelial cells after closure of genital folds
Midline, usually translucent and subcutaneous masses in ventral shaft
Lined by squamous, columnar, mucus-producing or apocrine-like epithelium
Micropenis
Penis small, but normal ratio of shaft length to circumference
Torsion
Fibrous tissue surrounding corpus spongiosum or short urethra causes rotational defect of penile shaft
Webbed penis
Scrotal skin extends to ventral portion of penis and hides it
Excision of foreskin
Associated with reduced incidence of penile cancer and bacterial infections in children
Associated with reduced incidence of HIV infection, apparently due to CD4+ T lymphocytes on inner mucosa of foreskin (see HIV)
Prolongation of erection associated with pain
May have fever and difficulty voiding
Associated with impotence in 17% to 50%
Usually due to obstruction of the deep dorsal vein of penis due to sickle cell disease, leukemia, cancer, trauma, drugs, idiopathic
Common presenting sign of carcinomas metastatic to the penis.
Treatment: prompt intervention is important with drugs or surgical aspiration of blood / clots
May open near fossa navicularis, become inflamed and produce symptoms
Infection of glans and foreskin, usually due to Candida, anaerobes, Garderella, pyogenic bacteria
Common in uncircumcised newborns or uncircumcised men with poor hygiene and accumulation of smegma
Due to propensity of pathogenic bacteria to adhere to inner mucosal surface of foreskin
Causes phimosis
More common in newborns and immunosuppressed
Usually involves scrotum
Usually caused by group A streptococcus
Caused by Haemophilus ducreyi
Soft painful ulcer, may extend rapidly and be associated with ruptured inguinal abscess
May destroy external genitalia if superimposed Fusobacterium infection is present
Micro: zonation; upper layer is ulcer base with fibrin, neutrophils and necrosis; middle layer has granulation tissue, pallisading blood vessels and thrombosis; deep layer has marked lymphoplasmacytic infiltrate
Cutaneous verruciform xanthoma
Rare, uncertain etiology, usually in oral mucosa, rarely in scrotum, penis
Etiology: initial keratinocyte damage attracts neutrophils, then dermal dendrocytes phagocytosize necrotic keratinocyte debris; probably not due to HPV; foam cells most likely derived from dermal dendritic cells.
Gross: solitary, raised or polypoid with cup-shaped craters
Micro: foam cell aggregates in vascularized submucosa or papillary dermis, associated with verrucous epithelial hyperplasia; cup shaped craters filled with parakeratotic cells blending into keratinocytes; also neutrophilic infiltrate near surface of epidermis between plump parakeratotic cells and keratinocytes of varying intensity; bandlike plasma cell infiltrate at base of epidermis
Positive staining (foam cells): Factor VIIIa, CD68, Mac387, cytokeratin (weak)
Negative staining: S100
References: AJSP 1998;22:479
Superficial or deep
Superficial: dermatophytes, spores often in keratinized epithelium, often spreads locally from groin
Deep: rare, usually spreads via blood from other sites
Candida albicans: usually sexually transmitted, 15% of men are asymptomatic carriers, may reinfect women
Necrotizing fasciitis of genitalia and perineum
Usually due to Staph or Strep in children; gram negative rods or anaerobic bacteria in adults
Affects Buck’s fascia and foreskin, sparing glans
Risk factors: trauma, burns, anorectal disease, diabetes, leukemia, alcoholic cirrhosis
Also called Corbus’s disease
Rapidly progressing necrotizing inflammatory disease due to anaerobes in glans penis
May cause total necrosis of glans; although foreskin may be secondarily involved in advanced cases, the site of the lesion is the glans, sparing the penile fascia and foreskin (contrary to Fournier’s gangrene)
Penile necrosis in diabetic patients produces similar changes in the distal penis
Sexually transmitted disease caused by Calymmatobacterium granulomatis, a gram negative rod
Initially small painful nodule at infection site; nodule ulcerates; may have satellite lesions
Micro: massive plasma cell infiltrate without lymphocytes, large mononuclear cells with Donovan bodies (large, intracytoplasmic encapsulated bipolar bodies, highlighted with Warthin-Starry stain)
Sexually transmitted disease, usually caused by HSV2
Multiple small (1-2 mm) vesicles that rupture and cause painful ulcers
Micro: ground glass nuclei due to intranuclear virus; multinucleated giant cells
Human immunodeficiency virus (HIV)
Most HIV-1 positive men are infected via the penis
Lack of circumcision confers 8x increased risk, apparently due to high lymphocyte density in foreskin mucosa (HIV-1 targets CCR5 and CXCR4 receptors on CD4+ T cells), higher than uterine ectocervix, AJPath 2002;161:867
No infiltration by HIV-1 of foreskin outer surface
Associated with chronic condom catheterization
Frequent lesion of glans and foreskin
Benign, although associated with melanomas
Gross: flat pigmented macules with irregular borders
Micro: melanocytic hyperplasia, hyperpigmentation of basal epithelium, elongation of rete ridges, no atypia
Lichen sclerosus (Balanitis xerotica obliterans )
Male equivalent of lichen sclerosus et atrophicus of vulva, a chronic and atrophic mucocutaneous condition
Affects older men, may have autoimmune etiology
More frequent in foreskin, but coronal sulcus, glans and even urethra may be affected
May cause narrowing of urethral meatus or phimosis.
Atypical lichen sclerosus shows epithelial dysplastic changes (low grade or high grade)
Associated with low grade squamous cell carcinoma in glans and foreskin (non HPV variants-squamous cell NOS, verrucous, papillary); unusual in basaloid or condylomatous (warty) carcinomas
Treatment: circumcision, but may recur at scar
Gross: gray-white foci of atrophy in foreskin or perimeatal glans
Micro: thinning or thickening of epidermis with orthokeratotic (i.e. anuclear as in normal epidermis) hyperkeratosis, lamina propria thickening and loss of structures due to edema, sclerosis or hyalinization; vacuolar degeneration of basal layer, diffuse fibrosis, deep lymphocytic infiltrate; usually spares corpus spongiosum of glans and foreskin dartos
References: AJSP 2003; 27:1448
Sexually transmitted disease caused by Chlamydia trachomatis
Painless papule or ulcer, followed by suppurative inflammation of inguinal lymph nodes, followed by lymphocytic hyperplasia and massive plasma cell infiltration; later get stellate abscess, then suppurative granuloma with sinuses and tracts
Caused by DNA pox virus; may be sexually transmitted
Gross: 3-6 mm dome shaped papule with central umbilication
Micro: prominent Henderson-Patterson bodies (intracytoplasmic eosinophilic inclusions containing virus particles) in stratum spinosum and granulosum
Due to trauma or herpes simplex infections
Gross: firm, subcutaneous cord-like structures along dorsal shaft of penis or around coronal sulcus
Micro: massive thrombosis of superficial venous plexus of penis
Inflammatory lesion due to accessory urethral canals, on foreskin or glans, associated with intraepithelial mucous cells or glands
Heterotopic bone in penis, most commonly in elderly, also children
The majority of mammals have an intrapenile bone, except some primates including men
Associated with Peyronie’s disease
Papillomatosis of glans corona
Also called hirsutoid papillomas, pearly penile papules
Benign, asymptomatic
Associated with male sexual partners of women with cervical HPV lesions, although perhaps due to greater surveillance
Gross: multiple pearly gray white fibroepithelial papillomas, 1-2 mm, in dorsal glans corona; usually in 2-3 rows
Micro: hyperkeratosis but no koilocytosis, no significant inflammation
DD: condyloma acuminatum
Forceful retraction of phimotic foreskin over glans may cause marked swelling which blocks replacement of foreskin
Painful, associated with urinary retention and constriction
Treat with circumcision
Fibrous thickening of dermis and Buck’s fascia between corpora cavernosa and tunica albuginea, causing curvature towards side of lesion and restricting movement of these structures during erection
May be associated with carcinoid syndrome, Dupuytren’s contracture
Usually considered a form of fibromatosis
By another theory, arises secondary to urethritis as a sclerosing inflammatory process
Treatment: may spontaneously regress, responds to small amounts of irradiation, steroids, excision
Micro: fibromatosis with dense fibrous nodules, calcification
Orifice of foreskin is too small to permit its retraction; usually due to scarring from repeated infection due to poor hygiene
May be congenital
Smegma (desquamated epithelial cells, debris) accumulates, causes secondary infections and possibly carcinoma
Micro: lymphoplasmacytic infiltrate in glans and foreskin
DD (requires liberal sampling of foreskin): carcinoma in situ, lichen sclerosus, atypical lichen sclerosus
Also known as balanitis circumscripta plasmacellularis, Zoon’s balanitis
Balanitis: inflammation of glans
Uncircumcised men
Etiology unknown, but probably reactive
Gross: well-defined brown/red plaques, solitary or multiple; resembles erythroplasia of Queyrat / Bowen’s disease
Micro: epidermal atrophy, band like infiltrate of plasma cells in dermis, pigment laden histiocytes, edema, numerous capillaries; rarely plasma cells are scant/absent
Most common parasitic infection of penis, usually part of generalized infection
30% transmission rate from sexual intercourse
Caused by Treponema pallidum, humans are the only natural host
Sexually transmitted disease with primary, secondary and tertiary phases (not very infectious are tertiary stage)
Primary syphilis: painless hard chancre (ulcer with indurated and punched out base) at site of inoculation, often in glans
Secondary syphilis: bacteremic stage with greatest number of organisms in the body; widespread rash (small red macular lesions), including on palms and soles and mucous membranes; condyloma lata (flat, rose/gray maculopapules in scrotum)
Tertiary syphilis: gummatous form (granulomas with epithelioid and giant cells, obliterative endarteritis, necrosis); also cardiovascular form and neurosyphilis; accelerated time course occurs with HIV infection (1 year to neurosyphilis)
Diagnosis: Warthin-Starry stain, darkfield examination (corkscrew motility)
Micro: plasma cells and lymphocytes underlying ulcer, endothelial cell proliferation and capillaritis
DD: lymphoma, plasma cell myeloma.
Tancho’s nodules and paraffinomas
Injection or insertion of paraffin or other foreign material under skin of penis with foreign body reaction
Custom among some Asiatic populations
May require local surgical resection
Penile tumors
Benign tumor caused by HPV 6 and 11, related to verruca vulgaris (common wart)
Usually sexually transmitted, affects men and women
Often near coronal sulcus and inner surface of foreskin
Recurs but does not evolve into invasive cancer
Section lesions thoroughly to rule out verrucous carcinoma
Note: lesions with HPV 6 and 11 by in situ hybridization usually have perinuclear halos and nuclear atypia; lesions with HPV DNA by PCR only may contain only focally thickened granular layer associated with epithelial crevices, AJSP 1992;16:269
Gross: papillary, fungating, wart-like, often multiple lesions, 1 mm or larger
Micro: complex papillary pattern with central fibrovascular cores, hyperplastic epithelium with preservation of orderly maturation; koilocytosis (vacuolization of cells of prickle cell layer near surface of papillae), T cells (CD4+), may have reactive atypia but no evidence of invasion
DD: pearly penile plaques (HPV negative, hyperkeratosis but no koilocytosis, no significant inflammation), verrucous carcinoma
Case reports in men ages 36 and 47 years, Archives 1985;109:51
Treatment: local excision
Gross: subcutaneous penile nodules
Micro: nests/cords of plump epithelioid cells in loose stroma with lymphocytes and eosinophils; also vascular areas and solid areas with cytoplasmic vacuoles and nuclear atypia
Positive stains: Factor VIII
Giant condyloma acuminatum
Also called Buschke-Lowenstein tumor
Very rare, benign, exophytic papillary growth of penis
Intermediate properties between condyloma and warty carcinoma
Gross: usually involves foreskin and coronal sulcus, also glans; 5-10 cm cauliflower-like verruciform tumors with cobblestone surface; cut surface shows papillomatous growth with sharp demarcation from underlying stroma
Micro: resembles condyloma (papillae with prominent fibrovascular cores, koilocytosis) with bulbous expansion into underlying tissue
DD: warty carcinoma (probably related, has clearly malignant histology and jagged borders with stroma), verrucous carcinoma (no koilocytosis, no prominent papillae with fibrovascular cores)
Very rare
Small, painless, slow-growing masses in adults
Micro: well demarcated smooth muscle tumors, no atypia, no mitotic activity
Myointimal proliferation of corpus spongiosum of glans penis
Mean age 29 (range, 2 to 61 years)
Treatment: conservative local excision
Gross: 0.5 to 2 cm mass
Micro: prominent fibrointimal proliferation with plexiform architecture involving the vasculature of the corpus spongiosum; stellate and spindled cells with minimal atypia embedded in abundant fibromyxoid matrix; cells occasionally are myxoid with abundant eosinophilic cytoplasm, blunt-ended nuclei, and juxtanuclear vacuoles; also areas of degenerative changes with "ghost cell" morphology
Positive stains: alpha-smooth muscle actin, muscle-specific actin (HHF-35), calponin
Negative stains: CD31, CD34, S100, keratin, Factor VIII, desmin (may have minimum staining)
DD: myofibroma, nodular fasciitis, vascular leiomyoma, plexiform fibrohistiocytic tumor
References: AJSP 2000;24:1524
Thickening of squamous epithelium (more than 15 cell layers) without atypia
Benign, but associated with squamous cell carcinoma, particularly verrucous and low grade papillary subtypes
Gross: involves glans, coronal sulcus, foreskin, urethra; flat, smooth and pearly white mucosal lesion, may be papillary; may merge with adjacent low grade carcinoma
Micro: flat, papillary or mixed; also pseudoepitheliomatous (downward florid but superficial proliferation of squamous cell nests, often detached, but with no keratinization, no stromal reaction, no desmoplasia); hyperkeratosis, acanthosis, normal maturing of squamous epithelium; no parakeratosis, no atypia, no koilocytosis
DD of pseudoepitheliomatous hyperplasia: low grade squamous cell carcinoma with pseudohyperplastic features
Transitional papilloma of fossa navicularis
Rare, case report at Virchows Arch 2003;442:601
Dysplasia / carcinoma in situ
Penile intraepithelial neoplasia (PIN)
Various classification schemes, similar to cervix
(a) High grade and low grade penile intraepithelial lesions, with and without HPV changes; (b) mild, moderate or severe dysplasia; (c) PIN I, II or III
High grade / severe dysplasia and PIN III are synonymous with carcinoma in situ
In Paraguay, most cases of PIN are associated with invasive squamous cell carcinoma
75-100% are associated with HPV
Gross: varied appearance - flat or slightly elevated pearly white or moist erythematous; or dark brown/black macule, papule or plaque; sharp or subtle borders or focal or diffuse; occasionally papillary
Micro: low grade lesions have atypical cells in lower third of epithelium; high grade lesions have full-thickness atypia; both have variable koilocytosis
Squamous, basaloid and warty patterns exist, which usually correspond to pattern of invasive component, if present
High grade squamous intraepithelial lesion: similar to lesions at other sites; most common type of carcinoma in situ; large irregular cells with eosinophilic keratinized cytoplasm (DD: urothelial carcinoma in situ)
High grade basaloid intraepithelial lesion: composed entirely of small, basophilic immature basal cells with prominent mitotic figures; resemble similar lesions in vulva and cervix; present in >50% of invasive basaloid carcinomas; related to HPV, coexists with warty lesions
High grade warty intraepithelial lesion: flat or slightly ulcerated papillary growth; hyperkeratosis, atypical parakeratosis, marked nuclear pleomorphism, abnormal mitotic figures, full thickness koilocytosis; related to HPV, coexists with basaloid lesions
Also called Bowen’s disease, bowenoid papulosis and erythroplasia of Queyrat
All forms below are associated with HPV 16 (80% of cases)
Also called squamous cell carcinoma in situ
Age 35+; affects skin of shaft of penis and scrotum; also occurs in women
10% progress to invasive squamous cell carcinoma
1/3 may have unrelated visceral malignancy (lung, GI, urinary tract)
HPV positive
Gross: sharply demarcated, gray-white plaque with shallow ulcer and crusting
Micro: markedly dysplastic cells in all layers of epithelium, large hyperchromatic nuclei, multinucleated cells, dyskeratosis, vacuolization, acanthosis, hyperkeratosis, stroma with vascular proliferation and chronic inflammatory infiltrate; atypical mitoses but intact dermal epidermal junction
Sexually active young men (mean age 30), usually on skin of shaft, glans or scrotum
Associated with HPV 16 or 18
Almost never becomes invasive
May spontaneously regress
Gross: multiple, small, pigmented papular lesions, may resemble condyloma acuminatum
Micro: histologically resembles Bowen’s disease, but may have mild/heavy melanin pigmentation within the lesion; often spiky or flat appearance, may have less cytologic atypia
Affects penile squamous mucosa
One or more shiny red, velvety plaques, usually on glans and prepuce
Histologically similar to Bowen’s disease (which affects penile shaft squamous epithelium), also HPV positive
No association with visceral malignancy
Squamous cell carcinoma and variants
Squamous cell carcinoma-general
Rare in US (<1% of carcinomas in men vs. 10-20% in Asia [excluding Japan], Africa, South America)
Incidence: 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)
Risk factors: paraphimosis, phimosis and long foreskin (AJSP 2003;27:994), HPV 16 or 18 (although most cases are not related to HPV), smoking, psoriasis patients treated with UV B radiation, penile rash > 1 month (? Bowen’s disease)
1/3 of non-HPV cases are associated with lichen sclerosus (balanitis xerotica obliterans)
HPV: HPV positive cancers more likely to have high grade penile intraepithelial neoplasia than HPV negative cancers (AJCP 1992;97;272), HPV present in 42% of penile carcinomas, but frequency varies by histologic type: squamous cell 35%, verrucous 33%, basaloid 80%, warty 100% (AJPath 2001;159:1211)
Most tumors arise from glans or inner foreskin near coronal sulcus as slow growing, irregular mass; patients occasionally present with inguinal nodal metastases with occult penile cancer due to severe phimosis or very small primary tumor
Usually age 40-70 years, median age 58 years
Metastases: inguinal and pelvic lymph nodes, liver, lung, heart or bone; 15% have metastases at diagnosis
Note: nodes are often enlarged at clinical presentation due to infection, not metastases
5 year survival related to nodal involvement: 66% (not involved) vs. 27% (involved)
Histologic subtypes resemble those in vulva, anus, buccal mucosa; 70% are usual squamous cell carcinoma
Prognostic factors: histologic grade and depth of penetration into various anatomic compartments most important; poor prognostic factors are angiolymphatic invasion, vertical growth pattern, basaloid, sarcomatoid, solid, anaplastic and pseudoglandular subtypes; extension beyond foreskin and compromise of corpus cavernosum
Although prognosis related to depth of invasion (epithelium, lamina propria, corpus spongiosum, corpus cavernosum), anatomic variations exist (corpus cavernosum may not be located in glans in 25% of cases), AJSP 2001; 25:1091
Low grade: no regional metastases if only superficial invasion to 6 mm or less (Mod Path 2001;14:963)
[depth measured from deepest malignant cells to highest overlying dermal papilla]
High grade: deep invasion (8-10 mm) into corpus spongiosum, dartos or corpora cavernosa associated with 80% rate of metastases
Intermediate/high grade with invasion 5-10 mm have ~ 15% risk of metastases
Treatment: local resection, partial/total penectomy, National Cancer Institute page
NOS: not otherwise specified; i.e. usual histologic pattern
70% of squamous cell carcinomas
Case reports: metastatic disease in pleural effusion, Archives 1992;116:198
Gross: exophytic (resembles condyloma acuminatum) or flat (epithelial thickening with gray fissures in mucosa, later ulcerated papule); cut surface shows tan-white solid irregular tumor with superficial or deep penetration
Micro: classified according to growth pattern as superficial spreading, vertical growth, verruciform, multicentric or mixed (see below); usually keratinized with moderate differentiation; predominantly undifferentiated carcinomas are rare; unusual focal or diffuse patterns are acantholytic (pseudoglandular), spindle cell (sarcomatoid), lymphoepithelioma-like, trabecular, endocrine, giant cell pleomorphic and clear cell
Graded as 1 (well differentiated), 2 (moderated differentiated) or 3 (poorly differentiated)
Stroma has variable lymphoplasmacytic infiltrate; foreign-body type giant cells often seen in highly keratinized tumors; desmoplasia is unusual; most cases have associated penile intraepithelial neoplasia (high grade and low grade) and squamous hyperplasia; lichen sclerosus is associated with low grade foreskin carcinomas, especially verrucous carcinomas and multicentric tumors with pseudohyperplastic features
DD: pseudoepitheliomatous hyperplasia (elongated rete ridges, no atypia in separated nests, no keratinization, no stromal reaction); melanoma, epithelioid angiosarcoma, urothelial carcinoma (ventral surface of penis, no penile intraepithelial lesions, history of urothelial CIS or bladder tumor)
(a) Superficial spreading
Most common pattern; slow growing; involves mucosal and superficial layers of glans, coronal sulcus and foreskin; resembles melanoma subtype due to early horizontal phase and late vertical phase with deep invasion of corpus spongiosum and corpora cavernosum; histologic subtype is usual squamous cell carcinoma but verruciform tumors may show this growth pattern as well
Tends to recur if incompletely excised
Gross: slightly raised gray-white granular firm tumor
Micro: all in situ OR in situ plus invasive nodular component OR horizontal pattern of in-situ and invasive carcinoma; may involve resection margin
(b) Vertical growth
High risk of regional metastasis and death
Gross: large ulcerated or fungating mass; solid uniform cut surface with focal necrosis
Micro: high grade with prominent vascular invasion; may have satellite nodules in corpus spongiosum or corpora cavernosa; histologic subtypes are basaloid, sarcomatoid, anaplastic, solid and usual type
(c) Verruciform
25% of penile tumors; slow growing exophytic tumors with well-differentiated keratotic papillary configuration; usually superficial; histologic subtypes include verrucous, condylomatous (warty), papillary and usual type; may be difficult to differentiate benign from malignant tumors
(d) Multicentric
Two or more foci of carcinoma separated by benign tissue; behavior similar to superficial spreading carcinomas; patients prone to recurrences unless all anatomic compartments removed at surgery
Very rare
May originate in misplaced glandular cells in perimeatal region of penis
Case reports of superficial tumors at AJSP 1996;20:156
Gross: firm, gray-white, granular
Micro: squamous cell and glandular pattern, with squamous cell pattern usually predominating; glands produce mucin; squamous intraepithelial lesions present in glans mucosa
Positive stains: CEA in glandular portion
DD: adenoid squamous cell carcinoma (prominent acantholysis simulates glandular spaces but lining is composed of squamous epithelium and spaces with necrotic debris and keratin, not mucin); adenosquamous (mucoepidermoid) carcinoma of urethra (ventral in penis, restricted to periurethral tissue and corpus cavernosa); Littre gland adenocarcinoma (ventral in penis, restricted to periurethral tissue and corpus cavernosa)
Aggressive, high grade, deeply invasive
50% have enlarged inguinal nodes (due to metastasis) at diagnosis; 59% mortality
80% associated with HPV
5-10% of penile cancers
Median age 52 years
May arise from squamous-urothelial junction at urethral meatus
Gross: usually in glans; flat, ulcerated, irregular mass, with solid tan tissue replacing corpus spongiosum and invading tunica albuginea and corpus cavernosa
Micro: closely attached nests of tumor cells, often with central comedonecrosis; may have peripheral clefts due to retraction artifact; composed of small cells resembling basal cells with small nucleoli and numerous mitotic figures; prominent perineural and angiolymphatic invasion; occasionally peripheral pallisading and focal central keratinization; may have starry sky appearance due to apoptosis; may have associated basal cell hyperplasia or basaloid or warty carcinoma in situ
DD: basal cell carcinoma of skin, poorly differentiated squamous cell carcinoma NOS, small cell carcinoma, neuroendocrine carcinoma.
Exophytic, slow growing, low-grade squamous cell carcinoma without condylomatous features and with irregular infiltrating margin
Diagnosis of exclusion of other verruciform tumors
Inguinal nodal metastases are unusual
Gross: usually in glans; large gray-white exophytic destructive lesion, mean 6 cm, up to 14 cm; cut surface shows pearly white papillomatous tissue, poor demarcation between tumor and stroma
Micro: well differentiated papillary squamous neoplasm; prominent hyperkeratosis and acanthosis; variable papillae (long/short, variable fibrovascular cores); may have keratin cysts and intraepithelial abscesses; no prominent koilocytotic changes; irregular / infiltrative base
DD: squamous cell carcinoma NOS (no prominent papillary features, not as well differentiated); verrucous carcinoma (broad/bulbous boundary of tumor and stroma); warty carcinoma (pleomorphic cells with koilocytotic changes); pseudoepitheliomatous hyperplasia (no atypia, no keratinization, no desmoplastic stroma)
Rare, aggressive, large tumors with predominance of anaplastic spindle cells
Median age 60 years
Frequent recurrences due to inadequate surgery
Gross: usually involves glans, large gray-white or red fungating mass, 5-7 cm; cut surface shows deep invasion of corpus spongiosum or corpora cavernosa; superficial or deep tumor nodules
Micro: predominantly anaplastic spindle cells, occasional giant cells, usual squamous cell carcinoma is either focal or absent; prominent necrosis and mitotic activity; variable leiomyosarcomatous, malignant fibrous histiocytoma-like or prominent myxoid changes, squamous cell carcinoma in situ, benign and malignant bone, osteoid, cartilaginous metaplasia
Positive stains: keratin
DD: sarcoma, malignant melanoma (HMB45+, S100+)
A pattern, not a diagnosis
Penile exophytic tumors with verruciform gross appearance and low/intermediate grade papillary microscopic features
Condylomatous: giant condyloma, warty carcinoma
Non-condylomatous: verrucous carcinoma, low grade papillary squamous cell carcinoma
Median age 57 years
Rare, slow growing, extremely well differentiated variant of squamous cell carcinoma with low malignant potential
Locally invasive, one third recur (due to inadequate surgery or multifocal tumor) but rarely/never metastasizes
33% of cases associated with HPV (usually HPV 6, 11)
Gross: exophytic, papillary (resembles condyloma acuminatum but larger), warty; white-gray, usually ~ 3 cm, involves all penile compartments (glans most common)
Micro: very well differentiated with prominent intercellular bridges, minimal atypia and minimal 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, 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; central fibrovascular cores are uncommon
DD: giant condyloma and warty carcinoma (koilocytotic change present), papillary carcinoma (invasive and jagged border, more atypia, potential for inguinal node metastases)
References: Mod Path 1992;5:48
Warty (condylomatous) carcinoma
Rare, low-intermediate grade, slow growing carcinoma; identical to vulvar, uterine cervix or anal warty carcinoma
May have regional nodal metastases if deeply invasive
Intermediate behavior between low-grade verrucous or papillary carcinomas and usual squamous cell carcinomas of penis
Patients unlikely to die of disease, AJSP 2001;25:673, AJSP 2000;24:505
100% associated with HPV
Gross: verruciform; endophytic, white-tan, cauliflower-like, mean 5 cm; may have cobblestone surface; papillomatous cut surface, may penetrate deep into corpus spongiosum or corpora cavernosa with broad or irregular contours (but less likely than squamous cell carcinoma)
Micro: resemble condyloma due to HPV-related changes of cellular pleomorphism with clear cytoplasm resembling koilocytosis throughout entire tumor (not just surface); arborescent papillary pattern with long, rounded or spiky papillae with prominent fibrovascular cores; may have intraepithelial abscesses; prominent hyperkeratosis and atypical parakeratosis; early - sharply delineated interface between tumor and stroma with no invasion; later - jagged boundary between tumor and stroma;
DD: giant condylomas (benign, HPV changes only in superficial layers, no pleomorphism), verrucous carcinoma (no HPV changes), papillary carcinomas (no HPV changes)
Other malignancies
Basal cell carcinoma
Arise in skin of shaft, may be multicentric
No metastatic potential
Case report in 10 year old boy, Hum Path 1986;17:423
Positive stains: S100
EM: melanosomes
Sporadic in older patients, associated with AIDS in younger patients
Most common sarcoma of penis
Case report in glans penis in bisexual man, Archives 1986;110:346
Gross: single or most commonly multiple small 2-6 mm bluish lesions in glans
Micro: slit like spaces with numerous red blood cells, intracytoplasmic grape-like clusters of PAS+ diastase resistant hyaline globules, prominent lymphoplasmacytic inflammatory infiltrate; may have patch-plaque-like changes at periphery of nodular mass
Positive stains: CD34, CD31
Negative stains: desmin
Very rare, < 50 cases reported, but still second most common sarcoma of penis (after Kaposi’s sarcoma)
Mean age 51 years, range 43-62 years
Sites: usually shaft or base of penis but can occur at any site
Superficial lesions (above tunica albuginea) are asymptomatic, deep seated lesions may cause dysuria or difficulty voiding
Often recur locally
Prognostic features: tumor depth (2 cm or less vs. more than 2 cm), tumor size (5 cm or less vs. more than 5 cm)
Treatment: wide local excision if superficial, excision as necessary for complete removal of deeper tumors
Gross: median 1.5 cm (range 0.5 to 6.0 cm), often superficial; white-tan-gray, firm, may form nodular mass
Micro: smooth muscle cells (abundant eosinophilic cytoplasm, blunt ended nuclei, juxtanuclear vacuoles) arranged in fascicles with nuclear atypia, nuclear pleomorphism, focal necrosis and mitotic activity
Positive stains: desmin, muscle specific actin
References: AJSP 2004;28:115
DD: sarcomatoid carcinoma, metastases
Rare; case report at Urology 2003;62:551
Most common tumor in penis after squamous cell carcinoma, but still rare
Localized to glans, may involve foreskin, although 43% have inguinal nodal metastases at diagnosis
Poor prognosis
Unusual; when it occurs, primary usually from urogenital region (urinary bladder, prostate, kidney) or distal colon
Other primaries are lung (small cell carcinoma), lymphoma, melanoma
Preferred site is corpus cavernosum; also Buck’s fascia and corpus spongiosum
Typically produces “malignant priapism”, due to massive replacement of corpora cavernosa by tumor
Case report in glans penis, Archives 2000;124:148
Aggressive
Micro: sheets and nests of cells with large nuclei, prominent nucleoli, abundant cytoplasm with well defined borders, mucin in 25% of cells; minor component of well-differentiated nonkeratinizing squamous cell carcinoma; resembles similar tumor of cervix
Proximal type epithelioid sarcoma
Aggressive tumor of men and women, median age 35 years old
Usually are metastatic and cause death
Resembles atypical epithelioid sarcoma, rhabdoid tumor, undifferentiated carcinoma
Usually pelvic/perineal, pubic region, buttocks; also penis, forearm, axilla, AJSP 1997;21:130
Micro: prominent large cell epithelioid or rhabdoid features, marked cytologic atypia, often multinodular pattern with necrosis, invasion of subcutaneous or deep soft tissues; usually no granuloma type pattern
Positive stains: keratin, EMA, vimentin, often desmin, CD34, smooth muscle actin; occasionally HMB45 or CEA
Negative stains: CD31, S100
Sclerosing epithelioid fibrosarcoma
Rare, behaves as fully malignant sarcoma, AJSP 2001;25:699
Micro: small to moderate-size, round to ovoid, relatively uniform cells, often with clear cytoplasm, embedded in a hyalinized fibrous stroma; variable necrosis
Positive stains: