Female Reproductive System





Vulva


Inflammatory dermatologic diseases that affect hair-bearing skin elsewhere on the body may also occur on the vulva (see Chapter 2 ). A selected group of disorders are addressed here primarily because of the frequency with which they are seen on the vulva.


Lichen Sclerosus (Chronic Atrophic Vulvitis)


Clinical Features





  • Most common in postmenopausal white women



  • Tends to develop slowly but is insidious and progressive



  • Stenosis of introitus may occur



Gross Pathology





  • Flat, often symmetric white plaques involving labia majora, labia minora, clitoris, and often the perineum



Histopathology





  • Hyperkeratosis, thinned epidermis with blunting of rete ridges ( Figure 12.1A )




    Figure 12.1


    A, Lichen sclerosus. Hyperkeratosis and collagenization of the superficial dermis are evident. A patchy inflammatory cell infiltrate is present below the zone of dermal changes. B, Lichen planus. Hyperkeratosis, wedge-shaped hypergranulosis, irregular epidermal hyperplasia, and a bandlike inflammatory cell infiltrate that obscures the dermoepidermal junction.



  • Hydropic degeneration of basal cells



  • Papillary dermal edema and homogenization of collagen



  • Patchy bandlike lymphocytic infiltrate underlying the abnormal dermis



  • Loss of melanocytes in affected area



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Lichen Planus





  • Dense bandlike lymphoid infiltrate that obscures the dermoepidermal junction ( Figure 12.1B )



  • Other sites (mucosal and nonmucosal) often involved



  • Colloid bodies (degenerated keratinocytes and basement membrane material) may be present



Lichen Simplex Chronicus





  • Hyperkeratosis associated with epidermal hyperplasia rather than atrophy



  • No papillary dermal edema or homogenization



Pearls





  • Lichen sclerosus may be present adjacent to squamous cell carcinoma; however, it is not regarded as a precancerous condition



  • Associated with a small but significant risk of squamous cell carcinoma in postmenopausal women (up to 5% of cases)



  • Topical corticosteroids are the mainstay of treatment





Selected References




  • Chiesa-Vottero A., Dvoretsky P.M., Hart W.R.: Histopathologic study of thin vulvar squamous cell carcinomas and associated cutaneous lesions: a correlative study of 48 tumors in 44 patients with analysis of adjacent vulvar intraepithelial neoplasia types and lichen sclerosus. Am J Surg Pathol 2006; 30: pp. 310-318.



  • Fistarol S.K., Itin P.H.: Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol 2013; 14: pp. 27-47.



  • Raspollini M.R., Asirelli G., Moncini D., et. al.: A comparative analysis of lichen sclerosus of the vulva and lichen sclerosus that evolves to vulvar squamous cell carcinoma. Am J Obstet Gynecol 2007; 197: pp. 592-595.


Lichen Simplex Chronicus (Squamous Cell Hyperplasia, Hyperplastic Dystrophy)


Clinical Features





  • Adult women



  • Commonly presents with vulvar pruritus



  • Treated with topical corticosteroids and antipruritics



Gross Pathology





  • Gray-white plaques, often edematous and excoriated



Histopathology





  • Hyperkeratosis, hypergranulosis, and epithelial thickening ( Figure 12.2 )




    Figure 12.2


    Squamous cell hyperplasia (exhyperplastic dystrophy).

    Hyperkeratosis, acanthosis, and mild chronic inflammation within the dermis.



  • Normal maturation of epidermal keratinocytes



  • In squamous cell hyperplasia, there are no significant dermal changes



  • In lichen simplex chronicus, there is dermal fibrosis with vertically oriented collagen bundles and a chronic inflammatory cell infiltrate



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Diagnosis of lichen simplex chronicus is one of exclusion because the changes may be superimposed on practically any dermatosis; a careful evaluation to exclude a primary dermatosis is necessary



Pearls





  • Lichen simplex chronicus and squamous cell hyperplasia are not known to be associated with an increased risk of squamous cell carcinoma





Selected References




  • Fox H., Wells M.: Recent advances in the pathology of the vulva. Histopathology 2003; 42: pp. 209-216.



  • Stewart K.M.: Clinical care of vulvar pruritus, with emphasis on one common cause, lichen simplex chronicus. Dermatol Clin 2010; 28: pp. 669-680.


Lichen Planus


Clinical Features





  • Most common in women older than 40 years old



  • Symptoms include vulvar pruritus, burning or asymptomatic



  • Vulvo-gingival syndrome: involvement of the vulva, vagina, and oral mucosa by white lacelike plaques



Gross Pathology





  • Variable appearance: white, lacelike plaques, papules, erosive desquamative lesions



Histopathology





  • Hyperkeratosis, hypergranulosis, and epithelial hyperplasia



  • Bandlike predominantly lymphoid infiltrate that obscures the dermoepidermal junction



  • Civatte (cytoid) bodies (degenerated keratinocytes forming eosinophilic bodies)



  • Parakeratosis is generally absent



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Lichen Sclerosus





  • Absence of wedge-shaped hypergranulosis, cytoid bodies, and bandlike lymphocytic infiltrate obscuring the dermoepidermal junction



  • There is epidermal atrophy in lichen sclerosus rather than hyperplasia



  • Presence of papillary dermal edema and homogenized collagen



Lichen Simplex Chronicus





  • Epidermal hyperplasia and hyperkeratosis similar to lichen planus



  • Bandlike lymphoid infiltrate at the dermoepidermal junction is not characteristic of lichen simplex chronicus



Pearls





  • Thinned epithelium and postinflammatory hypopigmentation in advanced disease may make it difficult to differentiate from lichen sclerosus



  • Involvement of vaginal and oral mucosa (vulvo-vaginal-gingival syndrome), regarded as an erosive form of lichen planus, is characteristic





Selected References




  • Ball S.B., Wojnarowska F.: Vulvar dermatoses: lichen sclerosus, lichen planus, and vulval dermatitis/lichen simplex chronicus. Semin Cutan Med Surg 1988; 17: pp. 182.



  • Cooper S.M., Ali I., Baldo M., et. al.: The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case-control study. Arch Dermatol 2008; 144: pp. 1432.



  • Simpson R.C., Thomas K.S., Leighton P., et. al.: Diagnostic criteria for erosive lichen planus affecting the vulva: an international electronic-Delphi consensus exercise. Br J Dermatol 2013; 169: pp. 337-343.


Vulvar Cysts


Clinical Features





  • Generally asymptomatic



  • Occur at any age



  • Incidental finding on clinical examination



Gross Pathology





  • Single or multiple thin-walled cysts several millimeters in diameter



Histopathology





  • None of the cysts show atypia of the lining epithelium



Epidermal Inclusion Cyst





  • Similar to those seen in skin



  • Lined by stratified squamous epithelium with a preserved granular layer



  • Laminated keratin material in the lumen



Bartholin Duct Cyst





  • Dilated segment of obstructed Bartholin gland duct



  • Noncornified squamous, transitional, or cuboidal lining



  • Accumulation of secretions in the lumen but no laminated keratin



Mucinous Cyst





  • Lined by a single layer of columnar mucinous epithelium ( Figure 12.3 )




    Figure 12.3


    Mucous cyst.

    Cystic space lined by simple mucus-secreting cells.



  • Focal squamous metaplasia may be present



Mesonephric-Like Cyst





  • Lined by a single layer of cuboidal to columnar epithelium



  • May be attenuated by pressure from cyst contents (clear fluid)



  • Smooth muscle layer around basement membrane



Ciliated Cyst





  • Rare



  • Ciliated and secretory columnar epithelial cell lining



  • May show pseudostratification



  • No muscle layer



  • Absent cellularity of surrounding stroma



Mesothelial Cyst





  • Thin-walled cyst lined by a single layer of flattened mesothelial cells



Periurethral Cyst





  • Cyst lined by transitional epithelium



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Ciliated Cyst versus Endometriosis





  • In endometriosis, the glands may be ciliated; however, endometrial-type stroma is necessary for diagnosis



Pearls





  • None of the listed cysts are associated with malignancy



  • Surgical excision is curative





Selected References




  • Hamada M., Kiryu H., Ohta T., et. al.: Ciliated cyst of the vulva. Eur J Dermatol 2004; 14: pp. 347-349.



  • Heller D.S.: Benign tumors and tumor-like lesions of the vulva. Clin Obstet Gynecol 2015; 58: pp. 526-535.



  • Patil S., Sultan A.H., Thakar R.: Bartholin’s cysts and abscesses. J Obstet Gynecol 2007; 27: pp. 241-245.


Papillary Hidradenoma (Hidradenoma Papilliferum)


Clinical Features





  • Occurs mainly in middle-aged women in the labia majora, labia minora, and perineum



  • Cutaneous adnexal origin (i.e., apocrine sweat glands)



  • Some may arise from the mammary-like glands that occur in the vulva (ectopic breast tissue)



  • Identical appearance to intraductal papillomas of the breast



Gross Pathology





  • Round, firm, dome-shaped nodule that is 1 to 2 cm in diameter



  • On occasion, slightly tender and ulcerated if neglected



Histopathology





  • Complex papillary structures with fine fibrovascular cores lined by two cell layers ( Figure 12.4 )




    Figure 12.4


    Papillary hidradenoma.

    Papillary structures with fibrovascular cores covered by two layers of cells: a basal layer of flattened myoepithelial cells and a luminal layer of tall columnar cells with decapitation secretions.



  • Inner layer of columnar or cuboidal cells, sometimes with apocrine appearance



  • Basal layer of flattened myoepithelial cells



Special Stains and Immunohistochemistry





  • S-100 protein, SMMS, and P63 are positive in the myoepithelial cells



  • Periodic acid–Schiff (PAS) focally positive in the epithelial cells



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Adenocarcinoma





  • Nuclear pleomorphism and mitotic figures



  • Absence of myoepithelial layer



Other Skin and Skin Adnexal Tumors





  • The vulva and its adnexal structures may be rarely affected by other skin tumors that occur in other sites (refer to Chapter 2 for a detailed discussion)



Pearls





  • Papillary hidradenoma is the only cutaneous adnexal tumor that is seen in the vulva with any frequency





Selected References




  • Baker G.M., Selim M.A., Hoang M.P.: Vulvar adnexal lesions: a 32-year, single-institution review from Massachusetts General Hospital. Arch Pathol Lab Med 2013; 137: pp. 1237-1246.



  • Goto K., Maeda D., Kudo-Asabe Y., et. al.: PIK3CA and AKT1 mutations in hidradenoma papilliferum. J Clin Pathol 2017; 70: pp. 424-427.


Herpes Virus Infection


Clinical Features





  • Genital herpes simplex virus (HSV) infection is a highly contagious sexually transmitted infection typically caused by HSV type II and occasionally by HSV type I



  • Typically presents with asymptomatic vesicles that may ulcerate and become painful or become infected secondarily by bacteria



  • Recurrences are common



Gross Pathology





  • Small, smooth vesicles, 3 to 6 mm



  • Often arranged in clusters



Histopathology





  • Balloon degeneration of epithelial cells



  • Epidermal necrosis and vesiculation ( Figure 12.5A )




    Figure 12.5


    A, Herpes virus infection. Epidermal necrosis and multinucleated giant cells with nuclear clearing and margination of chromatin. B, Molluscum contagiosum. Epidermal hyperplasia and invaginations filled with classic eosinophilic intracytoplasmic inclusions.



  • Multinucleated keratinocytes with ground-glass nuclear inclusions and margination of chromatin



Special Stains and Immunohistochemistry





  • In situ hybridization (ISH) or immunostain for HSV may be useful for confirmation



Other Techniques for Diagnosis





  • Polymerase chain reaction (PCR) and viral cultures



Differential Diagnosis





  • None, when the classic cytopathic effects of herpes virus are present



  • Identical histologic changes are seen in HSV and varicella-zoster virus infections



Pearls





  • Diagnosis can be made from a cytology preparation of the scraping of the base of a vesicle or ulcer (Tzanck smear)





Selected References




  • Bernstein D.I., Bellamy A.R., Hook E.W., et. al.: Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 2013; 56: pp. 344-345.



  • English E.M., Berger M.B.: Vulvar zoster. Am J Obstet Gynecol 2018; 218: pp. 138-139.


Molluscum Contagiosum


Clinical Features





  • Contagious DNA viral disease



  • Spreads by close contact



  • Most lesions regress spontaneously



Gross Pathology





  • Small, smooth papules that measure 0.3 mm to 1 cm



  • Central umbilication



  • Usually multiple and discrete



Histopathology





  • Marked epidermal hyperplasia surrounding a central crateriform invagination that may extend deep into the dermis ( Figure 12.5B )



  • Brightly eosinophilic intracytoplasmic inclusions within the hyperplastic squamous epithelium that are discharged into the crater as the epithelium matures with cornification



  • In older lesions, the inclusions may appear more basophilic



  • The crateriform invagination may rupture and invoke a marked inflammatory response in the dermis; the inclusions may be difficult to identify in the inflammatory background



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • PCR



Differential Diagnosis





  • None when the characteristic inclusions are identified



Pearls





  • Most lesions regress spontaneously



  • Central umbilication of papule is a helpful finding for clinical diagnosis



  • Diagnosis may be made by cytologic examination of scrapings from a papule





Selected References




  • Ishikawa M.K., Arps D.P., Chow C., et. al.: Histopathological features of molluscum contagiosum other than molluscum bodies. Histopathology 2015; 67: pp. 836-842.


Condyloma Acuminatum


Clinical Features





  • Spread by sexual contact



  • Human papillomavirus (HPV) types 6 and 11 are the most common associated types



  • Lesions turn white upon application of 3% to 5% acetic acid under colposcopic examination



  • Usually asymptomatic



Gross Pathology





  • Exophytic lesions of variable size



  • Usually multiple and often confluent



Histopathology





  • Papillomatous epidermal hyperplasia



  • Hyperkeratosis and parakeratosis ( Figure 12.6A )




    Figure 12.6


    Condyloma acuminatum.

    A, Low-power view demonstrates an exophytic lesion associated with acanthosis and hyperkeratosis. B, High-power view shows classic koilocytotic cells with prominent perinuclear halos.



  • Prominent granular cell layer



  • Koilocytes in superficial epithelial layer (pathognomic feature) ( Figure 12.6B )



  • Enlarged cells with perinuclear cytoplasmic clearing (halos)




    • Enlarged or pyknotic nuclei with irregular membranes (raisinoid)



    • Binucleate and multinucleate forms are common




  • In keratinized epithelium, koilocytes are not required for the diagnosis if other histologic features are present. In some cases, condyloma may coexist with high-grade squamous intraepithelial lesion (HSIL) (vulvar intraepithelial neoplasia [VIN] 2-3)



Special Stains and Immunohistochemistry





  • A p16 immunohistochemical stain is helpful in excluding aggressive HPV types (e.g., 16, 18, 31, 45)



Other Techniques for Diagnosis





  • PCR or ISH: identification of specific HPV type, usually 6 or 11



Differential Diagnosis


High-Grade Squamous Intraepithelial Neoplasia (VIN 2-3)





  • Usually flat lesions with or without koilocytic changes



  • Nuclear pleomorphism and hyperchromasia and abnormal mitoses



  • Cytologic atypia is present above the lower third of the epithelium



Squamous Cell Hyperplasia and Lichen Simplex Chronicus





  • No koilocytes are present



  • Lacks HPV by PCR and DNA analysis



Squamous Papilloma





  • Lacks hyperkeratosis



  • Lacks koilocytosis



Pearls





  • HPV-6 is most commonly associated with condyloma acuminatum



  • HPV-11 is not uncommon



  • Most lesions regress spontaneously



  • Progression to a HSIL and even to a squamous cell carcinoma has been reported





Selected References




  • Nelson E.L., Bogliatto F., Stockdale C.K.: Vulvar intraepithelial neoplasia (VIN) and condylomata. Clin Obstet Gynecol 2015; 58: pp. 512-525.



  • Srodon M., Stoler M.H., Baber G.B., et. al.: The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VAIN). Am J Surg Pathol 2006; 30: pp. 1513-1518.



  • Vinokurova S., Wentzensen N., Einenkel J., et. al.: Clonal history of papillomavirus-induced dysplasia in the female lower genital tract. J Natl Cancer Inst 2005; 97: pp. 1816-1821.


Vulvar Intraepithelial Neoplasia


Clinical Features





  • Low-grade squamous intraepithelial lesion (LSIL) is most common during reproductive age. The incidence of HSIL increases in premenopausal women.



  • Discolored, raised plaques, often white after application of (5%) acetic acid at colposcopic examination



Gross Pathology





  • Flat or papular discolored lesions, often white but may be red, gray, brown, or black



Histopathology


Low-Grade Squamous Intraepithelial Lesion (VIN 1)





  • LSIL is associated with both low- and high-risk HPV types



  • Koilocytosis or HPV cytopathic effect in the upper two-thirds of the epithelium, which includes nuclear pleomorphism, hyperchromasia, nuclear membrane irregularity and well-defined perinuclear vacuole around the nucleus



  • The proliferation of basal/parabasal-like cells extends no more than lower third of the epithelium



  • Mitotic figures are limited to the lower third of the epithelium



High-Grade Squamous Intraepithelial Lesion (VIN 2 and 3)





  • Associated with high-risk HPV



  • The lesion shows loss of maturation in the lower two-thirds (VIN 2) or full thickness of the epithelium (VIN 3) ( Figures 12.7A and B )




    Figure 12.7


    Vulvar intraepithelial neoplasia (VIN) 3.

    A, Vulvar skin with hyperkeratosis and finger-like projections showing severe nuclear atypia and lack of maturation. B, Full-thickness dysplasia of the epithelium with overlying parakeratosis. Notice the uniformity of the lesion.



  • The proliferating abnormal squamous cells have increased nuclear size, irregular nuclear membranes, and increased nucleocytoplasmic ratios



  • Atypical mitotic figures are readily identifiable



  • Koilocytosis may be seen within or adjacent to the lesion



Special Stains and Immunohistochemistry





  • Approximately a third of the LSILs show block positivity of p16 immunostain. HSILs are positive for p16, which differentiates HSIL from squamous metaplasia



  • MIB-1 index high



Other Techniques for Diagnosis





  • PCR, ISH: HPV-16 is commonly identified



  • Ploidy: High-grade VIN lesions usually contain an aneuploid population of cells



Differential Diagnosis


Paget Disease





  • Epidermis with scattered, highly atypical single cells with pale cytoplasm (adenocarcinoma cells)



  • Atypical cells positive for mucin, HER-2-neu, and carcinoembryonic antigen (CEA)



Pearls





  • The Lower Anogenital Squamous Terminology (LAST) standardization project for HPV-related lesions recommended a two-tiered nomenclature for noninvasive HPV-associated squamous proliferations of the lower anogenital tract, low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL), which may be further qualified with the appropriate intraepithelial neoplasia (IN) terminology that includes the site designation (vaginal intraepithelial neoplasia [VAIN] for vaginal, VIN for vulvar, and cervical intraepithelial neoplasia [CIN] for cervical)



  • Condyloma acuminatum including flat condyloma is regarded as an LSIL in the LAST terminology



  • Bowenoid papulosis is essentially synonymous with VIN 3 and by the LAST project recommendation should be reported as an HSIL (VIN 3, Bowenoid papulosis)



  • The term erythroplasia of Queyrat refers to an HSIL (VIN 3) in mucous membranes of the vulvar vestibule that are often red



  • Squamous intraepithelial lesions (SILs), particularly the low-grade lesions, may spontaneously regress, especially in young or pregnant women



  • Local excision is the current recommended therapy





Selected References




  • Bornstein J., Bogliatto F., Haefner H.K., et. al., ISSVD Terminology Committee: The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) terminology of vulvar squamous intraepithelial lesions. Obstet Gynecol 2016; 127: pp. 264-268.



  • Darragh T.M., Colgan T.J., Cox J.T., et. al.: The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012; 136: pp. 1266-1297.



  • Goffin F., Mayrand M.H., Gauthier P., et. al.: High-risk human papillomavirus infection of the genital tract of women with a previous history or current high-grade vulvar intraepithelial neoplasia. J Med Virol 2006; 78: pp. 814-819.



  • Yang E.J., Kong C.S., Longacre T.A.: Vulvar and anal intraepithelial neoplasia: terminology, diagnosis, and ancillary studies. Adv Anat Pathol 2017; 24: pp. 136-150.


Squamous Cell Carcinoma


Clinical Features





  • Generally three patient populations




    • One group usually has smoking history, high-risk HPV infection, and HSIL



    • Postmenopausal women with well-differentiated squamous cell carcinoma and no evidence of HPV infection. Lichen sclerosus and lichen planus are considered precursor lesions



    • Verrucous carcinoma which can be HPV-6 and HPV-11 related




Gross Pathology





  • Superficially invasive: red papule, white plaque, or irregular ulcerated lesion, smaller than 2 cm



  • Invasive: exophytic papillary mass or endophytic ulcer, usually solitary



Histopathology





  • Full-thickness involvement of epithelium by pleomorphic cells with high nuclear-to-cytoplasmic ratio and mitotic activity (carcinoma in situ [CIS]/HSIL)



  • Atypical mitotic figures are often readily identifiable



  • Superficially invasive squamous cell carcinoma




    • Depth of invasion of 1 mm or less as measured from the basement membrane of the nearest dermal papilla to the point of deepest point of invasion



    • Less than 2 cm in diameter




  • Invasive squamous cell carcinoma ( Figures 12.8A and B )




    • Greater than 1 mm in depth of invasion



    • Variable degree of squamous differentiation (i.e., keratin pearl formation)




      • Gynecologic Oncology Group (GOG) grade 1: no undifferentiated cells; keratin pearls are present



      • GOG grade 2: less than 50% undifferentiated cells



      • GOG grade 3: greater than 50% undifferentiated cells





    Figure 12.8


    Infiltrating squamous cell carcinoma.

    A, Well-differentiated infiltrating squamous cell carcinoma. B, High-power view shows infiltrating sheets of squamous cells with keratinization and prominent stromal reaction (desmoplasia).



Spindle Cell Squamous Carcinoma





  • Pleomorphic spindle cells that are keratin positive




    • Acantholytic squamous cell carcinoma




  • Pseudogland formation caused by acantholysis



Variants of Squamous Cell Carcinoma


Basaloid Carcinoma





  • Basaloid tumors are often HPV positive



  • Endophytic growth with dense hyalinized stroma



  • Nests and cords of basaloid cells with minimum cytoplasm



  • Overlying squamous epithelium often shows high-grade VIN



  • Associated with synchronous or metachronous tumors of the vagina and cervix



Verrucous Carcinoma





  • Synonymous with giant condyloma of Buschke-Löwenstein



  • Exophytic growth resembling papilloma



  • No fibrovascular cores or cytologic atypia



  • Invasion is defined by large, cytologically bland cells in bulbous nests with pushing borders



  • Usually p16 negative. When prominent koilocytotic atypia and HPV positivity are present, the tumor is better to be classified as giant condyloma



Warty (Condylomatous) Carcinoma





  • Squamous carcinoma with papillary exophytic growth



  • Fibrovascular fronds



  • Numerous koilocytes



  • Irregularly outlined nests of invasive tumor at base



Squamous Cell Carcinoma with Tumor Giant Cells





  • Nonkeratinizing with pleomorphic multinucleate tumor giant cells



Special Stains and Immunohistochemistry





  • Cytokeratin positive



  • Strongly positive p16 in basaloid and warty squamous cell carcinoma



Other Techniques for Diagnosis





  • PCR, ISH: HPV-16 detected in approximately 75% of tumors, especially in younger women with history of VIN



Differential Diagnosis


Basal Cell Carcinoma: As per Basal Cell Carcinoma of Skin





  • Adenoid pattern: in addition, has tubular and glandlike differentiation



  • Basosquamous: includes foci of squamous cell carcinoma



Amelanotic Malignant Melanoma





  • Negative for cytokeratin



  • Positive for S-100 protein, melan-A, and HMB-45



  • No keratinization or squamous pearl formation



Epithelioid Sarcoma





  • Absent intraepithelial component



  • Aggregates of atypical epithelioid cells resembling granulomas



  • Deeper location in the mucosa (near fascia)



Pseudoepitheliomatous Hyperplasia





  • Bland cytology



  • Normally maturing squamous epithelium



  • Usually a reactive process



Metastatic Squamous Cell Carcinoma





  • Clinical history is important



  • In general, metastatic tumor will be present deep in the dermis



  • No connection to the overlying epidermis



Pearls





  • According to the consensus recommendations of the LAST project, the term superficially invasive squamous cell carcinoma (SISCCA) is recommended for minimally invasive squamous cell carcinoma of the lower anogenital tract that has been completely excised and is potentially amenable to conservative therapy



  • Important prognostic factors are tumor thickness, depth of invasion, tumor diameter, and vascular and lymphatic space invasion



  • The risk for inguinal node involvement increases significantly in tumors with a depth of invasion greater than 1 mm



  • The invasive component is often better differentiated than the intraepithelial component



  • Tumors with a depth of invasion >1–2 mm have relatively low but unpredictable rates of inguinal node involvement



  • Wide local excision appears to be the preferred treatment for superficially invasive carcinoma



  • Tumors greater than 1 mm in depth could also be treated by partial or total vulvectomy with inguinal node dissection





Selected References




  • Chiesa-Vottero A., Dvoretsky P.M., et. al.: Histopathologic study of thin vulvar squamous cell carcinomas and associated cutaneous lesions: a correlative study of 48 tumors in 44 patients with analysis of adjacent vulvar intraepithelial neoplasia types and lichen sclerosus. Am J Surg Pathol 2006; 30: pp. 310-318.



  • Darragh T.M., Colgan T.J., Cox J.T., et. al.: The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012; 136: pp. 1266-1297.



  • Trietsch M.D., Nooij L.S., Gaarenstroom K.N., et. al.: Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: a review of the current literature. Gynecol Oncol 2015; 136: pp. 143-157.


Malignant Melanoma


Clinical Features





  • Vulva is the most common site of melanoma in the female genital tract



  • Melanoma is the second most common malignant neoplasm of the vulva



  • Most common in the labia and in older women



  • Most often diagnosed when deeply invasive



  • Local recurrences are frequent



  • Overall 5-year survival between 40% and 50%



Gross Pathology





  • Pigmented macule, papule, or plaque



Histopathology





  • Similar to melanoma in cutaneous sites (see Chapter 2 )



Special Stains and Immunohistochemistry





  • S-100 protein, melan-A, and HMB-45 positive



  • Cytokeratin and CEA negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Paget Disease





  • More common in skin from the breast



  • Immunohistochemical profile (mucin and CEA positive; melan-A and HMB-45 negative) is the opposite of the profile for malignant melanoma



High-Grade Squamous Intraepithelial Lesions (VIN 3)





  • Dysplastic cells lack prominent nucleoli



  • Positive for p16 and negative for mucin, CEA, HMB-45, melan-A, and S-100 protein



Pearls





  • Clinically pigmented appearance of the lesion is characteristic, but up to 35% of vulvar melanomas can be amelanotic



  • Vulvar melanoma is a disease of older women often associated with a worse prognosis than cutaneous melanomas and high rates of local recurrences and satellite lesions





Selected References




  • Mert I., Semaan A., Winer I., et. al.: Vulvar/vaginal melanoma: an updated surveillance epidemiology and end results database review, comparison with cutaneous melanoma and significance of racial disparities. Int J Gynecol Cancer 2013; 23: pp. 1118-1125.



  • Ragnarsson-Olding B.K., Kanter-Lewensohn L.R., Lagerlof B., et. al.: Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features. Cancer 1999; 86: pp. 1273-1284.


Bartholin Gland Carcinoma


Clinical Features





  • Presents in older women



  • Clinically may be mistaken for a cyst or abscess



  • Approximately 20% present with inguinal lymph node metastasis



  • Treated by wide excision or vulvectomy with inguinal-femoral lymph node dissection



Gross Pathology





  • Solid infiltrative tumor that occupies the anatomic site of the Bartholin gland



Histopathology





  • Squamous cell carcinoma (approximately 40%)




    • Usual appearance of squamous cell carcinoma




  • Adenocarcinoma (40%) ( Figure 12.9 )




    • In general, typical features of adenocarcinoma: malignant glands



    • Intracytoplasmic mucin



    • CEA-positive cells




    Figure 12.9


    Bartholin gland adenocarcinoma.

    High-power view shows papillary architecture, nuclear pleomorphism, and hyperchromasia.



  • Adenoid cystic carcinoma (approximately 10%)



  • Transitional cell carcinoma (approximately 5%)



  • Adenosquamous carcinoma (approximately 5%)



Special Stains and Immunohistochemistry





  • Cytokeratin positive



  • CEA positive



  • S-100 protein positive in adenoid cystic carcinoma



Other Techniques for Diagnosis





  • None



Differential Diagnosis


Metastatic Adenocarcinoma versus Primary Bartholin Gland Tumor





  • Metastases are rare in this location



  • May resemble organ of origin



  • Clinical history is most important



Skin Adnexal Adenocarcinoma versus Bartholin Gland Adenocarcinoma





  • Usually well differentiated



  • Morphologically the tumor resembles adnexal structure of origin



Metastatic Squamous Cell Carcinoma versus Bartholin Gland Squamous Cell Carcinoma





  • Usually only weakly positive for CEA



  • Clinical history is most important



Pearls





  • Nodal metastasis is seen in up to 40% of patients, and distant metastasis (lungs, bone) may also occur



  • Adenoid cystic type of Bartholin gland carcinoma generally has a better prognosis than other types



  • Adenosquamous type generally has a worse prognosis than squamous cell carcinoma of the vulva



  • Adenocarcinoma has the highest rate of lymph node metastasis





Selected References




  • Finnan M.A., Barre G.: Bartholin’s gland carcinoma, malignant melanoma and other rare tumours of the vulva. Best Pract Res Clin Obstet Gynaecol 2003; 17: pp. 609-633.



  • Nazeran T., Cheng A.S., Karnezis A.N., et. al.: Bartholin gland carcinoma: clinicopathologic features, including p16 expression and clinical outcome. Int J Gynecol Pathol 2019; 38: pp. 189-195.



  • Woida F.M., Ribeiro-Silva A.: Adenoid cystic carcinoma of the Bartholin gland: an overview. Arch Pathol Lab Med 2007; 131: pp. 796-798.


Extramammary Paget Disease


Clinical Features





  • Most common in postmenopausal women



  • Fluorescein is useful to visualize the lesion before excision



  • Often presents with pruritus



  • Most develop de novo in epidermis and probably represent adenocarcinoma in situ (AIS) of the cutaneous sweat ducts



  • Slowly progressive disease



  • Not necessarily associated with underlying vulvar invasive cancer in contrast to mammary Paget disease



  • Therapy is wide local excision



Gross Pathology





  • Pink to red eczematous patches with white foci due to hyperkeratosis



Histopathology





  • Irregularly defined lesion often larger than clinical impression



  • Abnormal cells in the epidermis concentrated in the basal layer but may also be present superficially and in skin appendages



  • Intraepithelial tumor cells singly or in small groups



  • Large cells with round nuclei often containing large nucleoli



  • Pale cytoplasm or vacuolated signet ring cells ( Figure 12.10 )




    Figure 12.10


    Paget disease.

    A, Neoplastic cells in small groups near the basal cell layer and above it. The cells have pale cytoplasm, round nuclei, and prominent nucleoli. B, Paget cells are strongly immunoreactive for cytokeratin 7.



  • Adenocarcinoma may be seen in underlying dermis in approximately 10% to 20% of cases



Special Stains and Immunohistochemistry





  • Cytokeratin 7 and CEA positive



  • PAS with diastase, mucin, and alcian blue positive



  • May be HER-2-neu, GCDFP-15, and androgen receptor positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Vulvar Intraepithelial Neoplasia





  • Usually associated with HPV infection



  • More regular involvement of basal layer



  • Smaller cells with less prominent nucleoli



  • Negative for mucin, CEA, low-molecular-weight cytokeratin (LMWCK), and HER-2-neu



Superficial Spreading Malignant Melanoma





  • Positive for S-100 protein, melan-A, and HMB-45



  • Negative for mucin, cytokeratin, and HER-2-neu



  • Cells may contain melanin pigment



Pearls





  • Generally not associated with HPV



  • Occasionally associated with underlying adenocarcinoma or primary breast carcinoma including Paget disease



  • Mucin positivity is a helpful diagnostic feature



  • Recurrences are frequent because lesions are often more extensive than can be appreciated clinically





Selected References




  • Baker G.M., Selim M.A., Hoang M.P.: Vulvar adnexal lesions: a 32-year, single-institution review from Massachusetts General Hospital. Arch Pathol Lab Med 2013; 137: pp. 1237-1246.



  • Petković S., Jeremić K., Vidakovic S., et. al.: Paget’s disease of the vulva: a review of our experience. Eur J Gynaecol Oncol 2006; 27: pp. 611-612.


Granular Cell Tumor


Clinical Features





  • Peripheral nerve sheath tumor seen uncommonly in the vulva



  • Presents as a painless, slow-growing, subcutaneous mass



  • Generally occurs in the labia majora, clitoris, or mons pubis



  • Local recurrences are common



  • Malignant tumors are extremely rare



Gross Pathology





  • Well-demarcated, firm mass



Histopathology





  • Nonencapsulated with pushing or infiltrative borders



  • Composed of irregular nests and sheets of polyhedral cells with indistinct borders, abundant eosinophilic granular cytoplasm, and relatively small nuclei



  • The overlying epithelium may show pseudoepitheliomatous hyperplasia



Special Stains and Immunohistochemistry





  • S-100 protein positive



  • PAS positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Leiomyoma, Neurofibroma, and Dermatofibroma





  • Generally lack the classic granular cytoplasm seen in granular cell tumors



Squamous Cell Carcinoma





  • Pseudocarcinomatous hyperplasia on the surface of granular cell tumor may be misdiagnosed as squamous cell carcinoma in superficial biopsies



Pearls





  • Much more common in other locations (i.e., tongue)



  • May enlarge rapidly during pregnancy



  • Examination of the margins of resection is most important





Selected References




  • Heller D.S.: Benign tumors and tumor-like lesions of the vulva. Clin Obstet Gynecol 2015; 58: pp. 526-535.



  • Kondi-Pafiti A., Kairi-Vassilatou E., Liapis A., et. al.: Granular cell tumor of the female genital system: clinical and pathologic characteristics of five cases and literature review. Eur J Gynaecol Oncol 2010; 31: pp. 222-224.


Angiomyofibroblastoma


Clinical Features





  • Rare benign tumor



  • Presents as a painless mass, typically less than 5 cm, occasionally pedunculated



  • Clinical impression is often a Bartholin gland cyst



Gross Pathology





  • Well circumscribed, nonencapsulated



  • Tan-white cut surface



Histopathology





  • Alternating zones of hyper- and hypocellularity with irregularly distributed abundant thin-walled blood vessels



  • Bland spindled, oval, plasmacytoid and epithelioid stromal cells with eosinophilic cytoplasm that tend to aggregate around the blood vessels ( Figure 12.11 )




    Figure 12.11


    Angiomyofibroblastoma.

    Spindle-shaped tumor cells with perivascular distribution. A prominent perivascular chronic inflammatory infiltrate is noted.



  • Variably edematous to collagenous matrix



  • Occasional multinucleated cells and rare to absent mitotic activity



  • Adipose tissue may be present within the tumor



  • Scattered lymphocytes and mast cells are usually present



Special Stains and Immunohistochemistry





  • Vimentin and desmin positive



  • Smooth muscle actin (SMA) negative



  • S-100 protein, estrogen receptor (ER), progesterone receptor (PR), and CD34 variably positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Aggressive Angiomyxoma





  • Less cellular, homogeneous, and characterized by infiltrative borders



  • Medium to large muscular vessels in clusters



Pearls





  • Treated by local excision





Selected References




  • Nasu K., Fujisawa K., Takai N., et. al.: Angiomyofibroblastoma of the vulva. Int J Gynecol Cancer 2002; 12: pp. 228-231.



  • Parra-Herran C., Nucci M.R.: Soft tissue lesions of the vulva and vagina.2018.Elsevier Ltd. Philadelphia, PApp. 197-223.


Aggressive Angiomyxoma


Clinical Features





  • Usually seen in premenopausal women



  • Presents as a poorly demarcated mass in the vulva, perineum, and pelvis



  • Locally aggressive, deeply invasive tumor, often larger than clinically appreciated



  • Wide local excision is the treatment of choice



Gross Pathology





  • Soft gelatinous mass with ill-defined margins



  • Clusters of vessels are visible on cut surface



Histopathology





  • Myxoid stroma with benign spindled fibroblasts and myofibroblasts ( Figure 12.12 )




    Figure 12.12


    Aggressive angiomyxoma.

    Prominent myxoid stroma with small blood vessels.



  • Numerous haphazardly arranged medium-large sized, often hyalinized blood vessels



  • Perivascular cuffs of collagen and bundles of smooth muscle cells



  • Entrapped fat, neural elements, or glandular elements may be present



Special Stains and Immunohistochemistry





  • Spindle cells positive for SMA, ER, and PR



  • S-100 protein and CD34 may be positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Superficial Angiomyxoma (Cutaneous Myxoma)





  • Superficial location, small size and good circumscription



  • Neutrophils are often present



  • Lack thick-walled muscular vessels



  • Negative for desmin, ER and PR



Angiomyofibroblastoma





  • Superficial location and well-defined margins



  • Cellular areas, thin-walled blood vessels, and perivascular condensation of cells



Pearls





  • Locally aggressive with significant rate of local recurrence





Selected References




  • Dierickx I., Deraedt K., Poppe W., et. al.: Aggressive angiomyxoma of the vulva: a case report and review of literature. Arch Gynecol Obstet 2008; 277: pp. 483-487.



  • Ribaldone R., Piantanida P., Surico D., et. al.: Aggressive angiomyxoma of the vulva. Gynecol Oncol 2004; 95: pp. 724-728.



  • Song M., Glasgow M., Murugan P., et. al.: Aggressive angiomyxoma of the vulva and bladder. Obstet Gynecol 2017; 130: pp. 885-888.



  • Sutton B.J., Laudadio J.: Aggressive angiomyxoma. Arch Pathol Lab Med 2012; 136: pp. 217-221.


Leiomyosarcoma


Clinical Features





  • Most common vulvar sarcoma but overall quite rare



  • Occurs in women of any age



  • Usually arises in labia majora



  • Often presents with pain



  • Treatment is wide excision



  • Metastasis to lung and liver have been reported



Gross Pathology





  • Well-defined firm mass with infiltrative edges



  • Focal hemorrhage, necrosis, and cystic degeneration



Histopathology





  • Interlacing bundles of spindle cells with perinuclear clearing and nuclear atypia



  • A prominent epithelioid cell component is seen rarely



  • The background may be myxoid and or hyalinized



  • Coagulative necrosis and areas of hemorrhage



  • Greater than 5 mitotic figures/10 high-power fields (hpf)



Special Stains and Immunohistochemistry





  • Cytokeratin: occasional positive cells



  • Vimentin, desmin, and SMA positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Dermatofibrosarcoma Protuberans





  • Storiform pattern



  • Rare cytologic atypia and mitotic figures



  • Negative for SMA and desmin but positive for CD34



Aggressive Angiomyxoma





  • Multiple clusters of muscular blood vessels



  • Generally lacks cytologic atypia and mitotic activity



Pearls





  • Tumors >5 cm in diameter have a higher rate of recurrence



  • Some tumors may have minimal cytologic atypia, but infiltrative margins, coagulative necrosis, and a mitotic count >5 mitotic figures/10 high-power fields help to distinguish them from leiomyomas





Selected References




  • Nielsen G.P., Rosenberg A.E., Koerner F.C., et. al.: Smooth-muscle tumors of the vulva: a clinicopathological study of 25 cases and review of the literature. Am J Surg Pathol 1996; 20: pp. 779-793.



  • Shankar S., Todd P.M., Rytina E., et. al.: Leiomyosarcoma of the vulva. J Eur Acad Dermatol Venereol 2006; 20: pp. 116-117.


Other Sarcomas





  • The following mesenchymal tumors rarely arise in the vulvar subcutaneous tissue:




    • Embryonal rhabdomyosarcoma, generally in children



    • Dermatofibrosarcoma protuberans



    • Undifferentiated pleomorphic sarcoma



    • Epithelioid sarcoma



    • Malignant rhabdoid tumor



    • Angiosarcoma



    • Hemangiopericytoma



    • Kaposi sarcoma



    • Alveolar soft part sarcoma



    • Malignant schwannoma (neural)



    • Liposarcoma




  • In the vulva, these sarcomas are identical to their counterparts in soft tissue



  • Refer to Chapter 17 , Chapter 2 for detailed discussions




Selected References




  • Nucci M.R., Fletcher C.D.M.: Vulvovaginal soft tissue tumors: update and review. Histopathology 2000; 36: pp. 97-108.



  • Ulutin H.C., Zellars R.C., Frassica D.: Soft tissue sarcoma of the vulva: a clinical study. Int J Gynecol Cancer 2003; 13: pp. 528-531.



  • Wheeler L.J., Behbakht K., Karam A.K.: Vulvar sarcoma subtype influences outcome and behavior: a surveillance epidemiology and end results database review. Gynecol Oncol 2018; 149: pp. 197.


Vagina


Both atresia and total absence of the vagina are extremely uncommon.


Vaginal Polyp (Fibroepithelial Polyp, Mesodermal Stromal Polyp)


Clinical Features





  • Occurs in women of childbearing age



  • One third of tumors are found during pregnancy



  • Usually discovered incidentally during pelvic examination



Gross Pathology





  • Soft polypoid or papillary mass usually in the lower third of the vagina, typically less than 4 cm in size



Histopathology ( Figure 12.13 )





  • Squamous epithelium with underlying fibrovascular stroma



  • Plump, cytologically atypical myofibroblasts may be present in the stroma



  • Bizarre multinucleate giant cells may also be present



  • Mitotic activity is generally low




Figure 12.13


Vaginal (fibroepithelial) polyp.

Polypoid lesion composed of fibrous connective tissue covered by mature squamous epithelium.


Special Stains and Immunohistochemistry





  • Stromal cells positive for vimentin, desmin, ER, PR



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Embryonal Rhabdomyosarcoma





  • Patients are generally younger than 5 years



  • Population of small round blue undifferentiated cells



  • Cellular cambium layer



  • Rhabdomyoblasts



Pearls





  • Clinically benign; important to recognize to avoid misdiagnosing as condyloma or sarcoma





Selected References




  • Kurman R.J., Ronnett B.M., Sherman M.E., et. al.: AFIP Atlas of Tumor Pathology.2010.Armed Forces Institute of PathologyWashington, DCpp. 170-172.



  • Nucci M.R., Young R.H., Fletcher C.D.M.: Cellular pseudosarcomatous fibroepithelial stromal polyps of the lower female genital tract: an underrecognized lesion often misdiagnosed as sarcoma. Am J Surg Pathol 2000; 24: pp. 231-240.


Squamous Papilloma


Clinical Features





  • May be seen in vagina, vulvar vestibule, or cervix



  • Usually asymptomatic



Gross Pathology





  • Several millimeters or larger in diameter



  • Clustered papillary lesions



Histopathology





  • Fibrovascular core with papillary fronds



  • Mature, squamous epithelial lining ( Figure 12.14 )




    Figure 12.14


    Squamous papilloma.

    Papillary lesion lined by mature nonkeratinizing squamous epithelium.



  • No koilocytes



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Condyloma Acuminatum





  • Arborizing architecture



  • Koilocytosis



  • HPV-6 or HPV-11 associated



Vaginal (Fibroepithelial) Polyp





  • Thinner squamous lining



  • Polypoid rather than papillary



  • Cellular stroma with occasional large pleomorphic cells



Pearls





  • Clinically benign; important to recognize to avoid misdiagnosing as condyloma or squamous cell carcinoma





Selected Reference




  • Kurman R.J., Ronnett B.M., Sherman M.E., et. al.: AFIP Atlas of Tumor Pathology.2010.Armed Forces Institute of PathologyWashington, DCpp. 141.


Vaginal Intraepithelial Neoplasia


Clinical Features





  • Relatively rare compared with the incidence of cervical SILs



  • LSIL is most common during reproductive age. HSIL incidence increases in premenopausal women



  • Frequently associated with squamous cell carcinomas of cervix or vulva



  • HPV infection and cervical or VIN are risk factors



  • Usually asymptomatic



Gross Pathology





  • Most vaginal SILs, including LSIL and HSIL tend to be located in the upper third of the vagina



  • Roughened pink or white discolored epithelium



  • Occasional gross abnormality



Histopathology


Low-Grade Squamous Intraepithelial Lesion (VAIN 1)





  • LSIL is associated with both low- and high-risk HPV types



  • Koilocytosis or HPV cytopathic effect in the upper two-thirds of the epithelium, which includes nuclear pleomorphism, hyperchromasia, nuclear membrane irregularity and well-defined perinuclear vacuole around the nucleus



  • The proliferation of basal/parabasal-like cells extends no more than lower third of the epithelium



  • Mitotic figures are limited to the lower third of the epithelium



  • Flat condylomata acuminata are best classified as LSIL



High-Grade Squamous Intraepithelial Lesion (VAIN 2 and VAIN 3)





  • Associated with high-risk HPV



  • The lesion shows loss of maturation in the lower two-thirds (VAIN II) or full thickness of epithelium (VAIN III) ( Figure 12.15 )




    Figure 12.15


    A, Vaginal intraepithelial neoplasia (VAIN) 2. Dysplastic cells occupy the lower two-thirds of the epithelium. B, VAIN 3. The dysplastic cells are present throughout the full thickness of the epithelium.



  • The proliferating abnormal squamous cells have increased nuclear size, irregular nuclear membranes, and increased nucleocytoplasmic ratios



  • Binucleate and multinucleate cells are often present



  • Atypical mitotic figures are readily identifiable



  • Koilocytosis may be seen within or adjacent to the lesion



Special Stains and Immunohistochemistry





  • Approximately a third of the LSILs show block positivity of p16 immunostain. HSILs are positive for p16, which differentiates HSIL from squamous metaplasia.



Other Techniques for Diagnosis





  • HPV subtypes may be identified by PCR or ISH



Differential Diagnosis


Atrophy





  • Thinned epithelium without squamous atypia or koilocytosis



  • No mitotic activity



Immature Squamous Metaplasia





  • Nuclear pleomorphism is not dramatic



  • Minimal if any mitosis



Radiation Change





  • Preserved nuclear-to-cytoplasmic ratio



  • Vacuolated cytoplasm



  • Smudged chromatin



  • Multinucleation



  • Lack of mitotic activity



Reactive Atypia





  • Prominent nucleoli



  • Lack of nuclear membrane irregularities



Pearls





  • Less than 10% progress to invasive carcinoma



  • Laser ablation and topical 5-fluorouracil are alternative treatments





Selected References




  • Bertoli H.K., Rasmussen C.L., Sand F.L., et. al.: Human papillomavirus and p16 in squamous cell carcinoma and intraepithelial neoplasia of the vagina. Int J Cancer 2019; 145: pp. 78-86.



  • Darragh T.M., Colgan T.J., Thomas Cox J., et. al.: The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012; 136: pp. 1266-1297.



  • Drodon M., Stoler M.H., Baber G.B., et. al.: The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VAIN). Am J Surg Pathol 2006; 30: pp. 1513-1518.


Squamous Cell Carcinoma


Clinical Features





  • The majority are associated with high-risk HPV



  • Most common malignant vaginal neoplasm, but rare



  • To diagnose as vaginal primary squamous cell carcinoma, there should be no preexistent cervical and/or vulvar squamous cell carcinoma



  • One-fiftieth of the incidence of cervical squamous cell carcinoma



  • Most common in postmenopausal women



  • Treatment is radiation therapy



Gross Pathology





  • Most vaginal squamous cell carcinomas are located in the posterior wall and upper third of the vagina



  • Superficially invasive: red papule, white plaque, or irregular ulcerated lesion



  • Invasive: exophytic papillary mass or endophytic ulcer, usually solitary



Histopathology





  • Keratinizing with squamous pearl formation or nonkeratinizing



  • Syncytial sheets of cells with variable amounts of eosinophilic cytoplasm ( Figure 12.16 )




    Figure 12.16


    Infiltrating squamous cell carcinoma.

    Nests and clusters of neoplastic cells invade the stroma.



  • Distinct cell borders and intercellular bridges



  • Variants




    • Verrucous carcinoma




      • Rare variant



      • Bulbous solid masses composed of bland squamous cells that push into the stroma



      • In general, koilocytes are not evident



      • Lymph node metastasis is rare




    • Papillary squamous cell carcinoma (squamotransitional carcinoma, please refer to cervix section for histologic features)



    • Warty (condylomatous) carcinoma




      • Squamous cell carcinoma with numerous koilocytes



      • Exophytic growth





Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Amelanotic Malignant Melanoma





  • Negative for cytokeratin



  • Positive melan-A and HMB-45



  • Absent keratinization and squamous pearl formation



Pseudoepitheliomatous Hyperplasia





  • Bland cytology



  • Normally maturing squamous epithelium



  • Absent stromal nests dissociated from basal layer



  • Commonly a reactive process



Metastatic Squamous Cell Carcinoma





  • Clinical history is fundamental



  • In general, metastatic tumor will be present deep in the submucosa



  • Absent overlying intraepithelial component



Pearls





  • Tumors with less than 3 mm depth of stromal invasion and also verrucous carcinomas have low rates of lymph node metastasis



  • Verrucous carcinomas should not be treated with radiation therapy because they are radioresistant and may transform to higher-grade squamous carcinomas





Selected References




  • Medeiros F., Nascimento A.F., Crum C.P.: Early vulvar squamous neoplasia: advances in classification, diagnosis, and differential diagnosis (review). Adv Anat Pathol 2005; 12: pp. 20-26.



  • Roma A.A., Hart W.R.: Progression of simplex (differentiated) vulvar intraepithelial neoplasia to invasive squamous cell carcinoma: a prospective case study confirming its precursor role in the pathogenesis of vulvar cancer. Int J Gynecol Pathol 2007; 26: pp. 248-253.


Vaginal Adenosis


Clinical Features





  • Associated with diethylstilbestrol (DES) exposure, most frequently in utero



  • Occurs in approximately one-third of women exposed to DES



  • Young women aged 30 to 50 are most commonly affected



  • Red granular spots that do not stain with iodine



  • Excessive mucoid vaginal discharge is a common symptom



  • Glandular epithelium may be observed colposcopically



  • May also occur with 5-fluorouracil and carbon dioxide laser therapy



Gross Pathology





  • Red granular patches



  • Upper third of anterior wall is the most common location



Histopathology





  • Endocervical type mucosa replaces squamous lining of vagina



  • Mucinous glands are present in the lamina propria ( Figure 12.17 )




    Figure 12.17


    Vaginal adenosis.

    Low-power view demonstrates glandular epithelium at the junction of the mucosa and submucosa/lamina propria in the vagina.



  • On occasion, ciliated epithelium or endometrial-type glands are present, particularly in lower third of vagina



  • In longstanding lesions, the glands undergo replacement by metaplastic squamous epithelium; obliterated glands or mucin droplets may still be identified in these lesions



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Metastatic Adenocarcinoma





  • Cytologic atypia



  • Clinical history of a primary adenocarcinoma



Pearls





  • DES was prescribed to women in the 1940s and 1950s to prevent miscarriages



  • History of exposure to DES is important



  • Vaginal adenosis usually regresses spontaneously



  • Rarely associated with clear cell carcinoma of vagina and cervix



  • No treatment is required





Selected References




  • Haefner H.K., Crum C.P.: Benign conditions of the vagina.2018.Diagnostic Gynecologic and Obstetric Pathology. Elsevier Ltd. Philadelphia, PApp. 258-274.



  • Kurman R.J., Ronnett B.M., Sherman M.E., et. al.: AFIP Atlas of Tumor Pathology.2010.Armed Forces Institute of PathologyWashington, DCpp. 146-152.



  • McCluggage W.G.: Recent developments in vulvovaginal pathology. Histopathology 2009; 54: pp. 156-173.



  • Robboy S.J., Hill E.C., Sandberg E.C., et. al.: Vaginal adenosis in women born prior to the diethylstilbestrol era. Hum Pathol 1986; 17: pp. 488-492.


Clear Cell Adenocarcinoma


Clinical Features





  • Often but not always associated with in utero exposure to DES



  • Occurs in less than 0.2% of women exposed to DES



  • Generally occurs in women about 20 years of age



  • Often presents with vaginal bleeding and discharge



  • May be asymptomatic



Gross Pathology





  • Most tumors are located on the anterior wall of the upper third of the vagina



  • Polypoid or nodular mass



  • Less commonly flat or ulcerated



Histopathology





  • Tubulocystic and solid are the most common patterns



  • Papillary, tubular, and trabecular patterns may also be seen



  • Tumor cells are polyhedral with round, atypical nuclei and clear cytoplasm containing glycogen ( Figure 12.18 )




    Figure 12.18


    Clear cell adenocarcinoma, papillary pattern.

    The papillae are lined by large pleomorphic cells showing clear cytoplasm. Focal necrosis is present.



  • Hobnail cell is a characteristic finding (cell with a nucleus that protrudes beyond the boundaries of the cell into a luminal, tubular, or cystic space)



  • Less commonly, the epithelial cells are flattened, cuboidal, oxyphilic, or signet ring



  • Adenosis is usually identified adjacent to tumor



  • Intracellular hyaline structures and psammoma bodies are common



Special Stains and Immunohistochemistry





  • Cytokeratin positive



  • PAS positive (intracytoplasmic glycogen)



  • PAS with diastase and mucin negative (mucin may be positive in glandular lumina)



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Metastatic Clear Cell Carcinoma from the Ovary





  • Clinical history is essential



Metastatic Renal Cell or Adrenal Carcinoma





  • Clinical history is fundamental



  • Centrally located nuclei with prominent nucleoli



  • Absent gland formation and hobnail cells



  • Prominent vascularity



Pearls





  • Associated with in utero exposure to DES



  • Adenosis believed to be a precursor lesion



  • High risk for nodal metastasis if depth of invasion is greater than 3 mm



  • More aggressive than squamous cell carcinoma



  • Treatment of early-stage disease: vaginectomy with radical hysterectomy and lymphadenectomy to prevent recurrence



  • Radiation therapy indicated for advanced disease





Selected References




  • Herbst A.L., Anderson S., Hubby M.M., et. al.: Risk factors for the development of diethylstilbestrol associated clear cell adenocarcinoma: a case-control study. Am J Obstet Gynecol 1986; 154: pp. 814-822.



  • Huo D., Anderson D., Palmer J.R., et. al.: Incidence rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: update after 40-year follow-up. Gynecol Oncol 2017; 46: pp. 566-571.



  • Robboy S.J., Anderson M.C., Russell P.: Pathology of the Female Reproductive Tract.2002.Churchill LivingstoneLondonpp. 92-97.


Rhabdomyoma


Clinical Features





  • Rare; occurs in middle-aged women



  • Presents with vaginal bleeding and dyspareunia



Gross Pathology





  • Polypoid mass, less commonly flat or ulcerated



Histopathology





  • Bland skeletal muscle cells with fetal or adult-type appearance



  • Cells are spindle to oval with abundant eosinophilic cytoplasm with cross striations and plump oval nuclei without atypia or mitosis



  • Cells are surrounded by a fibrous stroma



Special Stains and Immunohistochemistry





  • Positive for actin, desmin, caldesmon, myoglobin, and myosin



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Embryonal Rhabdomyosarcoma





  • Occurs at a younger age as a rapidly growing infiltrative mass



  • Presence of cambium layer



  • Pleomorphic strap cells with mitosis



Pearls





  • Fewer than 25 cases reported



  • Unremarkable overlying squamous mucosa



  • Benign behavior





Selected References




  • López Varela C., López de la Riva M., La Cruz Pelea C.: Vaginal rhabdomyomas. Int J Gynaecol Obstet 1994; 47: pp. 169-170.



  • Schoolmeester J.K., Xing D., Keeney G.L., et. al.: Genital rhabdomyoma of the lower female genital tract: a study of 12 cases with molecular cytogenetic findings. Int J Gynecol Pathol 2018; 37: pp. 349-355.


Embryonal Rhabdomyosarcoma


Clinical Features





  • Most common vaginal sarcoma



  • Occurs in infants and girls younger than 5 years



  • Aggressive tumor



  • Classically presents as a mass of small translucent nodules protruding from the vagina



  • May present with bleeding and discharge and extension to bladder and rectum



  • Metastasis to lung or bone usually occurs later in the course of the disease



Gross Pathology





  • Classic appearance is a sessile or pedunculated tumor of numerous translucent gray, grapelike, polypoid masses



  • Hemorrhagic areas



  • Most common location is anterior vaginal wall



Histopathology





  • Tumor is organized histologically in layers ( Figure 12.19 )




    • Superficial attenuated layer of squamous epithelium



    • Underlying cambium layer composed of small, round to spindled, primitive blue cells with dense hyperchromatic nuclei and minimal cytoplasm; cells may invade the overlying epidermis



    • Underlying sparsely cellular region with scattered small round blue cells as noted previously in an edematous or myxoid stroma




      • Rhabdomyoblasts are found in this region




        • Large irregular, elongated, or “strap” cells with prominent eosinophilic cytoplasm



        • Cross-striations may be seen but are not required to make the diagnosis




      • Cells may appear to condense around blood vessels



      • Brisk mitotic activity



      • Small islands of hyaline cartilage may be present





    Figure 12.19


    Embryonal rhabdomyosarcoma.

    A, Low-power view demonstrates a proliferation of pleomorphic tumor cells beneath the squamous epithelium. B, High-power view demonstrates myxoid stroma containing round to spindled neoplastic cells with eosinophilic cytoplasm.



Special Stains and Immunohistochemistry





  • Vimentin, desmin, myogenin, and myo-D1 positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Müllerian Papilloma





  • In the differential not because of histologic similarity, but rather because of its similar clinical presentation in infants and young girls



  • Papillary tumor with broad fibrovascular cores lined by cuboidal or mucinous epithelium



  • Absence of cytologic atypia and mitotic activity



Vaginal Polyp (Mesodermal Stromal Polyp)





  • Usually seen in adult women



  • Essentially a fibroepithelial polyp as seen histologically in other sites



  • Polypoid (as opposed to grapelike) mass



  • Edematous fibrous tissue covered by squamous epithelium



  • Lymphocytes may be present in the fibrous stroma



  • No cambium layer



  • Absent small round undifferentiated blue cells and rhabdomyoblasts



  • Negative for desmin, myogenin, and myo-D1



Rhabdomyoma





  • Usually occurs in middle-aged women



  • Numerous well-developed rhabdomyoblasts



  • No nuclear atypia or mitotic figures



  • Absence of cambium layer



  • Absent small round undifferentiated blue cells



Pearls





  • Aggressive tumor with rapid local invasion and high rate of local recurrence



  • Survival has significantly improved by combination of surgery, radiation, and new multiagent chemotherapeutic regimens





Selected References




  • Fernandez-Pineda I., Spunt S.L., Parida L., et. al.: Vaginal tumors in childhood: the experience of St. Jude Children’s Research Hospital. J Pediatr Surg 2011; 46: pp. 2071-2075.



  • Hemida R., Goda H., Abdel-Hady El-S., et. al.: Embryonal rhabdomyosarcoma of the female genital tract: 5 years’ experience. J Exp Ther Oncol 2013; 10: pp. 135-137.



  • Nasioudis D., Alevizakos M., Chapman-Davis E., et. al.: Rhabdomyosarcoma of the lower female genital tract: an analysis of 144 cases. Arch Gynecol Obstet 2017; 296: pp. 327-334.


Other Sarcomas





  • Leiomyosarcoma, epithelioid sarcoma, and undifferentiated pleomorphic sarcoma may also present as primary sarcomas of the vagina



  • Refer to Chapter 17 for a detailed discussion



Cervix


Endocervical Polyp


Clinical Features





  • Most common new growth of the cervix



  • Multigravidas during the fourth to sixth decades are the typical patients with polyps



  • Majority are discovered as incidental finding; most common symptom is abnormal vaginal bleeding



Gross Pathology





  • Rounded or elongated with a smooth or lobulated surface



  • Most commonly single



  • May measure from millimeters to a few centimeters



Histopathology





  • Variety of patterns



  • Varying amounts of squamous or endocervical epithelium depending on proximity to cervical os ( Figure 12.20 )




    Figure 12.20


    Endocervical polyp.

    Polypoid lesion composed of endocervical mucous glands.



  • Stroma consists of dense fibroconnective tissue with thin and thick-walled vessels



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Microglandular Adenosis (Hyperplasia)





  • Tightly packed glands in a relatively ordered distribution



  • Neutrophils are commonly present in the glandular lumina



  • Acute and chronic inflammation in the stroma



Papillary Adenofibroma





  • Extremely rare and benign



  • Leaflike pattern of glandular epithelium compressed by a dense fibrous stroma



Pearls





  • Most common new growth of the cervix



  • Characterized by dense fibrous stroma with thick-walled vessels





Selected References




  • Kurman R.J., Ronnett B.M., Sherman M.E., et. al.: AFIP Atlas of Tumor Pathology.2010.Armed Forces Institute of PathologyWashington, DCpp. 77-78.



  • McCluggage W.G.: A practical approach to the diagnosis of mixed epithelial and mesenchymal tumours of the uterus. Mod Pathol 2015; 29: pp. 78.


Microglandular Hyperplasia


Clinical Features





  • Incidental finding in cervical specimens mostly in women of reproductive age



  • May present with postcoital spotting or bleeding



  • Associated with history of oral contraceptive use, pregnancy, or postpartum condition



Gross Pathology





  • Single or multiple polypoid lesions resembling small cervical polyps



Histopathology





  • Single or multiple foci of crowded glands have variable amounts of mucin ( Figure 12.21 )




    Figure 12.21


    Microglandular hyperplasia.

    Tightly packed variously sized glands lined by flattened to cuboidal cells.



  • Variably sized glands include rare mitotic figures (1 mitotic figure/10 hpf)



  • Uniform small round nuclei have even chromatin



  • Focal squamous metaplasia and some signet ring cells may be present



  • Neutrophils are commonly present in the glandular lumina



  • Stroma separating the glands shows acute and chronic inflammatory cells



Special Stains and Immunohistochemistry





  • CEA generally negative



  • Mucin positive



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Clear Cell and Classic Cervical Adenocarcinoma





  • Papillary and glandular patterns



  • Irregular infiltration of cervical stroma by markedly atypical cells with nuclear pleomorphism



  • Brisk mitotic rate



  • Clear cytoplasm contains mostly glycogen rather than mucin



  • Subnuclear vacuoles which are usually present in microglandular hyperplasia help to differentiate from adenocarcinoma



Pearls





  • Commonly associated with oral contraceptive use



  • Usually polypoid lesions



  • Tightly packed benign endocervical glands





Selected References




  • Stewart C.J., Crook M.L.: PAX2 and cyclin D1 expression in the distinction between cervical microglandular hyperplasia and endometrial microglandular-like carcinoma: a comparison with p16, vimentin, and Ki67. Int J Gynecol Pathol 2015; pp. 90-100.



  • Witkiewicz A.K., Hecht J.L., Cviko A., et. al.: Microglandular hyperplasia: a model for the de novo emergence and evolution of endocervical reserve cells. Hum Pathol 2005; 36: pp. 154-161.



  • Young R.H., Scully R.E.: Atypical forms of microglandular hyperplasia of the cervix simulating carcinoma. Am J Surg Pathol 1989; 13: pp. 50-56.


Squamous Intraepithelial Lesion or Cervical Intraepithelial Neoplasia and Carcinoma in Situ


Clinical Features





  • LSIL is most common during reproductive age. HSIL incidence increases in premenopausal women



  • Discolored raised plaques, often white after application of acetic acid (3% to 5%), at colposcopy



  • High-grade lesions (HSILs and CIS) may have a mosaic or cobblestone appearance



  • Variety of risk factors, including high number of sexual partners, early age at initiation of sexual activity, and unprotected sex



  • Smoking is a cofactor



  • Greater than 95% of cervical dysplasias are related to HPV infection



Gross Pathology





  • Flat or papular discolored lesions, often white or red



Histopathology


See Figures 12.22 and 12.23 .




Figure 12.22


Cervical condyloma (cervical intraepithelial neoplasia 1 with human papillomavirus). Hyperplastic epithelium with cells containing irregular cytoplasmic halos and enlarged, binucleate, pyknotic nuclei.



Figure 12.23


A, Low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia grade 1 [CIN 1]). Dysplastic cells occupy the lower third of the epithelium. The upper two-thirds show koilocytosis. B, High-grade squamous intraepithelial lesion (CIN 2). Squamous mucosa featuring dysplastic cells that involve the endocervical gland. C, High-grade squamous intraepithelial lesion (carcinoma in situ) with gland involvement. Atypical squamous cells involving endocervical gland. D, High-grade squamous intraepithelial lesion (CIN 3). Squamous mucosa with atypical cells and mitotic figures involving the full thickness of the epithelium.

E, High-grade squamous intraepithelial lesion (carcinoma in situ) with gland involvement. A p16 stain showing strong and diffuse positivity. F, Microinvasive squamous cell carcinoma. Irregular nests of squamous cell carcinoma surrounded by stromal reaction.




Low-Grade Squamous Intraepithelial Lesion (Cervical Intraepithelial Neoplasia 1)





  • LSIL is associated with both low- and high-risk HPV types



  • Koilocytosis or HPV cytopathic effect in the upper two-thirds of the epithelium, which includes nuclear pleomorphism, hyperchromasia, nuclear membrane irregularity and well-defined perinuclear vacuole around the nucleus



  • The proliferation of basal/parabasal-like cells extends no more than lower third of the epithelium



  • Increased mitotic activity in the lower third



  • Condylomata acuminata are considered LSIL



High-Grade Squamous Intraepithelial Lesion (CIN 2 or 3 and CIS)





  • Associated with high-risk HPV



  • The lesion shows loss of maturation in the lower two thirds (CIN 2) or full thickness of the epithelium (CIN III)



  • The proliferating abnormal squamous cells have increased nuclear size, irregular nuclear membranes, and increased nucleocytoplasmic ratios



  • Atypical mitotic figures are readily identifiable



  • Involvement of underlying endocervical glands may be seen and should not be confused with microinvasive carcinoma



Special Stains and Immunohistochemistry





  • Approximately one third of the LSILs show block positivity of p16 immunostain



  • Strong and diffuse nuclear and cytoplasmic positivity for p16 in the full thickness or at least two-thirds of the thickness helps to confirm a diagnosis of HSIL



  • MIB-1/Ki-67 positivity in the lower two thirds to full thickness of the epithelium in HSIL



Other Techniques for Diagnosis





  • PCR and ISH: High-risk HPV types 16 and, less commonly, 18 are present in HSIL, whereas a spectrum of types rarely including 6 and 11 can be found in LSIL



  • Ploidy: dysplastic lesions usually contain an aneuploid population of cells



Differential Diagnosis


Atrophy





  • Preserved polarity



  • Basal cells in the full thickness of the epithelium



  • No nuclear pleomorphism or mitotic figures



  • Resolves after a 2-week course of locally applied estrogen therapy



Immature Squamous Metaplasia





  • Retains cellular polarity



  • Clearly defined cell membranes



  • Absent nuclear atypia and atypical mitoses



  • Residual mucin may be seen



Reactive Atypia





  • Associated with inflammation



  • Prominent nucleoli



  • Retained polarity and nuclear-to-cytoplasmic ratio



  • No atypical mitoses



  • Changes more pronounced at the base



  • Halos mimicking koilocytosis may be present



Microinvasive Carcinoma versus HSIL (CIN 3/CIS) with Gland Involvement





  • No basement membrane around invasive foci



  • Irregular infiltration of stroma instead of rounded nests



  • Stromal reaction, either desmoplastic or inflammatory



Pearls





  • SIL is usually multifocal



  • SIL, particularly low-grade lesions (CIN 1), may spontaneously regress, especially in young or pregnant women



  • LSIL may be followed clinically, whereas HSIL CIN (2 or 3) and CIS are generally followed by loop electrocautery excision procedure (LEEP) or cold knife cone and endocervical curetting to determine the extent of dysplasia



  • Because of the preceding statement, it is essential to distinguish between LSIL (CIN 1) and HSIL (CIN 2-3); if both low- and high-grade lesions are present, a diagnosis of HSIL is appropriate



  • Vaccination for HPV is effective in approximately 60%–70% of patients





Selected References




  • Bosch F.X., de Sanjose S.: The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers 2007; 23: pp. 213-227.



  • Liu Y., Alqatari M., Sultan K., et. al.: Using p16 immunohistochemistry to classify morphologic cervical intraepithelial neoplasia 2: correlation of ambiguous staining patterns with HPV subtypes and clinical outcome. Hum Pathol 2017; 66: pp. 144-151.



  • Mahajan A.: Practical issues in the application of p16 immunohistochemistry in diagnostic pathology. Hum Pathol 2016; 51: pp. 64-74.



  • Song S.H., Lee J.K., Oh M.J., et. al.: Risk factors for the progression or persistence of untreated mild dysplasia of the uterine cervix. Int J Gynecol Cancer 2006; 16: pp. 1608-1613.



  • Waxman A.G., Zsemlye M.M.: Preventing cervical cancer: the Pap test and the HPV vaccine. Med Clin North Am 2008; 92: pp. 1059-1082.


Invasive Squamous Cell Carcinoma


See Figure 12.24A to H .




Figure 12.24


A, Invasive squamous cell carcinoma of the cervix (gross photograph). Endocervix with endophytic, deeply invasive white to tan ill-defined tumor involving the cervical wall. B, Invasive squamous cell carcinoma, keratinizing type. Irregular nests of pleomorphic squamous cells with dyskeratosis infiltrating reactive stroma with inflammatory cells. C, Squamous metaplasia. In contrast to invasive squamous cell carcinoma, the sheets of metaplastic cells show rounded borders as they involve endocervical glands. The nuclear-to-cytoplasmic ratio is not altered, and desmosomes are obvious. D, Nonkeratinizing squamous cell carcinoma (invasive). Continuous sheets of malignant cells with no discernible intercellular bridges adjacent to an unremarkable endocervical gland (grade 3). E, Warty (condylomatous) squamous cell carcinoma. Low-power view demonstrates frondlike papillae with marked keratinization. Stromal invasion is present. F, Warty (condylomatous) squamous cell carcinoma. High-power view demonstrates classic epithelial papillae with condylomatous changes. G, Lymphoepithelioma-like carcinoma. Large pleomorphic neoplastic cells with abundant eosinophilic cytoplasm, irregular nuclei, and prominent nucleoli. Notice the marked lymphoplasmacytic infiltrate in the background. H, Malignant melanoma. Melanoma cells infiltrate the submucosa. Melanin pigment is present focally.


Clinical Features





  • The etiology of cervical squamous cell carcinoma includes persistent high-risk HPV infection and progression of HSIL (CIN III) to invasive carcinoma



  • HPV-16 and HPV-18 account for approximately 70% of the cases



  • Microinvasive or invasive



  • Microinvasive tumors rarely metastasize



Gross Pathology





  • Microinvasive: red papule, white plaque, or irregular ulcerated lesion



  • Invasive: exophytic papillary mass or endophytic ulcer, usually solitary



Histopathology





  • Usually associated with high-grade dysplasia or CIS




    • Full-thickness involvement of epithelium or cervical glands by pleomorphic cells with high nuclear-to-cytoplasmic ratio and mitotic activity




  • Atypical mitotic figures are often readily identifiable



  • Variable degree of squamous differentiation, including keratin pearl formation




    • GOG grading as described under “Vulva”




  • Desmoplastic reaction is a helpful finding associated with invasion



  • Microinvasive




    • Tumor depth less than 3 mm as measured from basal layer of overlying surface epithelium to the point of deepest invasion by the tumor



    • If invasion is present only adjacent to an involved gland, the measurement is from the top of the gland to the point of deepest invasion by tumor



    • Tumor diameter is less than 7 mm



    • Vascular space invasion is not present in microinvasive carcinoma




  • Invasive




    • Greater than 3 mm in depth of invasion



    • Generally greater than 7 mm in diameter




  • Types of squamous cell carcinoma of cervix




    • Keratinizing




      • Keratinizing tumors contain keratin pearls and abundant keratohyaline granules or display dense cytoplasmic keratinization and may be of any grade



      • Nests, cords, or single malignant polygonal epithelial cells with high nuclear-to-cytoplasmic ratio, nuclear pleomorphism with irregular chromatin, and eosinophilic cytoplasm



      • Atypical mitoses



      • Variable degree of necrosis




    • Nonkeratinizing




      • Usually rounded nests, as earlier



      • Absent keratin pearl formation




    • Basaloid




      • An aggressive type of squamous cell carcinoma that is considered high grade



      • Nests of immature basal type squamous cells with scant cytoplasm, resembling the HSIL cells of the cervix



      • Basaloid tumors are typically associated with high-risk HPV and higher stages at diagnosis




    • Verrucous




      • Well-differentiated squamous cell carcinoma with minimal cytologic atypia



      • Exophytic, often bulky tumor



      • Hyperkeratosis on the surface



      • Characterized by a bulbous pushing border rather than a truly invasive border



      • Lymphovascular involvement usually not present. Tumor does not metastasize



      • Absence of koilocytes



      • Associated with HPV-6 and its subtypes




    • Warty (condylomatous)




      • Papillary exophytic growth



      • Fibrovascular fronds



      • Squamous differentiation



      • Numerous koilocytes



      • Irregularly outlined nests of invasive tumor at base




    • Papillary (transitional)




      • Rare variant with papillary architecture



      • Papillae are lined by several layers of cytologically atypical spindled cells with frequent mitotic activity



      • Squamous differentiation may be focally present



      • Resembles transitional cell carcinoma of the genitourinary tract histologically




    • Lymphoepithelioma-like carcinoma




      • Well-circumscribed tumor



      • Discrete nests of nonkeratinizing epithelial cells with vesicular nuclei and abundant cytoplasm



      • Prominent lymphoplasmacytic inflammatory infiltrate between and around nests



      • Negative for Epstein-Barr virus (EBV)



      • Tumor is HPV related and positive for p16





Special Stains and Immunohistochemistry





  • Most cervical squamous cell carcinomas are positive for p16



  • Cytokeratin and p63 positive



  • CEA focally positive



  • Mucin negative



Other Techniques for Diagnosis





  • PCR and ISH




    • HPV types 16, 18, 31, and 35 and other types have been detected in greater than 95% of tumors, especially in younger women with history of CIN



    • HPV-16 has been detected in approximately 75% of tumors




  • Ras oncogene product p21 overexpression: detected by PCR or ISH; associated with poor prognosis in large cell keratinizing and nonkeratinizing carcinomas



Differential Diagnosis


Squamous Metaplasia with Gland Involvement





  • Nuclear atypia absent



  • Rare mitotic figures



  • Metaplastic glands rounded



  • No stromal reaction



Glassy Cell Carcinoma





  • High mitotic activity



  • Distinct cell borders



  • Prominent nucleoli



  • Ground-glass cytoplasm



Small Cell Carcinoma





  • Neuroendocrine patterns (e.g., round nests, trabeculae, ribbons, and rosettes)



  • Hyperchromatic smudged chromatin



  • No nucleoli



  • Neuroendocrine differentiation by immunohistochemistry (chromogranin, synaptophysin and CD56 positive) or electron microscopy (dense neurosecretory granules)



Malignant Melanoma





  • Although rare, both primary and metastatic melanomas can occur in the cervix



  • Melanin pigment when present is helpful in differentiating melanoma from poorly differentiated carcinoma; however, melanoma can be amelanotic



  • Negative for cytokeratin



  • Positive for SOX10, melan-A, and HMB-45



Metastatic Squamous Cell Carcinoma





  • Clinical history is important



  • In general, metastatic tumor is present deep in the mucosa



Pearls





  • Important prognostic indicators are tumor thickness, depth of invasion, tumor diameter, and vascular space invasion



  • The invasive component is often better differentiated than the intraepithelial component



  • Microinvasive carcinoma may be treated with cervical cone (cold knife) and endocervical curettage if the cone shows focal microinvasion and free margins



  • If curettage is positive, hysterectomy may be indicated



  • Invasive carcinomas are treated by radical hysterectomy with or without adjuvant therapy depending on stage of the tumor





Selected References




  • Chao A., Wang T.H., Lee Y.S., et. al.: Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression. Int J Cancer 2006; 119: pp. 91-98.



  • Horn L.C., Hentschel B., Braumann U.D.: Malignancy grading, pattern of invasion, and juxtatumoral stromal response (desmoplastic change) in squamous cell carcinoma of the uterine cervix. Int J Gynecol Pathol 2008; 27: pp. 606-607.



  • Hsu K.F., Huang S.C., Shiau A.L., et. al.: Increased expression level of squamous cell carcinoma antigen 2 and 1 ratio is associated with poor prognosis in early-stage uterine cervical cancer. Int J Gynecol Cancer 2007; 17: pp. 174-181.



  • Kokka F., Verma M., Singh N., et. al.: Papillary squamotransitional cell carcinoma of the uterine cervix: report of three cases and review of the literature. Pathology 2006; 38: pp. 584-586.



  • Pecorelli S.: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009; 105: pp. 103-104.



  • Schwartz L.E., Khani F., Bishop J.A., et. al.: Carcinoma of the uterine cervix involving the genitourinary tract. Am J Surg Pathol 2016; 40: pp. 27-35.


Adenocarcinoma in Situ


Clinical Features





  • Occurs in women in third and fourth decades



  • Significantly less common than squamous cell CIS



  • Precursor lesion to invasive adenocarcinoma, but not in all cases



  • Usually asymptomatic



  • Often diagnosed incidentally during work-up of abnormal Papanicolaou (Pap) test or cervical dysplasia



  • Most common symptom is vaginal bleeding (60% of patients)



  • Increasing incidence (related to improved detection in Pap smears collected with the current endocervical brush)



  • Associated with HPV-18 infection more often than squamous lesions



  • Risk factors include obesity, hypertension, and oral contraceptives with progesterone content



  • Thirty to 50% of cases are associated with CIN and invasive squamous cell carcinoma of the cervix



Gross Pathology





  • Usually above the squamocolumnar junction



  • Unifocal lesion but can be multifocal occasionally



  • Rarely visible colposcopically



Histopathology


See Figure 12.25A .




  • Replacement of the normal glandular epithelium by malignant epithelium



  • High nuclear-to-cytoplasmic ratio



  • Irregular chromatin and inconspicuous nucleoli



  • Cellular stratification



  • Mitotic activity and apoptotic bodies are characteristic



  • Endocervical (most common), intestinal, and endometrioid types



  • Absent stromal desmoplasia



  • Morphologic types include endocervical, intestinal, endometrioid, villoglandular, and adenosquamous variants




Figure 12.25


Adenocarcinoma in situ of the cervix.

A, Endocervical glands lined by cells with hyperchromatic nuclei and mitosis. B, Immunohistochemical stain for p16 is strongly positive.


Special Stains and Immunohistochemistry





  • A p16, usually positive



  • Vimentin generally negative



  • CEA and mucin positive



Other Techniques for Diagnosis





  • PCR or ISH often positive for HPV



Differential Diagnosis


Reactive Glandular Atypia





  • Prominent nucleoli



  • No stratification



  • Associated with inflammation



Microinvasive Adenocarcinoma





  • Adenocarcinoma infiltrates less than 5 mm of the cervical stroma and is less than 7 mm wide



  • Reactive stroma, glands extending deeper than normal glands, and glands adjacent to thick-walled blood vessels are features that distinguish microinvasive adenocarcinoma from AIS



Invasive Adenocarcinoma





  • Infiltration of the stroma by malignant glands



  • Glands present deep in the wall of the cervix



  • Glands may show budding, papillary growth, or cribriforming



  • Stromal response includes inflammatory cells and desmoplasia



Microglandular Hyperplasia





  • Small polypoid lesion



  • Lobular arrangement



  • Dense concentration of benign glands with luminal neutrophils



Tubal Metaplasia





  • Few glands involved



  • Nuclear atypia absent



  • Ciliated epithelium



Endometriosis





  • Endometrial glands and stroma are present in cervical tissue



  • Hemosiderin-laden macrophages may also be present



Pearls





  • Associated with HPV infection



  • Increasingly detected in Pap smears as a result of the use of the endocervical brush, which reaches higher into the endocervical canal than does the spatula



  • Treatment is cervical cone with free surgical margins or hysterectomy



  • Recurrence may follow second conization because of residual adenocarcinoma in situ at the endocervical canal or lower uterine segment or hysterectomy



  • 30%–50% of cases coexist with CIN



  • Glandular dysplasia is suggested as the precursor lesion; however, the coexistence of glandular dysplasia and AIS is uncommon





Selected References




  • Carleton C., Hoang L., Sah S., et. al.: A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas. Am J Surg Pathol 2016; 40: pp. 636.



  • Ceballos K.M., Shaw D., Daya D.: Microinvasive cervical adenocarcinoma (FIGO stage 1A tumors): results of surgical staging and outcome analysis. Am J Surg Pathol 2006; 30: pp. 370-374.



  • McCluggage W.G.: Immunohistochemistry as a diagnostic aid in cervical pathology. Pathology 2007; 39: pp. 97-111.



  • Park J.J., Sun D., Quade B.J., et. al.: Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia?. Am J Surg Pathol 2000; 24: pp. 1414-1419.



  • Stolnicu S., Barsan I., Hoang L., et. al.: International Endocervical Adenocarcinoma Criteria and Classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018; 42: pp. 214-226.


Invasive Adenocarcinoma


See Figure 12.26A to F .




Figure 12.26


A, Moderately differentiated invasive adenocarcinoma of the cervix. Crowded glands and nuclear pleomorphism. B, Mucinous adenocarcinoma of the cervix. Clusters of neoplastic mucinous epithelium in desmoplastic stroma. C, Well-differentiated endometrioid adenocarcinoma of the cervix. Confluent glandular pattern with minimal desmoplastic stroma identical to uterine corpus endometrioid adenocarcinoma. D , Minimal deviation adenocarcinoma (adenoma malignum). Low-power view demonstrates irregular neoplastic endocervical glands associated with desmoplasia. E, Clear cell carcinoma of the cervix. Solid proliferation of neoplastic cells with clear cytoplasm. F, Glassy cell carcinoma of the cervix. Large neoplastic cells with finely granular ground-glass cytoplasm, prominent nuclei, and nucleoli.


Clinical Features





  • Increased percentage rate of cervical cancer due to decline in the incidence of squamous cell carcinoma



  • Affected patients are slightly older (fourth and fifth decades) than patients with squamous cell carcinoma



  • Associated with high-risk HPVs, most commonly types 18, 16, and 45



  • Risk factors include obesity, hypertension, and oral contraceptives with progesterone content



  • More than 40% of cases are associated with SIL and on occasion invasive squamous cell carcinoma of the cervix



  • May present with a watery discharge



Gross Pathology





  • Generally exophytic, polypoid, nodular, or papillary



Histopathology





  • Variable combinations of cell types



  • Mixed cell type if any two or more of the following types listed represent more than 10% of the total tumor volume



  • Usual type




    • The most common form of endocervical adenocarcinoma



    • Tumor shows complex architectural patterns composed of round to oval mucin-poor glands that exhibit cribriform or papillary structures



    • The neoplastic epithelium shows a characteristic pseudostratified architecture with enlarged and hyperchromatic nuclei




  • Mucinous gastric




    • Gastric type differentiation with abundant clear to eosinophilic cytoplasm and nuclear atypia



    • The atypical glands extend below the normal level expected for benign endocervical glands



    • Not HPV related and negative for p16




  • Mucinous intestinal




    • Pseudostratified columnar epithelium with goblet cells




  • Mucinous signet ring cell




    • Compressed nucleus with abundant intracytoplasmic mucin



    • Usually not a prominent component




  • Endometrioid




    • Stratified epithelial cells with minimal granular cytoplasm resembling malignant endometrial glands



    • Intracytoplasmic mucin absent




  • Minimal deviation adenocarcinoma (adenoma malignum)




    • Cytologically bland glands, usually mucinous endocervical type



    • Irregular, branching glands of variable sizes



    • Increased numbers of glands at surface and extending deep into the wall of the cervix (>5 mm)



    • Stromal desmoplasia may be present



    • Cervical biopsy may not be deep enough to permit the diagnosis




  • Well-differentiated papillary villoglandular




    • Patients generally in third or fourth decade



    • The exophytic portion of the tumor shows villous fronds of variable thickness, which are covered by tall columnar cells with scant mucin



    • Invasion is typically superficial



    • Occasionally complex branching papillary architecture



    • Minimal cytologic atypia




  • Clear cell




    • Patient is usually young if related to DES exposure and often involves the ectocervix



    • Tubulocystic and solid are the most common patterns



    • Papillary, tubular, and trabecular patterns may also be seen



    • Tumor cells are polyhedral with round, atypical nuclei and clear cytoplasm containing glycogen



    • The hobnail cell is a common and characteristic finding: cell in which the nucleus protrudes beyond the boundaries of the cell into the luminal, tubular, or cystic space



    • Less commonly, the epithelial cells are flattened, cuboidal, oxyphilic, or signet ring



    • Psammoma bodies or intracellular hyaline bodies may be seen




  • Serous carcinoma




    • Exceedingly rare



    • It can be related to HPV in young patients and usually caused by p53 mutation in older patients




  • Adenocarcinoma with features of carcinoid tumor




    • Occasionally an adenocarcinoma may contain areas of neuroendocrine carcinoma positive for neuroendocrine markers



    • Paraendocrine syndromes are rare



    • Not responsive to the usual treatment modalities




  • Grading (not as definitive as corpus cancer)




    • Well-differentiated: more than 50% glands



    • Moderately differentiated: 10% to 50% glands



    • Poorly differentiated: less than 10% glands




  • Depth of invasion is measured from the surface




    • Microinvasive adenocarcinoma




      • Adenocarcinoma infiltrates less than 5 mm of the cervical stroma and is less than 7 mm wide



      • The measurement is from the basement membrane of the overlying endocervical or ectocervical surface



      • Most are associated with synchronous and often extensive AIS



      • Reactive stroma, glands extending deeper than normal glands, and glands adjacent to thick-walled blood vessels are features that distinguish AIS from microinvasive adenocarcinoma



      • Excellent prognosis with conservative surgical therapy





Special Stains and Immunohistochemistry





  • CEA usually positive in mucinous adenocarcinomas and negative in normal endocervical glands



Other Techniques for Diagnosis





  • HPV often detected by PCR or ISH



Differential Diagnosis


Microglandular Hyperplasia





  • Polypoid lesion



  • Lobular arrangement



  • Dense concentration of benign glands



  • CEA negative



Adenocarcinoma in Situ





  • Glands are not present deep in the wall of cervix



  • Minimal glandular budding, papillary growth, or cribriforming



  • Absence of stromal response (or desmoplasia)



Metastatic Adenocarcinoma





  • Clinical history essential



  • Surface involvement is generally absent



  • Extensive lymphatic invasion



Direct Extension of Endometrial Adenocarcinoma





  • Clinical history of endometrial carcinoma



  • Absence of endocervical glandular or in situ adenocarcinoma



  • Negative for HPV infection



  • The distinction may be difficult



  • Mucinous endometrial adenocarcinoma is also positive for CEA and negative for vimentin



Pearls





  • Associated with HPV infection



  • Increasingly detected in Pap smears as a result of the use of the endocervical brush, which reaches higher into the endocervix than does the spatula



  • Standard treatment is radical hysterectomy with pelvic lymphadenectomy



  • Radiation therapy is preferred for tumors that are larger than 5 cm at the time of diagnosis



  • In general, tumors smaller than 1 cm do not metastasize to lymph nodes



  • Prognosis correlates with stage and grade (of the tumor)





Selected References




  • Ceballos K.M., Shaw D., Daya D.: Microinvasive cervical adenocarcinoma (FIGO stage 1A tumors): results of surgical staging and outcome analysis. Am J Surg Pathol 2006; 30: pp. 370-374.



  • Kurman R.J., Ronnett B.M., Sherman M.E., et. al.: AFIP Atlas of Tumor Pathology.2010.Armed Forces Institute of PathologyWashington, DCpp. 197.



  • Stolnicu S., Barsan I., Hoang L., et. al.: Diagnostic algorithmic proposal based on comprehensive immunohistochemical evaluation of 297 invasive endocervical adenocarcinomas. Am J Surg Pathol 2018; 42: pp. 989-1000.



  • Stolnicu S., Barsan I., Hoang L., et. al.: International Endocervical Adenocarcinoma Criteria and Classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018; 42: pp. 214-226.



  • Wang S.S., Sherman M.E., Silverberg S.G., et. al.: Pathological characteristics of cervical adenocarcinoma in a multi-center US-based study. Gynecol Oncol 2006; 103: pp. 541-546.



  • Zaino R.J.: Symposium part I: adenocarcinoma in situ, glandular dysplasia, and early invasive adenocarcinoma of the uterine cervix. Int J Gynecol Pathol 2002; 21: pp. 314-326.


Adenosquamous Carcinoma


Clinical Features





  • Occurs in women of all ages



  • Risk factors as in squamous cell carcinoma: smoking, multiple sexual partners, and low socioeconomic status



  • Less common than adenocarcinoma



Gross Pathology





  • Polypoid endocervical mass



Histopathology





  • Both squamous and adenocarcinoma components are present



  • Usually poorly differentiated squamous cell carcinoma intermingled with high-grade adenocarcinoma



  • Intracytoplasmic and luminal mucin usually present in the glandular component



Special Stains and Immunohistochemistry





  • CEA may be positive in adenocarcinoma



  • Mucin positive if mucin is present



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Direct Extension of Adenocarcinoma of Endometrium





  • Bulky tumor in the endometrium



  • Usually less squamous differentiation



  • More likely endometrioid than mucinous adenocarcinoma



  • Precursor lesion in the uterine corpus (i.e., endometrial hyperplasia) is helpful



Endocervical Carcinoma with Synchronous Squamous Cell Carcinoma





  • Separate tumors with no intermingling



  • Endometrial or endocervical precursor lesions (i.e., hyperplasia or dysplasia [CIN], respectively) are helpful



Pearls





  • Mixed carcinoma



  • Occurs in women of any age



  • Treatment and prognosis as for other invasive cervical carcinomas





Selected Reference




  • Stolnicu S., Hoang L., Hanko-Bauer O., et. al.: Cervical adenosquamous carcinoma: detailed analysis of morphology, immunohistochemical profile, and clinical outcomes in 59 cases. Mod Pathol 2019; 32: pp. 269-279.


Neuroendocrine Tumors


Clinical Features





  • Uncommon



  • Occurs in women in third and fourth decades



  • Aggressive tumor



  • Paraendocrine syndromes may manifest



Gross Pathology





  • Often ulcerating tumors



Histopathology


See Figure 12.27 .




  • Low-grade neuroendocrine tumors are rare in the cervix and include grade 1 and grade 2 tumors



  • Low-grade neuroendocrine tumor consists of organoid, nested or islands of uniform cells with small round nuclei, salt and pepper chromatin and moderate amount of cytoplasm



  • High-grade tumors are very cellular



  • Sheets of tightly packed small cells with minimal cytoplasm and round to spindled nuclei



  • Smudged chromatin with inconspicuous nucleoli



  • Few scattered larger pleomorphic cells



  • Brisk mitotic rate is often present



  • Vascular space invasion is frequently identified



  • Squamous or glandular differentiation makes up less than 10% of tumor volume



  • Similar to pulmonary small cell carcinoma




Figure 12.27


Small cell carcinoma of the cervix.

Low-power view demonstrates a solid proliferation of small uniform neoplastic cells mimicking a malignant lymphoma.


Special Stains and Immunohistochemistry





  • Cytokeratin positive



  • Chromogranin positive in about 50% of tumors



  • Synaptophysin and neuron-specific enolase (NSE) positive in a significant number of tumors



  • Serotonin and somatostatin rarely positive



Other Techniques for Diagnosis





  • PCR, ISH: HPV-18 has been detected; less commonly HPV-16



Differential Diagnosis


Poorly Differentiated, Nonkeratinizing Squamous Cell Carcinoma





  • May be difficult to distinguish if cells are small



  • No neuroendocrine differentiation



Poorly Differentiated Adenocarcinoma





  • Gland formation makes up less than 10% of tumor volume



  • Neuroendocrine differentiation is absent



Lymphoma





  • Cells less tightly packed



  • Positive for CD45 (leukocyte common antigen)



  • No neuroendocrine differentiation



Pearls





  • Treatment is radical hysterectomy with bilateral pelvic and periaortic lymph node dissection



  • Adjuvant radiation therapy if lymph node metastases are present



  • Aggressive tumor with frequent recurrence and poor survival



  • Distant metastases common





Selected References




  • Ambros R.A., Park J.S., Shah K.V., et. al.: Evaluation of histologic, morphometric, and immunohistochemical criteria in the differential diagnosis of small cell carcinomas of the cervix with particular reference to human papillomavirus types 16 and 18. Mod Pathol 1991; 4: pp. 586-593.



  • Ganesan R., Hirschowitz L., Dawson P., et. al.: Neuroendocrine carcinoma of the cervix: review of a series of cases and correlation with outcome. Int J Surg Pathol 2016; 24: pp. 490-496.



  • Gersell D.J., Mazoujian G., Mutch D.G., et. al.: Small-cell undifferentiated carcinoma of the cervix: a clinicopathologic, ultrastructural, and immunocytochemical study of 15 cases. Am J Surg Pathol 1988; 12: pp. 684-698.



  • Tempfer C.B., Tischoff I., Dogan A., et. al.: Neuroendocrine carcinoma of the cervix: a systematic review of the literature. BMC Cancer 2018; 18: pp. 530.


Metastatic Adenocarcinoma


Clinical Features





  • Ovarian carcinoma is the most common tumor metastatic to the cervix



  • Breast is the most common extragenital source of tumor metastatic to the cervix



  • Endometrial carcinomas may spread by direct extension to the cervical stroma; this occurrence increases the stage of the corpus cancer (II vs. I)



  • Metastases may present with vaginal bleeding



Gross Pathology





  • In general, tumors metastasize to the outer surface



  • Direct extension from the endometrium may be detected within the endocervical canal



Histopathology





  • As per the primary tumor



  • Tumors from the endometrium may be difficult to distinguish from primary cervical tumors, which may arise simultaneously



  • The absence of CIN in the presence of subepithelial infiltrates or prominent lymphatic permeation suggests metastatic disease



Special Stains and Immunohistochemistry





  • As per the primary tumor



Other Techniques for Diagnosis





  • CEA is generally positive in cervical adenocarcinoma but negative in endometrial tumors, whereas vimentin is positive in endometrial tumors but not cervical adenocarcinoma



  • CDX2 is commonly positive in cervical adenocarcinoma (mucinous type) but negative in endometrial carcinoma



  • In general, p16 is positive in cervical adenocarcinomas



Differential Diagnosis


Metastatic Carcinoma versus Primary Cervical Carcinoma





  • The absence of CIN and AIS in the presence of subepithelial infiltrates or prominent lymphatic permeation suggests metastatic disease



  • Endometrial and cervical adenocarcinomas may be synchronous and indistinguishable



  • Clinical history is essential



Pearls





  • The absence of CIN in the overlying epithelium suggests metastatic disease



  • Clinical history is essential





Selected References




  • Kurman R.Blaustein’s Pathology of the Female Genital Tract.2011.SpringerNew York:pp. 295.



  • Lemoine N.R., Hall P.A.: Epithelial tumors metastatic to the uterine cervix: a study of 33 cases and review of the literature. Cancer 1986; 57: pp. 2002-2005.



  • Pirog E.C., Park K.J., Kiyokawa T., et. al.: Gastric-type adenocarcinoma of the cervix: tumor with wide range of histologic appearances. Adv Anat Pathol 2019; 26: pp. 1-2.


Uterus


Endometrium


Acute Endometritis


Clinical Features





  • Most often associated with pelvic inflammatory disease (PID)



  • May be associated with pregnancy



  • Elevated temperature, leukocytosis, discomfort, and pain



Gross Pathology





  • When secondary to PID, presents with a tubo-ovarian complex with fibrous adhesions, fibrinous exudate, congestion, and edema



  • Associated with intrauterine device (IUD) use and may be seen in compressed endometrium overlying large leiomyomas



Histopathology





  • Numerous neutrophils in the stroma and several glands



  • Ectatic blood vessels



  • Fibrin exudate



  • Hemorrhage



Special Stains and Immunohistochemistry





  • Tissue Gram stain to identify microorganisms



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Menstruation





  • Vacuoles in the distended glands



  • Decidual change in the stroma and stromal neutrophils



Pearls





  • Clinical history is important, particularly as it relates to the menstrual cycle



  • Aseptic abortion is a possibility in some areas of United States and worldwide



  • Patient may present with acute abdomen





Selected References




  • Chiesa-Vottero A.G.: Actinomycotic endometritis. Int J Gynecol Pathol 2019; 38: pp. 138-142.



  • Silverberg S.G.: The endometrium. Arch Pathol Lab Med 2007; 131: pp. 372-382.


Chronic Endometritis


Clinical Features





  • Common condition



  • May be asymptomatic, although may present with pelvic pain when associated with menstrual irregularities



  • Associated with IUD use and may be identified in compressed endometrium overlying large leiomyomas



Gross Pathology





  • In general, the findings are nonspecific



Histopathology





  • Plasma cells must be identified in the endometrial stroma ( Figure 12.28 )




    Figure 12.28


    Chronic endometritis.

    Endometrial glands and stroma in which plasma cells are present.



  • Endometrium is difficult to date (i.e., glands appear variable in terms of phase [early, mid, and late secretory endometrium or proliferative])



  • Focal crowding mimicking hyperplasia



  • Glandular epithelium may show mild cytologic atypia and focal or diffuse spindled stroma



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Endometrial Hyperplasia





  • Stromal plasma cells are unusual



  • Diffuse process



Endometrial Adenocarcinoma





  • Confluent or cribriform glandular architecture with cytologic atypia



  • Stromal desmoplasia or necrosis may be present


Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Female Reproductive System
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