Chapter Outline
Cysts 95
Follicular (‘Epidermoid’) Cyst 95
Steatocystoma Multiplex 96
Bartholin Cyst 96
Mucinous Cyst 97
Ciliated Cyst (Paramesonephric Cyst) 97
Paraurethral (Skene) Gland Cyst 97
Mesonephric-Like Cyst 97
Cyst of the Canal of Nuck 98
Extramammary Paget Disease 98
Melanocytic Lesions 101
Lentigo 101
Common Acquired Melanocytic Nevus 101
Melanocytic Nevus of the Genital Type 102
Blue Nevus (Dermal Melanocytoma) 102
Atypical (Dysplastic, Clark) Nevus 102
Melanoma 103
Skin Appendage Neoplasms and Lesions of the Anogenital Mammary-Like Glands 106
Hidradenoma Papilliferum (Papillary Hidradenoma or Mammary-Like Gland Adenoma of the Vulva) 106
Syringoma 106
Trichoepithelioma 107
Vascular Lesions 108
Infantile Hemangioma (‘Strawberry’ Hemangioma) 108
Venous Malformation (Cavernous Hemangioma) 108
Deep Lymphatic Malformation (Cavernous Lymphangioma) 108
Miscellaneous Lesions 109
Acrochordon (Fibroepithelial Polyp, Skin Tag, Squamous Papilloma) 109
Endometriosis 109
Heterotopic Breast 109
Rare Tumors and Tumor–Like Conditions 110
Langerhans Cell Histiocytosis (Histiocytosis X) 110
Merkel Cell Carcinoma (Trabecular Carcinoma, Small Cell Carcinoma of the Skin, Primary Cutaneous Neuroendocrine Carcinoma) 110
Metastatic Tumors 112
Tumors of the Bartholin Gland 112
Urethra 113
Cysts
Follicular (‘Epidermoid’) Cyst
Definition
Follicular cyst is a cystic dilatation of the hair follicle epithelium.
Clinical Features
Follicular cyst presents as a solitary, creamy-white or yellowish lesion on the labium majus ( Figure 5.1 ). It is generally asymptomatic, but rupture may induce inflammation with enlargement, tenderness, erythema, and induration. Follicular cysts usually occur spontaneously and after age 30. Onset at an early age or occurrence in great numbers should prompt consideration of Gardner syndrome.
Microscopic Features
Most vulvar follicular cysts represent dilatations of the most distal portion of the follicle, the infundibulum, hence they have thin, flat, squamous epithelium lacking rete ridges, contain a granular layer, and are filled with loose-packed keratin. Its rupture may lead to leakage of keratin, resulting in an acute and chronic inflammatory foreign-body reaction.
Steatocystoma Multiplex
Definition
Widespread, multiple, thin-walled cysts of the skin, lined by squamous epithelium , and including lobules of sebaceous cells.
Clinical Features
Steatocystoma multiplex is the dominantly inherited occurrence of numerous small, creamy-colored cysts exhibiting sebaceous ductal differentiation. The lesions usually appear after adolescence and may be solitary. Most common locations are the presternum, axillae, abdomen, and labia majora. Rarely, they first present as multiple vulvar cysts at an older age ( Figure 5.2 ).
Microscopic Features
Steatocystomas are composed of an intricately folded, thin layer of stratified squamous epithelium lined internally by a corrugated, thin, compact, and strongly eosinophilic cuticle, lacking a granular layer. There may be associated small sebaceous glands ( Figure 5.3 ). Although this finding raises the differential diagnosis of dermoid cyst, the latter is extremely rare in the vulva and shows miniaturized hair follicles.
Bartholin Cyst
Definition
Bartholin cyst is the cystic dilatation of a major vestibular (Bartholin) gland or its duct.
Clinical Features
Bartholin cyst is the most common form of vulvar cyst, and is the presenting complaint for 2% of women during their annual gynecologic visit. The Bartholin glands ( Figure 5.4 ) are located behind the labia minora and their ducts open into the posterior lateral vestibules, just anterior to the hymeneal tegmentum. Bartholin cysts result from blockage of the drainage duct and resultant retention of secretions, perhaps following infection. Bartholin cysts are most common in the reproductive years. If large, they may partially obstruct the introitus. Bartholin cysts usually present as smooth-domed nodules, generally 1–10 cm in diameter. If brown or blue, they may be mistaken clinically for melanocytic nevi. The cysts contain mucoid fluid, which stains with mucicarmine, periodic acid–Schiff (PAS; with and without diastase), and Alcian blue at pH 2.5. They may recur after incision and drainage, and may require surgical excision, particularly in postmenopausal women, to rule out the possibility of associated carcinoma. Bartholin abscess is an acute process usually caused by Neisseria gonorrheal infection. Excision, drainage, and antibiotics are the treatments of choice.
Microscopic Features
Bartholin cysts show a lining of transitional epithelium, with frequent focal squamous metaplasia ( Figure 5.5 ). Smaller mucus-filled cysts may show some remnant of the original mucus-secreting glandular epithelium, but it may be flattened or cuboidal. Normal remnants of mucus glands may be presented adjacent to the cyst. Microscopically, the Bartholin duct abscess shows abundant neutrophilic infiltrate within the stroma surrounding the duct.
Mucinous Cyst
Definition
Mucinous cyst is the cystic dilatation of a minor vestibular gland or its duct.
Clinical Features
True mucinous cysts most commonly occur in the vulvar vestibule, including the medial labium minus and near the Bartholin glands. Onset is typically between puberty and the fourth decade, usually in parous women or those exposed to oral contraceptives. Mucinous cysts are 2 mm to 3 cm in diameter and are usually solitary. They may cause pain or urinary complaints. Excision is curative. They presumably are due to obstruction.
Microscopic Features
These cysts are lined almost entirely by columnar or cuboidal mucus-secreting epithelium like that of endocervical glands without peripheral muscle fibers or myoepithelial cells. Foci of squamous metaplasia are sometimes present; they are considered to be of urogenital sinus origin.
Ciliated Cyst (Paramesonephric Cyst)
An occasional cyst may be lined partially by ciliated columnar epithelium ( Figure 5.6 ). Usually this occurs as a focal change within a mucinous cyst or a Bartholin cyst; it is likely a nonspecific metaplastic change.
Paraurethral (Skene) Gland Cyst
Definition
Paraurethral gland cyst is the cystic dilatation of the paraurethral (Skene) gland or its duct.
Clinical Features
The paired paraurethral glands (the female homolog of the male prostate gland) are located on either side of the urethral meatus. Ductal occlusion, probably a consequence of infection (e.g., gonococcal), leads to formation of a retention cyst, generally less than 2 cm in size, located in the upper lateral introitus. Paraurethral gland cysts affect from neonates to premenopausal women, with an incidence of 1 per 2000–7000 women. Patients may be asymptomatic or complain of urinary obstruction or dyspareunia. Surgical excision should be done after medical therapy for any underlying infection.
Microscopic Features
Paraurethral gland cysts are probably derived from the duct rather than the acini, and are lined by transitional or stratified squamous epithelium upon a basement membrane, with only rare luminal cells containing intracytoplasmic mucin. Rarely, they contain calculi.
Mesonephric-Like Cyst
Definition
Mesonephric-like cysts are lined by cuboidal or low columnar epithelium and encased by a small amount of smooth muscle.
Clinical Features
These cysts occur in the lateral walls of the vulva as superficial, single, domed, blue or red cysts with clear, watery contents. They resemble mesonephric ducts but their embryologic basis is unclear.
Cyst of the Canal of Nuck
Definition
Cyst of the canal of Nuck is a cystic remnant of the processus vaginalis peritonei.
Clinical Features
These cysts are most common in the inguinal canal, where they must be distinguished from hernias. They also occur in the mons pubis and in the superior, outer region of the labium majus. Ultrasonography or magnetic resonance imaging may be helpful for definitive clinical diagnosis. They are homologous to hydroceles in males. The processus vaginalis peritonei (canal of Nuck) is a rudimentary sac of peritoneal mesothelium carried down by the round ligament as it passes through the inguinal canal and inserts into the labium majus. Failure of this structure to obliterate normally during fetal development leads to blockage and cystic dilatation. While these cysts are usually solitary, more than one may arise if obstruction occurs at multiple sites. Generally asymptomatic, they may become tender to pressure, and may then require a procedure similar to herniorrhaphy.
Microscopic Features
In their pristine state, these are thin-walled and lined by flattened mesothelium. By the time they present clinically, repeated external trauma has usually induced fibrosis of their walls, reduced or destroyed their mesothelial lining, and caused hemosiderin deposition from old haemorrhage.
Follicular (‘Epidermoid’) Cyst
Definition
Follicular cyst is a cystic dilatation of the hair follicle epithelium.
Clinical Features
Follicular cyst presents as a solitary, creamy-white or yellowish lesion on the labium majus ( Figure 5.1 ). It is generally asymptomatic, but rupture may induce inflammation with enlargement, tenderness, erythema, and induration. Follicular cysts usually occur spontaneously and after age 30. Onset at an early age or occurrence in great numbers should prompt consideration of Gardner syndrome.
Microscopic Features
Most vulvar follicular cysts represent dilatations of the most distal portion of the follicle, the infundibulum, hence they have thin, flat, squamous epithelium lacking rete ridges, contain a granular layer, and are filled with loose-packed keratin. Its rupture may lead to leakage of keratin, resulting in an acute and chronic inflammatory foreign-body reaction.
Clinical Features
Follicular cyst presents as a solitary, creamy-white or yellowish lesion on the labium majus ( Figure 5.1 ). It is generally asymptomatic, but rupture may induce inflammation with enlargement, tenderness, erythema, and induration. Follicular cysts usually occur spontaneously and after age 30. Onset at an early age or occurrence in great numbers should prompt consideration of Gardner syndrome.
Microscopic Features
Most vulvar follicular cysts represent dilatations of the most distal portion of the follicle, the infundibulum, hence they have thin, flat, squamous epithelium lacking rete ridges, contain a granular layer, and are filled with loose-packed keratin. Its rupture may lead to leakage of keratin, resulting in an acute and chronic inflammatory foreign-body reaction.
Steatocystoma Multiplex
Definition
Widespread, multiple, thin-walled cysts of the skin, lined by squamous epithelium , and including lobules of sebaceous cells.
Clinical Features
Steatocystoma multiplex is the dominantly inherited occurrence of numerous small, creamy-colored cysts exhibiting sebaceous ductal differentiation. The lesions usually appear after adolescence and may be solitary. Most common locations are the presternum, axillae, abdomen, and labia majora. Rarely, they first present as multiple vulvar cysts at an older age ( Figure 5.2 ).
Microscopic Features
Steatocystomas are composed of an intricately folded, thin layer of stratified squamous epithelium lined internally by a corrugated, thin, compact, and strongly eosinophilic cuticle, lacking a granular layer. There may be associated small sebaceous glands ( Figure 5.3 ). Although this finding raises the differential diagnosis of dermoid cyst, the latter is extremely rare in the vulva and shows miniaturized hair follicles.
Clinical Features
Steatocystoma multiplex is the dominantly inherited occurrence of numerous small, creamy-colored cysts exhibiting sebaceous ductal differentiation. The lesions usually appear after adolescence and may be solitary. Most common locations are the presternum, axillae, abdomen, and labia majora. Rarely, they first present as multiple vulvar cysts at an older age ( Figure 5.2 ).
Microscopic Features
Steatocystomas are composed of an intricately folded, thin layer of stratified squamous epithelium lined internally by a corrugated, thin, compact, and strongly eosinophilic cuticle, lacking a granular layer. There may be associated small sebaceous glands ( Figure 5.3 ). Although this finding raises the differential diagnosis of dermoid cyst, the latter is extremely rare in the vulva and shows miniaturized hair follicles.
Bartholin Cyst
Definition
Bartholin cyst is the cystic dilatation of a major vestibular (Bartholin) gland or its duct.
Clinical Features
Bartholin cyst is the most common form of vulvar cyst, and is the presenting complaint for 2% of women during their annual gynecologic visit. The Bartholin glands ( Figure 5.4 ) are located behind the labia minora and their ducts open into the posterior lateral vestibules, just anterior to the hymeneal tegmentum. Bartholin cysts result from blockage of the drainage duct and resultant retention of secretions, perhaps following infection. Bartholin cysts are most common in the reproductive years. If large, they may partially obstruct the introitus. Bartholin cysts usually present as smooth-domed nodules, generally 1–10 cm in diameter. If brown or blue, they may be mistaken clinically for melanocytic nevi. The cysts contain mucoid fluid, which stains with mucicarmine, periodic acid–Schiff (PAS; with and without diastase), and Alcian blue at pH 2.5. They may recur after incision and drainage, and may require surgical excision, particularly in postmenopausal women, to rule out the possibility of associated carcinoma. Bartholin abscess is an acute process usually caused by Neisseria gonorrheal infection. Excision, drainage, and antibiotics are the treatments of choice.
Microscopic Features
Bartholin cysts show a lining of transitional epithelium, with frequent focal squamous metaplasia ( Figure 5.5 ). Smaller mucus-filled cysts may show some remnant of the original mucus-secreting glandular epithelium, but it may be flattened or cuboidal. Normal remnants of mucus glands may be presented adjacent to the cyst. Microscopically, the Bartholin duct abscess shows abundant neutrophilic infiltrate within the stroma surrounding the duct.
Clinical Features
Bartholin cyst is the most common form of vulvar cyst, and is the presenting complaint for 2% of women during their annual gynecologic visit. The Bartholin glands ( Figure 5.4 ) are located behind the labia minora and their ducts open into the posterior lateral vestibules, just anterior to the hymeneal tegmentum. Bartholin cysts result from blockage of the drainage duct and resultant retention of secretions, perhaps following infection. Bartholin cysts are most common in the reproductive years. If large, they may partially obstruct the introitus. Bartholin cysts usually present as smooth-domed nodules, generally 1–10 cm in diameter. If brown or blue, they may be mistaken clinically for melanocytic nevi. The cysts contain mucoid fluid, which stains with mucicarmine, periodic acid–Schiff (PAS; with and without diastase), and Alcian blue at pH 2.5. They may recur after incision and drainage, and may require surgical excision, particularly in postmenopausal women, to rule out the possibility of associated carcinoma. Bartholin abscess is an acute process usually caused by Neisseria gonorrheal infection. Excision, drainage, and antibiotics are the treatments of choice.
Microscopic Features
Bartholin cysts show a lining of transitional epithelium, with frequent focal squamous metaplasia ( Figure 5.5 ). Smaller mucus-filled cysts may show some remnant of the original mucus-secreting glandular epithelium, but it may be flattened or cuboidal. Normal remnants of mucus glands may be presented adjacent to the cyst. Microscopically, the Bartholin duct abscess shows abundant neutrophilic infiltrate within the stroma surrounding the duct.
Mucinous Cyst
Definition
Mucinous cyst is the cystic dilatation of a minor vestibular gland or its duct.
Clinical Features
True mucinous cysts most commonly occur in the vulvar vestibule, including the medial labium minus and near the Bartholin glands. Onset is typically between puberty and the fourth decade, usually in parous women or those exposed to oral contraceptives. Mucinous cysts are 2 mm to 3 cm in diameter and are usually solitary. They may cause pain or urinary complaints. Excision is curative. They presumably are due to obstruction.
Microscopic Features
These cysts are lined almost entirely by columnar or cuboidal mucus-secreting epithelium like that of endocervical glands without peripheral muscle fibers or myoepithelial cells. Foci of squamous metaplasia are sometimes present; they are considered to be of urogenital sinus origin.
Clinical Features
True mucinous cysts most commonly occur in the vulvar vestibule, including the medial labium minus and near the Bartholin glands. Onset is typically between puberty and the fourth decade, usually in parous women or those exposed to oral contraceptives. Mucinous cysts are 2 mm to 3 cm in diameter and are usually solitary. They may cause pain or urinary complaints. Excision is curative. They presumably are due to obstruction.
Microscopic Features
These cysts are lined almost entirely by columnar or cuboidal mucus-secreting epithelium like that of endocervical glands without peripheral muscle fibers or myoepithelial cells. Foci of squamous metaplasia are sometimes present; they are considered to be of urogenital sinus origin.
Ciliated Cyst (Paramesonephric Cyst)
An occasional cyst may be lined partially by ciliated columnar epithelium ( Figure 5.6 ). Usually this occurs as a focal change within a mucinous cyst or a Bartholin cyst; it is likely a nonspecific metaplastic change.
Paraurethral (Skene) Gland Cyst
Definition
Paraurethral gland cyst is the cystic dilatation of the paraurethral (Skene) gland or its duct.
Clinical Features
The paired paraurethral glands (the female homolog of the male prostate gland) are located on either side of the urethral meatus. Ductal occlusion, probably a consequence of infection (e.g., gonococcal), leads to formation of a retention cyst, generally less than 2 cm in size, located in the upper lateral introitus. Paraurethral gland cysts affect from neonates to premenopausal women, with an incidence of 1 per 2000–7000 women. Patients may be asymptomatic or complain of urinary obstruction or dyspareunia. Surgical excision should be done after medical therapy for any underlying infection.
Microscopic Features
Paraurethral gland cysts are probably derived from the duct rather than the acini, and are lined by transitional or stratified squamous epithelium upon a basement membrane, with only rare luminal cells containing intracytoplasmic mucin. Rarely, they contain calculi.
Clinical Features
The paired paraurethral glands (the female homolog of the male prostate gland) are located on either side of the urethral meatus. Ductal occlusion, probably a consequence of infection (e.g., gonococcal), leads to formation of a retention cyst, generally less than 2 cm in size, located in the upper lateral introitus. Paraurethral gland cysts affect from neonates to premenopausal women, with an incidence of 1 per 2000–7000 women. Patients may be asymptomatic or complain of urinary obstruction or dyspareunia. Surgical excision should be done after medical therapy for any underlying infection.
Mesonephric-Like Cyst
Definition
Mesonephric-like cysts are lined by cuboidal or low columnar epithelium and encased by a small amount of smooth muscle.
Clinical Features
These cysts occur in the lateral walls of the vulva as superficial, single, domed, blue or red cysts with clear, watery contents. They resemble mesonephric ducts but their embryologic basis is unclear.
Cyst of the Canal of Nuck
Definition
Cyst of the canal of Nuck is a cystic remnant of the processus vaginalis peritonei.
Clinical Features
These cysts are most common in the inguinal canal, where they must be distinguished from hernias. They also occur in the mons pubis and in the superior, outer region of the labium majus. Ultrasonography or magnetic resonance imaging may be helpful for definitive clinical diagnosis. They are homologous to hydroceles in males. The processus vaginalis peritonei (canal of Nuck) is a rudimentary sac of peritoneal mesothelium carried down by the round ligament as it passes through the inguinal canal and inserts into the labium majus. Failure of this structure to obliterate normally during fetal development leads to blockage and cystic dilatation. While these cysts are usually solitary, more than one may arise if obstruction occurs at multiple sites. Generally asymptomatic, they may become tender to pressure, and may then require a procedure similar to herniorrhaphy.
Microscopic Features
In their pristine state, these are thin-walled and lined by flattened mesothelium. By the time they present clinically, repeated external trauma has usually induced fibrosis of their walls, reduced or destroyed their mesothelial lining, and caused hemosiderin deposition from old haemorrhage.
Clinical Features
These cysts are most common in the inguinal canal, where they must be distinguished from hernias. They also occur in the mons pubis and in the superior, outer region of the labium majus. Ultrasonography or magnetic resonance imaging may be helpful for definitive clinical diagnosis. They are homologous to hydroceles in males. The processus vaginalis peritonei (canal of Nuck) is a rudimentary sac of peritoneal mesothelium carried down by the round ligament as it passes through the inguinal canal and inserts into the labium majus. Failure of this structure to obliterate normally during fetal development leads to blockage and cystic dilatation. While these cysts are usually solitary, more than one may arise if obstruction occurs at multiple sites. Generally asymptomatic, they may become tender to pressure, and may then require a procedure similar to herniorrhaphy.
Microscopic Features
In their pristine state, these are thin-walled and lined by flattened mesothelium. By the time they present clinically, repeated external trauma has usually induced fibrosis of their walls, reduced or destroyed their mesothelial lining, and caused hemosiderin deposition from old haemorrhage.
Extramammary Paget Disease
Definition
Extramammary Paget disease is a form of in situ adenocarcinoma of the squamous mucosa. For a number of these cases, recent evidence suggests an origin from Toker cells, which are found in the breast with clear cytoplasm that reacts for cytokeratin 7 (CK7) and are thought to derive from the ostia of the mammary-like glands found in the vulva, perineum, and perianal skin.
Clinical Features
The vulva is the most common site of extramammary Paget disease, accounting for about 5% of all vulvar neoplasms. It usually presents in older women as a moist, red, eroded or eczematous-appearing plaque. One or both sides of the vulva can be involved, often with spread to the perianal skin ( Figure 5.7 ). The plaques are usually irritated and sore, and may be clinically misinterpreted as an inflammatory skin disease (e.g., intertrigo, fungal infections, immunobullous disorders, Hailey–Hailey disease). The diagnosis requires biopsy confirmation.
Treatment may be difficult because the disease usually extends well beyond the clinically apparent margins. Moreover, even surgical margin status is not particularly helpful in predicting recurrence, as about a third of patients experience recurrence regardless of whether the margins after initial surgery are positive or negative. The extent of the operation (wide local excision, simple vulvectomy, or modified radical vulvectomy) during the initial treatment also poorly correlates with disease recurrence. Mohs micrographic surgery, topical chemotherapy, and photodynamic therapy may play a role in selected cases. HER-2/neu expression has been demonstrated by some Paget disease of the vulva; thus, some patients may benefit from trastuzumab (Herceptin), a recombinant monoclonal antibody against HER-2/neu.
Microscopic Features
Histologically, the epidermis contains pale-staining cells that are larger than adjacent keratinocytes, arranged singly or in small to large nests ( Figure 5.8 ). When numerous, Paget cells may replace much of the epidermis, which appears swollen and thickened ( Figure 5.9 ). When Paget cells are single or few in number, they appear to be mainly above the basal layer or individually (pagetoid migration) into the upper epidermal layers. Cells appear not to be connected with the basement membrane and thus are different from melanoma in situ (see later; Figure 5.10A ). Paget cells may even be found growing down hair follicles as well as eccrine glands ( Figures 5.11 and 5.12 ). Occasionally, similar cells may be seen in the underlying dermis ( Figure 5.13 ), indicating invasion. While up to 50% of patients are reported to show invasion in some series, this is a distinctly unusual happening in our experience. Likewise, we find that metastases to lymph nodes are exceedingly rare.
The pale cytoplasm of the Paget cell is usually finely granular, and the nuclei are central and round to oval. Mitotic figures may be found. On routine staining, Paget disease may be confused with melanoma in situ . However, the Paget cells at the basal layer are usually discrete and characteristically compress and displace the normal keratinocytes, whereas melanoma cells generally form a continuous proliferation close to the basement membrane.
Paget cells usually contain intracytoplasmic mucin (neutral and acidic), as highlighted by PAS-diastase, Alcian blue, colloidal iron, and mucicarmine stains. In problematic cases, immunohistochemistry may be useful ( Table 5.1 ), with Paget cells selectively expressing cytokeratins CAM 5.2, CK7 ( Figure 5.10B ), MUC5AC, carcinoembryonic antigen (CEA) ( Figure 5.10C ), epithelial membrane antigen (EMA), and gross cystic disease fluid protein-15 (BRST-2). About one-fifth of Paget cases are reactive for CK20. Since S-100 protein is also sometimes expressed, such cases may require study for more specific melanocytic markers (MART-1/Melan-A, HMB45, etc.). A possible pitfall is those cases in which the tumor cells contain melanin pigment since the interspersed melanocytes may show prominent dendrites and thus may be interpreted as melanoma cells. Androgen receptors can be detected in some cases.
| Diagnosis | Keratin Cocktail | CK7 | CK20 | S-100 | MART-1/HMB45 |
|---|---|---|---|---|---|
| Paget disease | + | + | −/+ * | − ** | − |
| Squamous cell carcinoma | + | + | − | − | − |
| Melanoma | − | − | − | + | + |
* CK20 is usually negative in extramammary Paget disease. However, it is positive in cases of carcinoma of the genitourinary or gastrointestinal tract.
The origin of extramammary Paget disease is controversial. Some cases represent epidermotropic adenocarcinomas, but, unlike mammary cases (in which an underlying ductal carcinoma is almost invariably present), an underlying carcinoma is only rarely detected. Other postulated origins include a pluripotential stem cell within the epidermis or in situ malignant transformation of cells in the cutaneous sweat ducts as they insert into the epidermis. The most recent works point to the Toker cell ( Figure 5.14 ), which in the breast is an intraepidermal clear cell with bland nuclear features that is reactive for CK7 but not CK20. Cytogenetic findings suggest that at least some cases of Paget disease arise multicentrically within the epidermis from pluripotent stem cells, and have a molecular basis differing from other vulvar carcinomas.
Regarding the expression of mucin core proteins, vulvar Paget disease may arise from ectopic MUC5AC-positive cells originating from Bartholin or some other unidentified glands, while the unique expression of MUC2 in perianal Paget disease indicates that its origin from colorectal mucosa differs from that in the vulva.
Definition
Extramammary Paget disease is a form of in situ adenocarcinoma of the squamous mucosa. For a number of these cases, recent evidence suggests an origin from Toker cells, which are found in the breast with clear cytoplasm that reacts for cytokeratin 7 (CK7) and are thought to derive from the ostia of the mammary-like glands found in the vulva, perineum, and perianal skin.
Clinical Features
The vulva is the most common site of extramammary Paget disease, accounting for about 5% of all vulvar neoplasms. It usually presents in older women as a moist, red, eroded or eczematous-appearing plaque. One or both sides of the vulva can be involved, often with spread to the perianal skin ( Figure 5.7 ). The plaques are usually irritated and sore, and may be clinically misinterpreted as an inflammatory skin disease (e.g., intertrigo, fungal infections, immunobullous disorders, Hailey–Hailey disease). The diagnosis requires biopsy confirmation.
Treatment may be difficult because the disease usually extends well beyond the clinically apparent margins. Moreover, even surgical margin status is not particularly helpful in predicting recurrence, as about a third of patients experience recurrence regardless of whether the margins after initial surgery are positive or negative. The extent of the operation (wide local excision, simple vulvectomy, or modified radical vulvectomy) during the initial treatment also poorly correlates with disease recurrence. Mohs micrographic surgery, topical chemotherapy, and photodynamic therapy may play a role in selected cases. HER-2/neu expression has been demonstrated by some Paget disease of the vulva; thus, some patients may benefit from trastuzumab (Herceptin), a recombinant monoclonal antibody against HER-2/neu.
Microscopic Features
Histologically, the epidermis contains pale-staining cells that are larger than adjacent keratinocytes, arranged singly or in small to large nests ( Figure 5.8 ). When numerous, Paget cells may replace much of the epidermis, which appears swollen and thickened ( Figure 5.9 ). When Paget cells are single or few in number, they appear to be mainly above the basal layer or individually (pagetoid migration) into the upper epidermal layers. Cells appear not to be connected with the basement membrane and thus are different from melanoma in situ (see later; Figure 5.10A ). Paget cells may even be found growing down hair follicles as well as eccrine glands ( Figures 5.11 and 5.12 ). Occasionally, similar cells may be seen in the underlying dermis ( Figure 5.13 ), indicating invasion. While up to 50% of patients are reported to show invasion in some series, this is a distinctly unusual happening in our experience. Likewise, we find that metastases to lymph nodes are exceedingly rare.
The pale cytoplasm of the Paget cell is usually finely granular, and the nuclei are central and round to oval. Mitotic figures may be found. On routine staining, Paget disease may be confused with melanoma in situ . However, the Paget cells at the basal layer are usually discrete and characteristically compress and displace the normal keratinocytes, whereas melanoma cells generally form a continuous proliferation close to the basement membrane.
Paget cells usually contain intracytoplasmic mucin (neutral and acidic), as highlighted by PAS-diastase, Alcian blue, colloidal iron, and mucicarmine stains. In problematic cases, immunohistochemistry may be useful ( Table 5.1 ), with Paget cells selectively expressing cytokeratins CAM 5.2, CK7 ( Figure 5.10B ), MUC5AC, carcinoembryonic antigen (CEA) ( Figure 5.10C ), epithelial membrane antigen (EMA), and gross cystic disease fluid protein-15 (BRST-2). About one-fifth of Paget cases are reactive for CK20. Since S-100 protein is also sometimes expressed, such cases may require study for more specific melanocytic markers (MART-1/Melan-A, HMB45, etc.). A possible pitfall is those cases in which the tumor cells contain melanin pigment since the interspersed melanocytes may show prominent dendrites and thus may be interpreted as melanoma cells. Androgen receptors can be detected in some cases.
| Diagnosis | Keratin Cocktail | CK7 | CK20 | S-100 | MART-1/HMB45 |
|---|---|---|---|---|---|
| Paget disease | + | + | −/+ * | − ** | − |
| Squamous cell carcinoma | + | + | − | − | − |
| Melanoma | − | − | − | + | + |
* CK20 is usually negative in extramammary Paget disease. However, it is positive in cases of carcinoma of the genitourinary or gastrointestinal tract.
The origin of extramammary Paget disease is controversial. Some cases represent epidermotropic adenocarcinomas, but, unlike mammary cases (in which an underlying ductal carcinoma is almost invariably present), an underlying carcinoma is only rarely detected. Other postulated origins include a pluripotential stem cell within the epidermis or in situ malignant transformation of cells in the cutaneous sweat ducts as they insert into the epidermis. The most recent works point to the Toker cell ( Figure 5.14 ), which in the breast is an intraepidermal clear cell with bland nuclear features that is reactive for CK7 but not CK20. Cytogenetic findings suggest that at least some cases of Paget disease arise multicentrically within the epidermis from pluripotent stem cells, and have a molecular basis differing from other vulvar carcinomas.
Regarding the expression of mucin core proteins, vulvar Paget disease may arise from ectopic MUC5AC-positive cells originating from Bartholin or some other unidentified glands, while the unique expression of MUC2 in perianal Paget disease indicates that its origin from colorectal mucosa differs from that in the vulva.
Melanocytic Lesions
Lentigo
Definition
A lentigo is a circumscribed macule of increased pigmentation, generally 5 mm or less in diameter, and persisting even in the absence of sun exposure.
Clinical Features
Lentigines are common on the labia majora or minora. They are often deeply pigmented but usually have uniform color, sharp circumscription, and regular borders. Lentigines proper are not precursors of melanoma.
Microscopic Features
The epidermis of a lentigo has elongated rete ridges and increased melanin deposition in the keratinocytes ( Figure 5.15 ). The number of melanocytes should be approximately normal. Furthermore, the melanocytes lack cytologic atypia.
Common Acquired Melanocytic Nevus
Definition
A melanocytic nevus is a benign neoplasm composed of cells exhibiting melanocytic differentiation.
Clinical Features
Melanocytic nevi are the most common neoplasms to occur in humans. An average Caucasian adult has 10 or more. Nevi occur with some frequency on the vulva, usually on the labia majora ( Figure 5.16 ).
Microscopic Features
Intradermal, junctional, and compound nevi resemble those seen elsewhere in the body. A key element in assessing the benignity of a melanocytic lesion is to determine the presence of ‘maturation,’ i.e., the tendency to undergo a morphologic shift with progressive depth in the dermis as seen on both light microscopy and immunohistochemical expression. Another hallmark of benignity is a tendency for quiescence in the deeper component, with reduced numbers of proliferating cells in the deeper dermis and absence of mitotic figures. In contrast, most melanomas consist of large, pleomorphic cells throughout the entire lesion and exhibit mitotic figures in their deep component. However, an uncommon subset of melanomas exhibits a paradoxical pattern of maturation simulating that of nevi. A possible pitfall is the presence of mitotic figures in otherwise benign nevi from pregnant women.
Melanocytic Nevus of the Genital Type
Definition
A subset of nevi occurring on the vulva, perineum, or mons pubis exhibits particular stromal changes. It differs from the standard atypical (dysplastic, Clark) nevus, which can be found anywhere, occurs in young individuals, and lacks the characteristic stromal changes seen in the atypical ‘dysplastic’ nevus.
Clinical Features
Nevi of the genital type are more common on the labia minora or the mucosa of the clitoral region than on the labia majora. They have also been seen in other flexural areas such as the axillae and uncommonly on male genitalia. They occur at a much younger age (median 25 years) than vulvar melanoma.
Microscopic Features
These nevi show confluent and enlarged nests of nevus cells that vary in size, shape, and position at the dermoepidermal junction ( Figure 5.17 ). The nevus cells exhibit reduced cohesion. Finally, the stromal pattern at the dermoepidermal junction is often inconspicuous and nondescript in contrast to the concentric eosinophilic fibroplasia or lamellar fibroplasia seen in the usual atypical (dysplastic) nevus (see later).
Blue Nevus (Dermal Melanocytoma)
Definition
Blue nevus is a benign melanocytic neoplasm consisting almost exclusively of spindle and epithelioid dermal cells associated with prominent melanin pigment.
Clinical Features
Blue nevus is relatively uncommon in the vulva. It is fairly common on the buttock and acral extremities. These nevi are small, blue to black, well-circumscribed lesions, sometimes slightly raised.
Microscopic Features
The dermis has collections of spindle-shaped or dendritic cells containing delicate melanin pigment, intersecting with dense collagen fibers ( Figure 5.18 ). There are also melanophages containing coarse, clumped melanin pigment. In the cellular variant, the nevus cells are packed in dense fascicles, often forming a dumbbell-shaped nodule that may extend into the subcutis. Malignant change in blue nevi is extremely rare. We discourage the use of the term ‘malignant blue nevus’ and rather recommend ‘melanoma blue-nevus type’ for such melanoma cases showing spindle cells and pigmented melanocytes/melanophages (i.e., resembling blue nevus). Blue nevi with necrosis or mitotic figures or cytologic atypia are usually described as atypical forms and probably warrant conservative excision.
A related entity is the pigmented epithelioid melanocytoma (‘animal-type melanoma’). It is unclear whether this lesion is a low-grade melanoma or if it belongs to a spectrum of lesions between blue nevus and melanoma. Most pigmented epithelioid melanocytomas occur in the extremities but some lesions have been described in the vulva. Histologically, they resemble the epithelioid blue nevus seen in patients with the Carney complex. Lymph node metastasis may occur, but visceral metastasis is uncommon.
Atypical (Dysplastic, Clark) Nevus
Clinical Features
Both atypical nevi and melanomas customarily are relatively large (>5 mm), poorly circumscribed, and asymmetric, with an irregular border and a range of colors. Atypical nevi represent a strong, independent risk factor for development of melanoma, whether occurring sporadically or in the context of a familial melanoma diathesis. Moreover, there is a strong relationship between melanoma risk and the number of atypical nevi present. Apart from this role as a simple marker of melanoma risk, atypical nevi themselves may on occasion be precursors to melanoma.
Microscopic Features
The histopathologic features include abnormal architecture, host response, and cytology. In general, there is a high degree of consensus on the defining architectural features of atypical nevi, which include peripheral extension of the junctional component (shoulder) ( Figure 5.19 ), confluence of single melanocytes or via bridging of adjacent rete ridges, and irregular disposition, size, and shape of junctional nests ( Figure 5.20 ).
Melanoma
Definition
Melanoma is a malignant tumor of melanocytes.
Clinical Features
Vulvar melanoma accounts for 8–10% of all malignant tumors of the vulva. It occurs on the clitoris, labia minora, and labia majora with similar frequency, and may develop from a pre-existing pigmented lesion. It affects mainly older women, and only rarely younger women and girls. Vulvar bleeding is the most common symptom followed by vulvar mass, vulvar ulcer, and mole.
Except in the rare amelanotic variant, the clinical appearance of melanoma is characteristic. There is usually marked gross asymmetry, border irregularity, and color variegation, sometimes including a play of brown, black, blue, and red ( Figures 5.21 and 5.22 ). A white color suggests regression. Most melanomas have a prominent in situ (intraepidermal) component, which presents as a hyperpigmented macule. Elevation to form a plaque or nodule frequently indicates invasion, and is an ominous sign. Development of satellite lesions (approximately in 20% of cases) is a form of local metastasis and is associated with poor prognosis.
Microscopic Features
Historically, melanoma has been classified into four distinct histopathologic subtypes, including superficial spreading melanoma, nodular melanoma, acral–lentiginous (mucosal–lentiginous) melanoma, and lentigo maligna melanoma. Verrucous melanoma has also been described. Acral–lentiginous (mucosal–lentiginous) melanoma is the most common type of vulvar melanoma.
Melanoma in situ is composed of atypical melanocytes arranged both singly and in nests within the epithelium ( Figure 5.23 ). Single cells often predominate over nests, and confluence may be extensive. In superficial spreading melanoma, the tumor cells usually exhibit high-grade cytologic atypia (large, pleomorphic nuclei with large nucleoli), as well as marked architectural disorder including pagetoid spread through the upper epidermal layers ( Figure 5.24 ). The radial growth or the atypical melanocytes involves four or more adjacent rete ridges. In nodular melanomas, an intraepithelial component may be seen in continuity with an invasive component, but without a radial growth phase. The so-called acral–lentiginous variants usually show less pagetoid spread and the tumor cells often have less abundant cytoplasm; these melanomas are composed of relatively small but hyperchromatic melanocytes, with a marked tendency to extend along the basal layer of the epidermis and adnexal epithelium. However, the distinctive cellular features of melanoma are seen in the invasive component, which often shows a desmoplastic stromal reaction.
Differential Diagnosis
Vulvar melanoma, particularly of the superficial spreading type, should be distinguished from Paget disease and vulvar intraepithelial neoplasia (VIN). The cells of Paget disease are larger than those of superficial spreading melanoma and, occasionally, form glandular structures. Sarcomatoid squamous cell carcinomas may mimic the invasive component of malignant melanoma of the acral–lentiginous type. However, foci of typical squamous cell carcinoma facilitate the correct diagnosis and are usually encountered in deeper sections. Melanomas are immunoreactive for S-100 protein, HMB45, and Melan-A, whereas the non-melanocytic tumors, (including Paget, VIN, and squamous cell carcinoma) are negative ( Table 5.1 ). Paget disease can be distinguished from melanoma with mucin stains and immunohistochemical reactions for CEA, S-100 protein, HMB45 (or Melan-A), and cytokeratins ( Table 5.1 ). Paget cells typically contain cytoplasmic mucin, as shown with mucicarmine stain, and are immunoreactive for CEA and cytokeratins, whereas melanomas are not. Spindle cell sarcomas and metastatic choriocarcinoma may also enter in the differential diagnosis. Muscle markers for leiomyosarcoma or rhabdomyosarcoma (e.g., desmin, smooth muscle actin) and human chorionic gonadotropin (hCG) for choriocarcinoma may be helpful. Nevertheless, it should be emphasized that the diagnosis of melanoma must be seriously considered when examining any poorly differentiated tumor of the vulva ( Table 5.2 ). To confirm the diagnosis of vulvar melanoma, immunoreactions for epithelial markers (e.g., AE1/3, CK7 and CK20, EMA, CEA, GCDFP-15), neural and neuroendocrine tumor markers (e.g., S-100, chromogranin, synaptophysin, CD56), and melanoma markers may be done ( Figure 5.25 ; Table 5.2 ).
| Diagnosis | Keratin Cocktail | CK7 | CK20 | CK5/6 | CEA | S-100 | MART-1/HMB45 | Chromogranin Synaptophysin |
|---|---|---|---|---|---|---|---|---|
| Squamous cell carcinoma | + | + | − | + | − | − | − | − |
| Merkel cell carcinoma | + | − * | + | − | − | − | − | + |
| Adenocarcinoma | − | − | − | − | + | − ** | + | − |
| Melanoma | *** | − | − | + | − † | + | + | − |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
