Fig. 7.1
Vulvar melanosis. An asymmetric, poorly circumscribed, variegated patch mimicking melanoma is evident (left panel). Histopathologically, vulvar (genital) melanosis exhibits, in most cases, increased melanization of the basal keratinocytes, subepithelial fibrosis, and free melanin and melanophages in the submucosa (right panel)
The underlying cause and pathogenesis for vulvar melanosis is unknown, but it appears to be a reactive phenomenon [19] showing features that overlap with post-inflammatory hyperpigmentation, as it is known to occur in the setting of lichen sclerosus [20–22] and frequently associated with subepithelial fibrosis, melanophages, and sparse inflammatory infiltrates [23]. Some cases have been reported in patients with a clinical history of oral contraceptive usage [13] or psoralen ultraviolet A (PUVA) treatment [16]. Also, some consider the possibility that a defect in the normal transport of melanin to the suprabasal keratinocytes of the epidermis is responsible for the basal layer hyperpigmentation [24]. This theory is in line with the concept of “chromatic tendency” which determines the development of hyperpigmentation or hypopigmentation based on the robustness or lack thereof of melanocyte function and viability [25]. Lastly, no association has been shown between human papillomavirus (HPV) infection and vulvar melanotic macules [26]. However, reports in the literature of pigmented warts, frequent occurrence of pigmented high-grade vulvar intraepithelial neoplasia (VIN-3), and lentiginous melanocytic proliferations occurring in pigmented/nonpigmented warts and VIN as well as a possible association of HPV DNA with genital nevi and melanoma [27, 28] appear to provide indirect evidence of HPV infection inducing vulvar pigmentation in some instances. In a recent study of pigmented anogenital intraepithelial neoplasia [29], the main mechanisms of pigmented squamous intraepithelial neoplasia of the anogenital area include melanin incontinence and occurrence of melanin in dysplastic keratinocytes. Colonization of the dysplastic epithelium by dendritic melanocytes appeared to contribute but was rarely a prominent feature.
Vulvar melanosis tends to remain static, although new lesions may evolve over time [23]. Despite sometimes presenting with alarming features clinically indistinguishable from melanoma [13], genital melanosis is a benign entity as no reports of progression to vulvar melanoma exist. Nevertheless, cases of concomitant genital melanosis and melanoma of the urinary bladder, vulva, and/or vagina have been reported, suggesting a possible role of this pigmented lesion in the pathogenesis of melanoma [27, 28, 30]. In addition, vulvar melanosis is infrequently associated with lichen sclerosus, which is a known risk factor for squamous cell carcinoma [31] and has been reported in association with melanoma [27, 28]. Therefore, clinical follow-up of these patients would be a reasonable, prudent approach as a small, but increased association with melanoma exists. In syndrome-associated genital melanosis, the prognosis depends on the specific abnormalities of the syndrome.
Histopathology
In general, there is increased melanin pigmentation within the keratinocytes, most prominent at the tips of the rete ridges, with normal or slightly increased number of melanocytes arranged as solitary units with no significant cytologic atypia or pagetoid upward migration [26] (Fig. 7.1, right panel). Because of the latter finding and the lack of nest formation, the term “genital lentiginosis” has been advocated by some [16]. In contrast to true melanocytic neoplasms, the lesional melanocytes are separated by keratinocytes and associated with an increased ratio of single melanocytes to keratinocytes along the basement membrane zone [26]. In some cases, the melanocytes have prominent dendritic processes containing melanin extending up into the upper epidermis [32]. Overall these descriptions match those described by Chapel et al. [24] for volar melanotic macules: (1) increased melanization of the basal keratinocytes only; (2) increased melanization of all keratinocytes (basal, spinous, and corneal); or (3) prominent dendritic melanocytes with scant pigmentation of adjacent keratinocytes [22].
Elongation of the rete ridges due to mild keratinocytic hyperplasia coupled with melanin incontinence (free melanin in the papillary dermis) and dermal melanophages can also be observed in vulvar melanotic macules. These findings overlap with post-inflammatory hyperpigmentation. An example of this phenomenon is genital melanosis coexisting with lichen sclerosus, where fibrosis of the papillary dermis is intermixed with melanophages, lymphocytes, and sclerotic collagen, in addition to the presence of hypermelanotic basal keratinocytes of a melanotic macule [20, 22, 33] (Fig. 7.2). While these changes mimic regression (e.g., regressed melanoma) [20], this constellation of histopathologic findings also fulfills minimal criteria for the diagnosis of lichen sclerosus [22] as well as melanotic macules [24]. Thus, it appears that an inflammatory milieu could induce melanotic macules; or conversely, genital melanotic macules can elicit a host immune response that progresses from a lichenoid host response to lichen sclerosus.
Fig. 7.2
Vulvar melanosis. Warthin-Starry stain is an effective histochemical stain for demonstrating the density and distribution of melanin within the epidermis and papillary dermis. Compared to routine hematoxylin and eosin staining (a and c), Warthin-Starry stain highlights the circumscription of mucosal pigmentation and demonstrates that most of the melanin is located in the basal keratinocytes with lesser melanin deposition in the spinous and corneal layers. In addition, free melanin and melanophages are readily seen in the submucosa (b and d). Subepithelial fibrosis commonly underlies these pigmentary changes, with or without lymphocytic infiltrates and histologic features highlighting the overlap of genital melanosis with post-inflammatory hyperpigmentation
Differential Diagnosis
Vulvar melanosis needs to be differentiated from melanoma, benign melanocytic nevi, and post-inflammatory hyperpigmentation. The most important differential diagnosis is melanoma in situ. The larger the melanotic macule (e.g., >5 mm) and the more severe the irregularity of its borders, the greater the indication to biopsy to exclude the presence of melanoma in situ; patients with large or numerous macules of vulvar melanosis should be biopsied to confirm the diagnosis as the distinction from melanoma in situ cannot be made clinically with absolute certainty. In melanoma in situ, there is a significant increase of melanocytes along the basal layer of the epidermis that exhibits cytologic atypia and may form variably sized nests or extend into the spinous layer (pagetoid upward migration). Furthermore, mitoses may be present. Immunohistochemical studies are usually not necessary for the diagnosis of most vulvar melanotic macules because the presence of melanoma can be excluded by routine light microscopy [16]. However, in difficult cases, immunohistochemistry with Mart-1 and/or MiTF can be helpful in excluding melanoma in situ by demonstrating the absence of nests, lack of pagetoid upward migration, and/or no confluence of melanocytes along the basement membrane zone (similar to criteria applied in sun-damaged skin for lentigo maligna) [34]. In melanocytic nevi, the melanocytes form nests along the dermal-epidermal junction in a predictable and circumscribed fashion. In contrast, per definition, no melanocytic nests are seen in vulvar melanosis. In post-inflammatory hyperpigmentation, the basal layer of the epidermis is usually not hyperpigmented and the pigmentation is primarily due to the increase of melanophages and free melanin in the superficial dermis. See Vignette 1 at the end of this chapter.
Summary
Clinical Presentation
Melanotic macules are asymptomatic, small (<0.5 cm), well-circumscribed, black macules.
A minority are large macules/patches showing multiple macules with irregular borders, variegated pigmentation, and skip areas.
Histologic Features
Hyperpigmentation of the basal keratinocytes with prominence, but not increase of mostly dendritic melanocytes
Subjacent mucosal melanophages and fibrosis
Absence of melanocytic nests, cytologic atypia, pagetoid scatter
Differential Diagnosis
Post-inflammatory hyperpigmentation
Lentiginous junctional melanocytic nevus
Melanoma in situ
Takeaway Essentials
Clinical Relevant Pearls
Can have variegated color and very irregular contours raising concern for melanoma
Pathology Interpretation Pearls
Hyperpigmentation of the basal keratinocytes can be subtle
Comparing the hyperpigmented areas with the adjacent normal, non-hyperpigmented epidermis may provide the only clue
Immunohistochemical/Molecular Findings
In difficult cases immunohistochemistry for Mart-1 and/or MiTF-1 can be helpful in excluding melanoma in situ
Post-inflammatory Hyperpigmentation
Clinical Features
Post-inflammatory hyperpigmentation, as the name implies, is pigmentation that occurs in the setting of a genital eruption that has an inflammatory component, particularly one that is directed at the epithelium [7, 35]. Damage to the basement membrane zone, keratinocytes, and/or melanocytes allows melanin pigment to drop out of the epidermis into the dermis, most of which will be engulfed by macrophages (melanophages). Patients of all skin types can be affected, but it is more common and most pronounced in patients with darker skin. Notably, in dark-skin individuals, ongoing inflammation can appear more brown than red giving the impression of hyperpigmentation. Clinically, post-inflammatory hyperpigmentation presents as macules and patches with different shades of brown and gray (due to dermal melanin) and is usually asymmetric compared to the symmetry of physiologic hyperpigmentation (Fig. 7.3). Common causes include eczema (i.e., allergic or irritant contact dermatitis and seborrheic dermatitis) particularly those associated with chronicity such as lichen simplex chronicus, lichen sclerosus, lichen planus, lichenoid drug eruption, or fixed drug eruption [7, 32]. Typically, post-inflammatory hyperpigmentation is asymptomatic, as the primary process has resolved. Occasionally, symptoms related to the underlying causative skin disorder are present such as pruritus. Many times, the diagnosis can be made clinically based on the distribution and pattern of pigmentation as well as the history or clinical signs of an inflammatory process. However, there are some instances where clinical presentation is atypical, raising concern for melanoma; in those cases, the diagnosis should be confirmed with a biopsy. Lastly, the dark macules and patches of post-inflammatory hyperpigmentation are long lasting and diminish only slowly, if at all [7]. Control of the underlying causative inflammatory dermatosis is the most effective mode of management.
Fig. 7.3
Post-inflammatory hyperpigmentation due to lichen sclerosus. This is an example of an early lesion of lichen sclerosus presenting as an irregular, variegated brown and white patch, which occurs in 2 % of the cases [22]. The varying degrees of hyper- and hypopigmentation (a) are associated histopathologically with an irregularly melanized basal keratinocytic layer, fibrosis and sclerosis of the submucosa, lymphocytes infiltrating the fibrosis and basal layer, and rare melanophages (b, c). The (c) exhibits features that fulfill proposed minimal criteria for diagnosis of lichen sclerosus [22]
Histology
There is increased melanin and melanophages in the papillary dermis or submucosa and around blood vessels (Figs. 7.3 and 7.4). In addition, there may be increased amount of melanin within the basal layer of the epidermis although that is not usually the case. Occasionally, a superficial perivascular lymphocytic infiltrate and a mild increase in papillary dermal fibroblasts and collagen are present [32]. Usually, no evidence of the underlying causative dermatosis is identified by the time the patient presents for evaluation of vulvar pigmentation.
Fig. 7.4
Post-inflammatory hyperpigmentation due to fixed drug eruption. Fifty-eight-year-old woman presents complaining of recurring episodes of pruritus, swelling, and irregular vulvar pigmentation. Biopsy shows melanophages in the papillary dermis, irregular melanization of basal keratinocytes, and smudging of the basement membrane zone without significant inflammation consistent with a quiescent lesion of fixed drug eruption (a, b). Curiously, dermal sclerosis associated with dilated lymphatic spaces is also present (c). These later findings raise the possibility of early, evolving lichen sclerosus [36]
Differential Diagnosis
The differential diagnosis includes physiologic hyperpigmentation of the vulva and vulvar melanosis. Physiologic hyperpigmentation commonly occurs in dark-skin individuals and can change with different physiologic states such as pregnancy or the use of oral contraceptives. It is characterized by symmetric hyperpigmentation of the vulvar region, particularly in the perianal skin, posterior introitus, and the tips of the labia minora [7, 9]. The skin biopsy is usually nondiagnostic, although an increase of melanin and melanosomes in the melanocytes and basal keratinocytes has been reported [7]. Also, no dermal changes such as fibrosis or melanin incontinence would be present as these findings are expected for post-inflammatory hyperpigmentation. In general, if the pattern of hyperpigmentation is irregular, a biopsy to rule out a melanocytic lesion should be performed. Furthermore, since post-inflammatory hyperpigmentation can occur in patients with lichen sclerosus, and the latter disease is a risk factor for squamous cell carcinoma or melanoma [27, 28, 31], skin biopsies are often required in these patients to accurately diagnose the nature of the hyperpigmentation. Due to hemosiderin deposition, it is possible that vulvar purpura and/or plasma cell vulvitis could mimic post-inflammatory hyperpigmentation [37], albeit these disorders are consequences of chronic inflammation and/or irritation. If there is doubt histologically regarding the nature of the pigment, the use of iron and Fontana-Masson stain can be helpful; the former will highlight hemosiderin whereas the latter melanin. Positive iron staining due to hemosiderin formation from chronic localized hemorrhage found in pigmented purpuras and plasma cell vulvitis would be confirmatory. See Vignette 2 at the end of this chapter.
Summary
Clinical Presentation
Depends on the underlying inflammatory skin disease
Usually asymptomatic
Histologic Features
Melanin pigment and melanophages in the superficial dermis
Subjacent mucosal melanophages and fibrosis
A sparse perivascular lymphocytic infiltrate may be present
Differential Diagnosis
Physiologic hyperpigmentation
Genital melanosis
Vulvar intraepithelial neoplasia, pigmented
Takeaway Essentials
Clinical Relevant Pearls
Same distribution with the underlying inflammatory disease
Pathology Interpretation Pearls
Increased melanin and melanophages in the papillary dermis
Acanthosis Nigricans
Clinical Features
Acanthosis nigricans is a dermatosis that exhibits a symmetrical pattern of hyperpigmentation with brown, poorly demarcated, thickened velvet-textured plaques with verrucous excrescences [7, 9]. The most commonly affected areas are the flexural areas of the body, especially the axillae, the hair-bearing surface of the vulva, crural creases, proximal medial thighs, umbilicus, and the neck and face; rarely it can be generalized [38, 39]. Because of the accentuation of the underlying papillomatous process, it is often associated with skin tags within the plaques. Acanthosis nigricans is not typically pruritic. Native Americans are most commonly affected, followed by African-Americans and Hispanics [40]. Acanthosis nigricans can be a cutaneous manifestation of a wide variety of less obvious internal conditions. Acanthosis nigricans is classified into five types based on its associations [41]. Type 1 is a hereditary, autosomal-dominant genodermatosis, which is exceedingly rare (Down syndrome, FGFR3 mutations, and others) [32, 42]. Type 2 is a common asymptomatic manifestation of insulin resistance observed primarily in obese individuals [43, 44] associated with diabetes mellitus or other endocrinopathies (e.g., Cushing disease, Addison disease, or hypothyroidism). Type 3 is associated with obesity often in association with a metabolic syndrome. Type 4 is associated with various medications [45], especially niacin [46] and prednisone [9]. Type 5 is a paraneoplastic phenomenon, most commonly associated with adenocarcinoma but also seen in lymphoma, squamous cell carcinoma, and other malignancies [47]. The malignancy can precede, accompany, or follow the onset of acanthosis nigricans.
Biochemical mechanisms responsible for this hyperplastic lesion are unclear and depend on the associated disorder but likely involve local cutaneous growth factors [48] leading to the proliferation of keratinocytes and fibroblasts. Members of the tyrosine kinase receptor superfamily including epidermal growth factor receptor (EGFR), insulin growth factor receptor 1 (IGFR1), and fibroblast growth factor receptors (FGFRs) are some of the factors involved [49]. For example, in women with hyperandrogenism and insulin intolerance, anti-insulin receptor antibodies or loss of function mutation in the insulin receptor can be found [50]. In one study, 56 % of the women evaluated for hirsutism in a cohort of nondiabetic women with documented hyperandrogenism had acanthosis nigricans. Interestingly, although acanthosis nigricans was found in various body sites with different prevalences, vulvar acanthosis nigricans was always present in these women [51].
Acanthosis nigricans is benign albeit its course depends on the type. Type 1 becomes accentuated with time, but it can also regress in older patients. The course of type 2 depends on the underlying endocrinopathy while type 3 can regress after substantial weight loss. Type 4 resolves with withdrawal of the causative drug and type 5 with treatment of the malignancy. In thin individuals who develop acanthosis nigricans, particularly in atypical areas without evidence of insulin resistance, or of sudden onset, a thorough investigation for an internal malignancy should be performed [9, 52].
Histopathology
Acanthosis nigricans is a noninflammatory disorder characterized by marked papillomatosis with hyperkeratosis and mild acanthosis [53]. Fingerlike dermal papillae are covered by thin epidermis with overlying hyperkeratosis [54] (Fig. 7.5). A mild hyperpigmentation of the basal layer may be noted, but there is no increase of melanocytes. The thickened stratum corneum is largely responsible for the clinical pigmentation and hyperpigmentation found in acanthosis nigricans [41].
Fig. 7.5
Acanthosis nigricans manifests clinically as thickened-appearing, velvety, brown plaques in skinfolds of overweight and obese individuals [55]. Histopathologically, acanthosis nigricans is characterized by marked papillomatosis and orthokeratosis coupled with minimal acanthosis (a, b). This specimen shows a dermal nodular inflammatory infiltrate due to an adjacent suppurative folliculitis, which is another complication of obesity [55]. In this case, acanthosis nigricans was the secondary diagnosis, after confirmation of the folliculitis
Differential Diagnosis
The differential diagnosis includes lichenified eczema and physiologic hyperpigmentation. Clinically, lichenified eczema can exhibit hyperpigmentation and mimic the velvety texture of acanthosis nigricans via accentuation of skin markings due to chronic rubbing or irritation [7]; in addition, eczema patients complain of pruritus whereas acanthosis nigricans is asymptomatic. By histopathology, lichenified eczema shows marked acanthosis and vertically oriented collagen bundles separating rete ridges and does not exhibit papillomatosis. Clinically, physiologic hyperpigmentation does not show the velvety, leathery texture of acanthosis nigricans and does not display papillomatosis and hyperkeratosis [9]. Some lesions of seborrheic keratosis show papillated epidermal hyperplasia indistinguishable from acanthosis nigricans; however, its circumscription, presence of horn pseudocysts, acanthotic growth pattern, and/or reticulate growth pattern distinguishes it from acanthosis nigricans in most instances.
Summary
Clinical Presentation
Symmetrical, velvety, hyperpigmented plaques on the hair-bearing surface of the vulva and groins
Histologic Features
Papillomatosis and hyperkeratosis but with very mild acanthosis
No melanocytic proliferation and no dermal inflammation
Differential Diagnosis
Lichenified eczema
Physiologic hyperpigmentation
Takeaway Essentials
Clinical Relevant Pearls
Symmetrical hyperpigmentation with brown, poorly demarcated, thickened velvet-textured plaques with verrucous excrescences
Pathology Interpretation Pearls
Papillomatous hyperplasia without acanthosis
Hypopigmentation
Post-inflammatory Hypopigmentation
Clinical Features
Cutaneous infections (e.g., syphilis, leprosy, herpes) and many inflammatory conditions (atopic dermatitis, pityriasis lichenoides chronica (PLC), psoriasis, lichen striatus, and lichen sclerosus) can induce post-inflammatory hypopigmentation [25] (Figs. 7.6 and 7.7). Atopic dermatitis can show pigmentary changes, which can be particularly severe if high-potency corticosteroids are used [57]. In addition, cutaneous injuries from dermatologic procedures (such as laser therapy or cryotherapy), irritants (chemical peel), or burns can also lead to the same result [58]. The pathogenesis is not well understood as the melanocytes can react with normal, increased, or decreased melanin synthesis to the insult. Although post-inflammatory hypopigmentation depends on the duration, type, and severity of insult, there is definite predisposition of individuals to hypo- or hyperpigmentation, reflected by the concept of “individual chromatic tendency” where patients with “weak” melanocytes tend to develop hypopigmentation after inflammation whereas patients with “strong” melanocytes hyperpigmentation [25]; these outcomes are considered genetically determined and inherited in an autosomal-dominant pattern. Cutaneous inflammation may cause the release of multiple mediators, which can cause aberration of melanogenesis. It has been suggested that several factors play a role in the production of post-inflammatory hypopigmentation including defect in transfer of melanosomes to keratinocytes, melanocyte loss, and decreased/inhibited melanin production [25, 56, 58]. An example of the complexity of post-inflammatory hypopigmentation is found in lichen sclerosus, a disorder characterized clinically by cutaneous hypopigmentation of the anogenital area, particularly the vulva [22, 56] (Figs. 7.6 and 7.7). Several mechanisms, alone or in combination, likely play a role in lichen sclerosus’s leukoderma: (1) decreased melanin production, (2) block in transfer of melanosomes to keratinocytes, and (3) melanocyte loss [56]. Absence of melanocytes also characterizes vitiligo, an autoimmune inflammatory disorder frequently associated with lichen sclerosus (LS). This association may be the pathogenic connection (lichenoid dermatitis triggering an autoimmune reaction to melanocytes) that underlies the clinical association of LS with vitiligo [56].
Fig. 7.6
Hypopigmentation: vitiligo and lichen sclerosus. Vitiligo manifests as loss of pigmentation without any other cutaneous or mucosal findings (a). Warthin-Starry or Fontana-Masson stain shows a loss of epidermal melanin and absence of dendritic melanocytes whereas the melanocyte-specific markers such as Mart-1 or MiTF highlight the loss of melanocytes (c). Post-inflammatory hypopigmentation is due to a combination of decrease of melanocytes, melanin incontinence due to basal keratinocyte or melanocyte damage, or blockade of transfer of melanin from melanocytes to keratinocytes, and from screening from sunlight of the epidermis by the hyperkeratosis. This example of lichen sclerosus (b) shows hypopigmentation caused by hyperkeratosis and hypergranulosis (d) from persistent rubbing of a pruritic vulva (lichen simplex chronicus)
Fig. 7.7
Lichen sclerosus and hypopigmentation. Up to 98 % of vulvar lichen sclerosus cases show hypopigmentation that can mimic vitiligo [22]. Several mechanisms likely play a role in the pathogenesis of lichen sclerosus’s inflammatory hypopigmentation: (1) decreased melanin production, (2) block in transfer of melanosomes to keratinocytes, and (3) melanocyte loss [56]. Illustrated herein is an early, evolving lesion of lichen sclerosus with areas of diminished or loss of melanin (a) in the basal keratinocytes and an almost complete loss of melanocytes (b)
Most cases with minimal hypopigmentation improve spontaneously within weeks or months if the primary cause ceases [58]. However, in patients with severe post-inflammatory hypopigmentation, the condition can be permanent if there is complete destruction of the melanocytes.
Histopathology
Histologic sections show decreased to absent melanin in the basal keratinocytes, melanophages in the upper dermis, and a sparse superficial lymphohistiocytic infiltrate. Sometimes the causative inflammatory condition such as lichen sclerosus may also be evident (Figs. 7.6 and 7.7). Fontana-Masson or Warthin-Starry histochemistry can help document the decreased melanin content of basal keratinocytes and none or only rare dendritic melanocytes within the epidermis. Similarly, immunohistochemical melanocytic markers (microphthalmia-associated transcription factor (MITF), HMB-45, and melanoma antigen recognized by T-cells 1 (Mart1) may show a decreased number or regional loss of melanocytes (Figs. 7.6 and 7.7).
Differential Diagnosis
The clinical differential diagnosis includes sarcoidosis [59], lichen sclerosus [56], hypopigmented mycosis fungoides, hypopigmented extramammary Paget’s disease [60], hypopigmentation after high-potency topical corticosteroid usage, vitiligo, and chemical leukoderma [58]. Histologic examination and clinicopathologic correlation can easily differentiate these entities. In particular sarcoidosis shows noncaseating granulomas; mycosis fungoides, a lichenoid infiltrate of atypical lymphocytes with epidermotropism; extramammary Paget’s disease exhibits large atypical epithelioid cells within the epidermis; vitiligo, absence of melanocytes; and chemical leukoderma, a reduction of melanocytes. Nevertheless, even if the biopsy is not conclusive, the exclusion of some of the entities in the differential diagnosis is useful for diagnostic classification and management.
Summary
Clinical Presentation
More common in people with darker skin
Correlates with the configuration and distribution of the causative inflammatory dermatosis
Causes include inflammatory conditions, cutaneous injuries, irritants, or burns
Histologic Features
Decrease melanin of the basal keratinocytes
Upper dermal/submucosal melanophages
Sparse superficial lymphohistiocytic inflammation
Inflammatory cause may be coexisting
Differential Diagnosis
Sarcoidosis
Lichen sclerosus
Hypopigmented mycosis fungoides
Hypopigmented extramammary Paget’s disease
Hypopigmentation after medication
Vitiligo
Chemical leukoderma
Takeaway Essentials
Clinical Relevant Pearls
Correlates with distribution of the causative inflammatory dermatosis
Pathology Interpretation Pearls
Decreased melanin of the basal keratinocytes
Upper dermal/submucosal melanophages
Immunohistochemical/Molecular Findings
Fontana-Masson special stain may show decreased melanization of basal keratinocytes
Immunohistochemical melanocytic markers (MITF, HMB45, etc.) may show a decreased number of melanocytes
Vitiligo
Clinical Features
Vitiligo, an acquired leukoderma, is one of the most frequent disorders of pigmentation of the skin and is characterized by distinct areas of skin and mucous membranes depigmentation. It affects up to 2 % of the population, tends to be progressive, and is more common between the ages of 10 and 30 years with no predilection for either sex or ethnic origin. The genitalia are one of the most commonly affected areas along with the face, neck, body creases, scalp, and axillae [61]. Vitiligo can be divided in four subtypes, referred to as generalized, segmental or localized, universal, and acrofacial. The generalized type tends to be symmetric, whereas the localized form, which can follow a mosaic distribution, is more common in children and more difficult to treat [62, 63]. The Koebner phenomenon, where trauma triggers the development of vitiligo, is a common phenomenon in the generalized type [64].
A family history exists in 30 % of the patients. Vitiligo is considered to have primarily an autoimmune etiology [65, 66] as it is commonly associated with other diseases of autoimmune etiology such as Hashimoto’s thyroiditis, pernicious anemia, psoriasis, and lichen sclerosus [61]. The presence of anti-melanocyte antibodies supports the immune theory as an effector of melanocytic destruction. Patients with generalized form are more likely to have a concomitant autoimmune disease, whereas it is less frequent in patients with the localized, segmental (mosaic) form. Other theories implicate neural and cytotoxic factors, oxidant and antioxidant reactions, and alterations in melanocyte function in the pathogenesis of vitiligo; however, these mechanisms are not mutually exclusive and may exist in varied combinations [61].
On clinical examination, vitiliginous skin shows hypo- or depigmented macules and patches, sometimes with repigmentation that is frequently incomplete and ephemeral (Fig. 7.6). Ivory-white patches of skin with erythematous borders herald the initial stages and may indicate an ongoing inflammatory process. While hairs growing in patches of vitiligo are white, melanocytes sometimes remain in the hair follicles, resulting in tiny, annular rims of normally pigmented skin within the area of vitiligo. As vitiligo patients regain their pigmentation, the repigmentation process is believed to originate from these residual follicular (stem cell) melanocytes. Examination with the Wood’s light can greatly assist in revealing areas of hypo- and depigmentation [67]. Depigmented areas are brightly white in comparison to the subdued reflections of the hypopigmented areas by Wood’s light.
Histopathology
Vulvar skin affected by end-stage vitiligo is completely devoid of melanin within the basal keratinocytes, and melanocytes are entirely absent along the epidermal side of the basement membrane zone (Fig. 7.6). The ideal biopsy is taken through the edge of a lesion so that the vitiligo macule/patch can be compared with the adjacent normal skin. The edge of the vitiligo lesion may show a narrow zone of degenerating basal melanocytes and a lymphocytic infiltrate in the underlying papillary dermis and lower dermis hinting at the possibility that a local immune reaction is responsible for the melanocyte loss [65, 68]. Fontana-Masson or Warthin-Starry stain for melanin and immunohistochemical studies with various melanocytic markers such as S-100 protein, Mart1/MelanA, MITF-1, and HMB-45 are helpful in highlighting the differences in melanin content as well as the presence and density of melanocytes between normal and lesional skin samples (Fig. 7.6). In early vitiligo, some persistent melanocytes may be found, correlating with the clinically observed hypopigmentation instead of depigmentation. Since Langerhans cells are usually increased in vitiliginous skin, utilization of melanin/melanocyte-specific immunohistochemistry markers is recommended rather than the sensitive but nonspecific melanocyte marker S-100 protein, which could produce false-positive results [69].
Differential Diagnosis
In difficult cases, the differential diagnosis includes idiopathic guttate melanosis, tinea versicolor, post-inflammatory hypopigmentation, halo nevi, and regressing melanoma [61]. Histologically idiopathic guttate melanosis shows a decrease in melanin pigment and the number of melanocytes but never a complete absence of them; tinea versicolor, a fungal infection caused by Malassezia furfur, will demonstrate spores and hyphae within the stratum corneum; in post-inflammatory hyperpigmentation, melanophages in the upper dermis and a sparse superficial lymphohistiocytic infiltrate will be evident; halo nevi will show nevus cells in a dense lymphocytic infiltrate; and in regressing melanoma, areas of loose fibrosis, dilated vessels, lymphocytes, and melanophages will be noted adjacent to a malignant melanoma. In general none of the above entities will show a complete absence of melanocytes as seen in vitiligo. Sometimes in cases of depigmentation, it may be difficult to differentiate vitiligo from lichen sclerosus (Fig. 7.7). Both are autoimmune disorders and sometimes coexist in the same patient. However, vitiligo shows macular loss of pigment, whereas lichen sclerosus shows indurated, elevated white papules and plaques due to its hallmark sclerotic alteration of the dermis.
Summary
Clinical Presentation
Generalized, segmental/localized, universal, or acrofacial in distribution
Amelanotic macules and patches
Occasional repigmentation in vitiliginous skin
Histologic Features
Absence of melanin in keratinocytes
No melanocytes detected by light microscopy and immunohistochemistry
Absent to scant melanin in subjacent dermis/submucosa
Vacuolar interface alteration, but no significant inflammatory infiltrate
Differential Diagnosis
Idiopathic guttate melanosis
Tinea versicolor
Post-inflammatory hypopigmentation
Halo nevus
Regressing melanoma
Lichen sclerosus
Takeaway Essentials
Clinical Relevant Pearls
Ideal biopsy is from the edge to allow for comparison of normal and vitiliginous skin compared with adjacent normal skin
Pathology Interpretation Pearls
No melanocytes detected by light microscopy and immunohistochemistry
Immunohistochemical/Molecular Findings
Fontana-Masson or Warthin-Starry for melanin and immunohistochemical studies with various melanocytic markers such as S-100 protein, Mart-1, MiTF-1, and HMB-45 show absence of melanin and melanocytes in well-developed lesion
Melanocytic Nevi
Common Acquired Melanocytic Nevus
Clinical Features
Vulvar nevi are relatively uncommon, occurring in up to 2.3 % of women presenting with pigmented vulvar lesions [3–5]. In children, the prevalence of genital nevi is 3.5 %, with a male to female ratio of 1.3:1 [70]. Acquired nevi appear in early childhood and continue to develop into early adulthood. They can occur in modified mucous membranes or keratinized skin and virtually all are acquired [4, 70]. Usually they are solitary but occasionally can be multiple. In a consecutive series of 59 vulvar nevi, 12 % were junctional, 36 % compound, and 52 % intradermal [71]. Typically, common vulvar nevi are small in size (<7 mm), symmetric with regular borders, and uniformly tan to brown in color (Fig. 7.8). Rarely, they can have a bluish appearance due to dermal pigment. Vulvar nevi can be flat-topped, dome-shaped, or macular [7]. Nevi that vary from these characterizations require biopsy [9]. These deviations may well represent atypical vulvar melanocytic nevi, but melanoma must be excluded.
Fig. 7.8
Common vulvar junctional melanocytic nevus. Clinically, the pigmented macule could represent a genital melanotic macule, a junctional melanocytic nevus, or melanoma in situ. Twelve percent of vulvar nevi are junctional [71]
Histopathology
In general, on histologic examination, common vulvar melanocytic nevi display the same banal morphology without any cytologic atypia or unusual architectural patterns, indistinguishable from that of common nevi in other parts of the body [71] (Figs. 7.9, 7.10, and 7.11). Junctional melanocytic nevi are characterized by a proliferation of benign-appearing nevoid melanocytes arranged in solitary units and nests along the basement membrane zone of the epidermis with well-defined lateral margins and symmetric distribution. Although pure vulvar junctional melanocytic nevi are less frequently encountered under the microscope compared to compound and intradermal melanocytic nevi, the proportion of these three subtypes of common melanocytic nevi in the vulva does not differ significantly from the torso [71]. In compound melanocytic nevi, nests of benign-appearing nevoid melanocytes are present in the dermis in conjunction with an epidermal component. The dermal melanocytes usually do not display discernible pigmentation, although in rare cases, heavy pigmentation may be present focally in some superficial dermal nests. In addition to the absence of cytologic atypia and conspicuous mitotic activity, the dermal component demonstrates zonal maturation as the melanocytes become smaller and more spindled (instead of epithelioid) and lose cytoplasmic pigment (in cases with superficial heavy pigmentation) with descent into the deep dermis/submucosa. In intradermal melanocytic nevi, the melanocytes, depending on their extent into the dermis or submucosa, exhibit zonal maturation varying from junctional type A (epithelioid) melanocytes to superficial dermal type B (nevoid) melanocytes and deep dermal type C (spindle/neurotized) melanocytes. In contrast to atypical genital melanocytic nevi or dysplastic nevi, common vulvar nevi do not exhibit any architectural distortion or cytologically atypia.
Fig. 7.9
Vulvar junctional melanocytic nevus. A symmetric, circumscribed proliferation of type A melanocytes arranged as nests along the sides and bases of elongated rete ridges (a, b). The melanocytes are enlarged but cytologically banal; nests or melanocytes outnumber solitary melanocytes along the basement membrane zone (c)
Fig. 7.10
Vulvar polypoid lentiginous compound melanocytic nevus. Polypoid melanocytic nevi are common in the inguinal region and vulva; they are either compound or more frequently predominately intradermal with congenital features (melanocytes forming single files in the dermis/submucosa and surrounding adnexal structures) (a, b). Within the epidermis, melanocytes are arranged as either solitary cells or nests along the sides and bases of rete ridges (c, d)
Fig. 7.11
Common vulvar melanocytic nevus—predominately intradermal congenital pattern. The majority, approximately 88 % of genital nevi, are either compound or intradermal [71]
Differential Diagnosis
Clinically, vulvar melanocytic nevi can sometimes be difficult to differentiate from seborrheic keratosis, warts, pigmented vulvar intraepithelial neoplasia (VIN), or angiokeratomas; however, a biopsy can distinguish these entities from a vulvar melanocytic nevus without difficulty. Vulvar melanosis and lentigo simplex per definition do not show any melanocytic nests; the former shows an increase in dendritic melanocytes while the latter is associated with an increase in solitary, nevoid melanocytes along the sides of elongated, pigmented rete ridges. Nevoid melanoma of the anogenital region is rare but can be recognized by worrisome features such as deep dermal mitotic figures, absence of maturation, and subtle cytologic atypia [72, 73]. See Vignette 3 at the end of this chapter.
Summary
Clinical Presentation
Small in size (<5 mm)
Symmetric
Regular borders
Uniformly tan to brown in color
Histologic Features
No cytologic atypia
Maturation
Decreased pigmentation with descent
None to isolated mitotic figures
Differential Diagnosis
Seborrheic keratosis, warts
Pigmented VIN 3
Nevoid melanoma
Genital melanosis
Takeaway Essentials
Clinical Relevant Pearls
Small, symmetric, and uniformly tan to brown in color
Pathology Interpretation Pearls
Indistinguishable from common nevi in other parts of the body
Benign-appearing nevoid melanocytes
Well circumscribed with zonal maturation
Immunohistochemical/Molecular Findings
Positive for melanocytic markers such as S100-protein, Mart-1, and HMB-45 showing maturation: minimal or absence of expression of the antibody in the deep aspect of the lesion
Blue Nevus
Clinical Features
Blue nevus, common or cellular subtype, is very rare in the vulva but has been reported in a handful of cases [74–77]. Vulvar blue nevi are believed to arise from Schwann cells of stromal nerves/perineural precursor cells or from latent dendritic melanocytes which have migrated from the neural crest [17, 78] or from mutated precursor stem cells [79]. Clinically, it is gray blue in color, which has been attributed to the scattering of light by dermal collagen and transmission of the blue wavelengths (Tyndall effect).
Histopathology
The common blue nevus is composed of varied populations of heavily pigmented bipolar dendritic melanocytes and nonpigmented spindle cells within the dermis. The hallmark cells of blue nevus are the dendritic melanocytes, which are characterized by elongated, slender dendrites with cytoplasm containing variable but usually quite prominent, fine melanin granules (Figs. 7.12 and 7.13). They do not exhibit any pleomorphism and are located between dermal collagen bundles, which may appear slightly thickened. Melanophages are usually conspicuous but mitoses are absent. Of note, in a typical case of blue nevus, no melanocytic proliferation is identified in the overlying epidermis or epithelium.
Fig. 7.12
Vulvar blue nevus, dendritic and spindle cell type. Vulvar blue nevus composed of heavily pigmented bipolar dendritic/spindle cells within the dermis (a, b). No pleomorphism or mitotic figures are identified (c)
Fig. 7.13
Vulvar cellular blue nevi are cutaneous dermal melanocytic nevi that are rarely reported in the female genitalia. Marked cellularity and less pigmentation differentiate cellular from common blue nevus (a, c). Despite its cellularity, no worrisome findings are found such as mitotic figures, atypical cytology, or necrosis (b)
The cellular blue nevus is composed of spindle-type melanocytes that form a bulky nodule within the dermis, which commonly extends into the subcutaneous tissue in a characteristic dumbbell appearance. Typically, cellular blue nevus displays a biphasic pattern with clusters of clear, relatively light to nonpigmented spindle cells admixed with heavily pigmented spindle melanocytes. The tumor grows in an alveolar pattern with interspersed giant cells. Mitotic figures are sparse to absent. The spindle melanocytes may locally infiltrate superficial peripheral nerves and subcutaneous tissue, histologic features that should not be interpreted as malignancy [80]. A component of common blue nevus is frequently present at the periphery of the cellular nodule, whose recognition may facilitate the diagnosis of cellular blue nevus.
Another variant of blue nevus that can occur in genital mucosa is the epithelioid blue nevus [81]. This variant has been described mostly in patients with the Carney complex, but they may occur in isolation. Its pathognomonic features are polygonal epithelioid melanocytes situated within the dermis/submucosa that show no maturation with progressive depth of dermal infiltration. In contrast with the usual stromal changes in common blue nevi, epithelioid blue nevi exhibit no dermal fibrosis. In the genital region, no recurrence or metastasis has been reported and simple excision has been curative. However, epithelioid blue nevus is also known as pigmented epithelioid melanocytoma, which is a recently proposed term that encompasses melanocytic proliferations diagnosed as “animal-type melanoma” or “pigment-synthesizing melanoma.” This variant of melanocytic tumors is considered a low-grade melanocytic proliferation that can give rise to locoregional lymph node metastases and rarely to distant metastases [82, 83].
Lastly, atypical cellular blue nevus is an exceedingly rare variant of cellular blue nevus, which exhibits a combination of architectural atypia (deeply infiltrative border and/or asymmetry) or cytologic atypia (focal nuclear pleomorphism and hyperchromatism, bizarre cells, and increased mitotic activity). Although the atypical histologic and cytologic features of atypical cellular blue nevus are worrisome for a malignant melanocytic lesion, there are subtle clinical and morphologic differences between atypical cellular blue nevus and malignant blue nevus, its malignant counterpart [80]. However, there is a significant disagreement between experienced dermatopathologists in the diagnosis of atypical cellular blue nevus due to a lack of strict clinical and morphologic criteria for this variant of cellular blue nevus [84]. Of note, atypical cellular blue nevus has never been reported in the vulva [80]; however, malignant blue nevus has occurred in vulva [76]. Mitotic figures and significant cytologic atypia differentiate malignant blue nevus form atypical blue nevus [80].
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