Lichenoid dermatitis of the Vulva: Diagnosis and Differential Diagnosis for the Gynecological Pathologist

Transcription

1 Lichenoid dermatitis of the Vulva: Diagnosis and Differential Diagnosis for the Gynecological Pathologist Maria Angelica Selim, MD Professor of Pathology and Dermatology Duke University Medical Center Urogenital complains due to inflammatory process are among the most common problems encountered by family practitioners, gynecologists, and dermatologists (1). In response to the complexity of vulvar inflammatory disorders, the International Society for the Study of Vulvovaginal Disease (ISSVD) has created two classifications: one based on the pathologic inflammatory patterns (2006) (2) and the other using type of clinical primary lesions (2011) (3). These classifications do not exclude but complement each other. These classifications are available in the ISSVD website (issvd.org). Among these inflammatory diseases, lichenoid dermatoses in the vulva share a common dermatologic skin surface change: tightly adherent scale resembling lichen (lichen: plantlike organisms made up of an alga and a fungus growing in symbiotic association on a solid surface). Lichenoid in dermatology also refers to thick skin with pronounce cutaneous marks as seen in lichen simplex chronicus. Although these three inflammatory process in the vulva share some clinical changes, they belong to two different dermatopathologist inflammatory patterns: lichen simplex chronicus is part of the acanthotic pattern (epidermal acanthosis with irregular elongation of rete ridges) and lichen planus and lichen sclerosus are members of the lichenoid pattern (band like inflammation with vacuolar changes of the basal layer and dyskeratotic cells). This presentation will discuss in detailed each entity and the differential diagnosis as well as lichen sclerosus and differentiated VIN (vulva intraepithelial neoplasm). Lichen simplex chronicus (LSC): It denotes characteristic skin changes secondary to repeated scratch and or rubbing (4). Clinically present as thickened and erythematous scaly plaques with pronounced skin marks.

2 Associated hyperpigmentation and excoriations/ulcers are commonly identified. The most frequent location is the labia majora. Histologically is characterized by: 1) Hyperkeratosis with or without parakeratosis 2) Epidermal acanthosis 3) Hypergranulosis 4) Dermal fibrosis with collagen fibers localized perpendicular to surface 5) Perivascular chronic inflammation The differential diagnosis includes psoriasis. The latter in hair bearing skin shows hyperkeratosis with distinctive features not seen in LSC like confluent parakeratosis and present of neutrophilic collections in the stratum corneum (Munro microabscesses) and upper epidermis (Kogoj microabscesses). Another helpful feature is the presence of hypogranulosis instead of hypergranulosis as seen in LSC. Occasionally the differentiation is not easy to achieve as plaques of psoriasis may have superimposed changes of LSC due to scratching and rubbing. Examination of secondary events like superimposed fungal infection can explain in these patients the lack of treatment response. Lichen planus (LP): LP is a cell-mediated immune reaction affecting the hear-bearing and mucosal surfaces of the vulva. It affects middle-aged women (4 th to 7 th decade) with no ethnicity predisposition. Although the physiopathology behind this disease remains elusive, abnormal antigen in basal keratinocytes triggered by viruses, drugs or allogeneic cells may play a role in the development of the disease. Several clinical presentations are been described: hypertrophic, atrophic, linear, and bullous among others (1,5,6). Half of the women affected by this papulosquamous disease have genital involvement. The wide range of clinical presentations may be one of the reasons in the delay of its diagnosis. Although genital LP can affect hearing bearing skin, mucosal surfaces and/or combination; the most frequent presentation is the erosive form affecting mucosal or modified mucosal membranes. On the other hand, in the less common cutaneous form, it may be part of two types of presentations: one as part of generalized LP and the second one as a component of hypertrophic LP. The clinical lesions in generalized LP are well demarcated, erythematous to violaceous, flat-topped pruritic papules and plaques affecting the labia

3 majora as well as the mons pubis. Hypertrophic LP presents as hyperkeratotic white plaques frequently confused with malignancies. The mucosal LP, as vulvar cutaneous LP, has two types of presentations: reticulated and erosive type. Reticulated LP has the form of erythematous lines running crossed each other in an erythematous base. The latter is similar to the oral counterpart. Erosive LP has a characteristic bright red and eroded epithelium surrounded by reticulated white lacy plaques or Wickham striae (7). Diagnostic criteria for erosive LP have been recently published (8). This is a very symptomatic clinical presentation, with soreness, postcoital bleeding, dysuria and dyspareunia, leading to scarring. LP can affect the vaginal with shortening or narrowing of this organ. LP involving the oral-vaginal-vulvae mucosa is also known as the vulvovaginal gingival syndrome (9). The average clinical evolution encompasses a period of 1 to 2 years; however, mucosal manifestations may last longer. Some of the diseases associated with LP are: immunodeficiency states, malignancies, hepatitis C, hepatitis B and ulcerative colitis. Histologically, the features will vary depending on the area of involvement. The hair-bearing lesion shows: 1) Hyperkeratosis 2) V shaped hypergranulosis 3) Basal layer squamatization 4) Saw-toothed rete ridges 5) Basal layer hydropic degeneration 6) Civatte bodies formation 7) Band like (lichenoid) chronic inflammation in the upper dermis composed by lymphocytes 8) Melanin incontinence The mucosal or modified mucosal lesion shows: 1) Erosion/ulcer 2) Basal layer hydropic degeneration 3) Civatte bodies formation 4) Band like (lichenoid) inflammation composed of lymphocytes and plasma cells Step sections and/or special stains for microorganism (e.g. PAS and GMS) may be required to reach a final diagnosis due to the focal nature of the changes as well as the potential presence of secondary changes in the form of lichen simplex chronicus and/or fungal infection. The erosive

4 presentation of LP can be confused with a blistering disorder; therefore, a second biopsy for immunofluorescent tests can be further contributory in this differential diagnosis. The differential diagnosis includes: 1) Lichenoid drug reaction 2) Syphilis 3) Plasmacytosis mucosae 4) EMLA The presence of eosinophils in the infiltrate should alert of the possibility of LP-like eruption. Another finding seen in this type of drug eruption is the presence of deep perivascular inflammation. In addition, presence of plasma cells in a band like dermal infiltrate raises the differential diagnosis of syphilis and plasmacytosis mucosae (Zoon vulvitis). Immunohistochemical stain can help to evaluate for the presence of spirochetes. The minimal amount of dyskeratosis and the presence of endarteritis and deep perivascular inflammation support syphilis. Neutrophilic infiltrate (early lesions) and granulomatous infiltrate (late lesion) can also be seen. In plasmacytosis mucosae usually seen in the vestibule and labia minora has plasma cell infiltrate should be greater than 50%. Other inflammatory cells are also noted (e.g. neutrophils, eosinophils). Characteristic vascular proliferation in superficial dermis with red cell extravasation and/or hemosiderin is helpful for this diagnosis. There is also attenuation of the squamous epithelium with mild spongiosis with loss of granular and corneal layers. A local anesthetic, EMLA, can mimic the vacuolar changes seen in LP. Focal histologic changes similar to those seen in LP in the absence of clear clinical presentation should prompt the request of the type of anesthetic used previous to the biopsy (10). The presence of chronic LP can be associated with the precursor lesion differentiated VIN. These patients also have an increased risk of developing squamous cell carcinoma, specially around the clitoral area (11-13). Therefore, clinical follow-up in these patients is seminal to detect early dysplastic lesions. Lichen sclerosus (LS): LS is a chronic sclerotic dermatosis involving the genital and extra-genital skin. It has a bimodal peak in incidence affecting prepubertal girls and postmenopausal women (14). It affects 2-3% of

5 women presenting to gynecologist and it is the most common dermatosis seen in vulvar clinics. Although the etiology is not completely understood, infections, autoimmunity and environmental factors have been implicated (15). It can be associated with differentiated VIN (vulva intraepithelial neoplasm) and squamous cell carcinoma (16). Clinical genital lesions have a classic eight figure involving the vulva (clitoris, prepuce, frenulum, labia minora and vestibule) and anal region in the form of a porcelain white, scaly plaque with wrinkle surface. In 20% of the cases extra-genital involvement (e.g. arm and trunk) can be seen (14). Due to the intense pruritus, secondary changes of lichen simplex chronicus are detected in these patients. Beside itchy, frequent complains are dysuria, rectal bleeding and painful defecation. Of note, there is poor correlation between signs and symptoms. LS has a chronic clinical course with episodes of relapse and remission. Childhood LS can be confused with child abuse; however, they are not mutually exclusive and in a review of 42 cases of prepubertal LS, 28% presented with evidence of child abuse (17). Histologic features will depend on the age of the lesion and the location of the biopsy. Early lesion: 1) Psoriasiform epidermal hyperplasia with hyperkeratosis 2) Lymphocytes peppering the epidermis 3) Basal vacuolar alteration of the epidermis 4) Dyskeratotic cells 5) Band like lymphocytic infiltrate with scattered histiocytes Established lesion: 1) Atrophic epidermis with rete effacement 2) Vacuolar changes of the basal layer 3) Dyskeratotic cells 4) Superficial dermal edema 5) Sclerotic/hyalinized collagen bundles 6) Vascular drop-out and vascular ectasia of the remaining vessels 7) Bundle of lymphocytic infiltrate underneath the dermal sclerosis Previous to the early inflammatory lesion, the presence of epidermal hyperplasia, epidermotropism of lymphocytes and basement membrane thickening are helpful features in detecting LS (18).

6 Frequently superimposed changes of lichen simplex chronicus in the form of hyperkeratosis and hypergranulosis and epidermal acanthosis can be identified. Ancillary tests include the performance of elastic van Gieson (EVG) stain to highlights the decreased of elastic fibers. The differential diagnosis includes: 1) Radiation dermatitis 2) Lichen planus 3) Differentiated VIN (vulva intraepithelial neoplasia) In radiation dermatitis the presence of atypical endothelial cells and fibroblasts can be helpful diagnostic clues not seen in LS. In this disease also the sclerotic collagen is admixed with elastotic material. However, clinical history is seminal in this differential diagnosis. LS can be associated with vulva intraepithelial neoplasm (VIN), differentiated type (d-vin). On average d-vin can be estimated to comprise approximately 10% of the vulvar non-invasive neoplastic epithelial lesions. Although it could be a rare occurrence, it is suspected to have a higher incidence with the difficulty to identify the lesion contributing to under recognition of the condition. It is also possible that a rapid rate of progression to invasive carcinoma reduce the chances to diagnose this disease. The clinical appearance of dvin and the associated symptoms are very similar to those described in HPV related HSIL (high grade squamous intraepithelial lesion (19)); however the demographic of the affected patient is different specially affecting older women (mean age years) (20,21). Beside the age difference, dvin has a tendency to be less frequently multifocal (22-26) and most frequently it shows ill defined borders. Although the pathway of disease development from LS to dvin is still elusive, it is proposed that the chronic tissue damage from inflammation may play a role. Rare cases of HPV positive lesions have been reported, however, it does not appear to have any role in the development of d-vin (22,27). D-VIN is considered more aggressive than HPV related HSIL as evidence points to a more likely progression to invasion and appears to do so at a shorter period (23,28). The average rate of progression to invasive cancer is published in the literature at approximately 33% for d-vin, with

7 percentages as high as 85.7% (20,29). On the other hand, invasive carcinoma is detected in resections performed for the diagnosis of d-vin in a reported 20.5% to 83.3% of the cases (30). The median time from dvin to SCC is of approximately 22.8 months (31). Pathogenesis and clinical outcomes of HPV HSIL and d-vin lesions appears to be different; therefore treatments also vary with d-vin been undergoing larger excisions due to its strong association with invasive squamous cell carcinoma (24). D-VIN is notorious for being difficult to diagnose due to the subtle histologic changes. Opposite to HPV related HSIL, in d-vin the most atypical cells are located in the basal and parabasal layers of the epithelium; while the superficial layers appears nearly normal increasing the chances for failing to notice this lesion. D-VIN shows a paradoxical maturation with increase proportion of mature more differentiated cells rather than the little evidence of maturation seen in HPV related HSIL. Thus, the term differentiated used to refer to this lesion. Histologically, d-vin is characterized by: 1) Basal layer expanded by a population of atypical basal and parabasal cells with hyperchromatic enlarged nuclei with prominent nucleoli 2) These cells contains abundant hypereosinophlic cytoplasm indicating premature keratinization and differentiation 3) Mitotic figures, some atypical 4) Epithelium frequently acanthotic 5) Elongated and branched rete ridges with anastomosing pattern Early invasion will be evident, like in HPV related lesions, by disruption of the normally smooth basement membrane border by tongues and irregularly shaped nests or single cells. Because of the morphologic challenge d-vin present, there is significant attention on identifying diagnostic markers. Immunohistochemical study for p53 is reported as immunoreactive in the majority of the basal cells with superficial extension of the reactivity in 66% to 85% of d-vin. In addition, p53 stain has been identified in a quarter of normal vulvar epithelium and in up to 80% of LS cases (27) (32). While p53 study may be of value in confirming the diagnosis it appears to be neither sensitive nor specific as a marker, and results must be interpreted with caution. Morphology remains seminal to reach the diagnosis. The abnormal cells of d-vin are restricted to the basal and parabasal layers parallel to KI-67 expression (33). Therefore, the localization of the marker is not informative, but higher proportion of

8 cells is reactive to this marker in d-vin. As d-vin is not classically associated with HPV, p16 staining is typically negative in d-vin. Lifelong surveillance after therapy is of utmost importance as excision of the lesion does not a ensure prevention for invasive cancer. Bibliography: 1. Lewis FM, Shah M, Harrington CI. Vulval involvement in lichen planus: a study of 37 women. Br J Dermatol Jul.;135(1): Lynch PJ International Society for the Study of Vulvovaginal Disease classification of vulvar dermatoses: a synopsis. Journal of Lower Genital Tract Disease Jan.;11(1): Lynch PJ, Moyal-Barracco M, Scurry J, Stockdale C ISSVD Terminology and classification of vulvar dermatological disorders: an approach to clinical diagnosis. Journal of Lower Genital Tract Disease Oct.;16(4): O'Keefe RJ, Scurry JP, Dennerstein G, Sfameni S, Brenan J. Audit of 114 non-neoplastic vulvar biopsies. Br J Obstet Gynaecol Oct.;102(10): Lewis FM. Vulval lichen planus. Br J Dermatol Apr.;138(4): McPherson T, Cooper S. Vulval lichen sclerosus and lichen planus. Dermatol Ther Aug.;23(5): Mann MS, Kaufman RH. Erosive lichen planus of the vulva. Clinical Obstetrics and Gynecology Sep.;34(3): Simpson RC, Thomas KS, Leighton P, Murphy R. Diagnostic Criteria for Erosive Lichen Planus Affecting the Vulva: An international electronic- Delphi Consensus Exercise. Br J Dermatol Mar. 23; 9. Eisen D. The vulvovaginal-gingival syndrome of lichen planus. The clinical characteristics of 22 patients. Archives of Dermatology Nov.;130(11):

9 10. Lewis FM, Agarwal A, Neill SM, Calonje JE, Stefanato CM. The spectrum of histopathologic patterns secondary to the topical application of EMLA on vulvar epithelium: clinicopathological correlation in three cases. J. Cutan. Pathol Aug.;40(8): Dwyer CM, Kerr RE, Millan DW. Squamous carcinoma following lichen planus of the vulva. Clin. Exp. Dermatol Mar.;20(2): Franck JM, Young AW. Squamous cell carcinoma in situ arising within lichen planus of the vulva. Dermatol Surg Oct.;21(10): Zaki I, Dalziel KL, Solomonsz FA, Stevens A. The under-reporting of skin disease in association with squamous cell carcinoma of the vulva. Clin. Exp. Dermatol Sep.;21(5): Smith YR, Haefner HK. Vulvar lichen sclerosus : pathophysiology and treatment. Am J Clin Dermatol. 2004;5(2): Ball SB, Wojnarowska F. Vulvar dermatoses: lichen sclerosus, lichen planus, and vulval dermatitis/lichen simplex chronicus. Semin Cutan Med Surg Sep.;17(3): Carlson JA, Ambros R, Malfetano J, Ross J, Grabowski R, Lamb P, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Human Pathology Sep.;29(9): Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus: an increasingly common problem. Journal of American Dermatology May;44(5): Lester EB, Swick BL. Eosinophils in Biopsy Specimens of Lichen Sclerosus: a not uncommon finding. J. Cutan. Pathol Nov. 18; 19. Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, 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

10 American Society for Colposcopy and Cervical Pathology. Journal of Lower Genital Tract Disease Jul.;16(3): Scurry J, Campion M, Scurry B, Kim SN, Hacker N. Pathologic audit of 164 consecutive cases of vulvar intraepithelial neoplasia. International Journal of Gynecological Pathology Apr.;25(2): van de Nieuwenhof HP, van der Avoort IAM, de Hullu JA. Review of squamous premalignant vulvar lesions. Crit. Rev. Oncol. Hematol Nov.;68(2): MD MP, MD JS, MD CEM, MD LM. Vulvar intraepithelial neoplasia. Best Pract Res Clin Obstet Gynaecol Oct. 1;28(7): Van De Nieuwenhof HP, Massuger LFAG, Van Der Avoort IAM, Bekkers RLM, Casparie M, Abma W, et al. Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age. Eur. J. Cancer Mar.;45(5): Terlou A, Blok LJ, Helmerhorst TJM, van Beurden M. Premalignant epithelial disorders of the vulva: squamous vulvar intraepithelial neoplasia, vulvar Paget's disease and melanoma in situ. Acta Obstet Gynecol Scand Jun.;89(6): de Bie RP, van de Nieuwenhof HP, Bekkers RLM, Melchers WJG, Siebers AG, Bulten J, et al. Patients with usual vulvar intraepithelial neoplasia-related vulvar cancer have an increased risk of cervical abnormalities. Br. J. Cancer Jul. 7;101(1): McCluggage WG. Recent developments in vulvovaginal pathology. Histopathology Jan.;54(2): Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis. Journal of Clinical Pathology Jan. 7; 28. Eva LJ, Ganesan R, Chan KK, Honest H, Luesley DM. Differentiatedtype vulval intraepithelial neoplasia has a high-risk association with vulval squamous cell carcinoma. Int. J. Gynecol. Cancer May;19(4):

11 29. Skapa P, Zamecnik J, Hamsikova E, Salakova M, Smahelova J, Jandova K, et al. Human papillomavirus (HPV) profiles of vulvar lesions: possible implications for the classification of vulvar squamous cell carcinoma precursors and for the efficacy of prophylactic HPV vaccination. Am. J. Surg. Pathol Dec.;31(12): Mulvany NJ, Allen DG. Differentiated intraepithelial neoplasia of the vulva. International Journal of Gynecological Pathology Jan.;27(1): Preti M, Scurry J, Marchitelli CE, Micheletti L. Vulvar intraepithelial neoplasia. Best Pract Res Clin Obstet Gynaecol Jul. 18; 32. Carlson BC, Hofer MD, Ballek N, Yang XJ, Meeks JJ, Gonzalez CM. Protein Markers of Malignant Potential in Penile and Vulvar Lichen Sclerosus. JURO Aug. 1;190(2): Scurry J, Beshay V, Cohen C, Allen D. Ki67 expression in lichen sclerosus of vulva in patients with and without associated squamous cell carcinoma. Histopathology May;32(5):