Case 8 -

Pemphigus Vulgaris presenting with genital ulceration, with cervical cytology Dr. Gladwyn Leiman

Clinical History: Cervical Smear: A 43-year-old female was seen with a one month history of dyspareunia and an offensive vaginal discharge. The cervix appeared inflamed and hemorrhagic; a Pap smear was taken. Case 8 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Cytological Findings: The smear was markedly hypercellular, with a focally bloodstained background. The parabasal-sized abnormal cells lay singly and in loosely cohesive sheets. Their cytoplasm was dense and well defined, even within the sheets. Nucleo-cytoplasmic ratios were increased, but nuclear outlines appeared extremely smooth. The chromatin was vesicular to mildly granular, with 1-3 very prominent nucleoli visible. Numerous normal mitotic figures were identifiable. The cytologic features were similar to those seen in repair, except for the striking predominance of single cells. The diagnosis rendered was that of at least atypical squamous cells of uncertain significance (ASCUS), with a note appended indicating that the cytologic features were extremely unusual and that invasive carcinoma could not entirely be excluded. Biopsy was suggested in view of the clinical presentation, as well as the cytologic abnormality. Biopsy and Clinical features: The patient was referred to the Colposcopy Clinic, at which time extensive erosions of the cervix were noted macroscopically. Colposcopy indicated a highly vascular pattern, not characteristic of intraepithelial neoplasia or invasion. The erosions were geographically extensive over the cervix and the upper vagina. A colposcopically-directed biopsy showed classical acantholytic bullae of Pemphigus vulgaris. In areas, there was complete denudation of the surface epithelium, with free lying acantholytic cells and conspicuous vilification in relation to the blister floor. Areas of subtotal epithelial denudation were flanked by zones of incipient suprabasal acantholysis. Direct immunofluorescence performed on the cervical biopsies revealed 3+ intercellular fluorescence for IgG and C3. Indirect immunofluorescence studies revealed 2-3+ epidermal intercellular fluorescence. These findings were diagnostic of Pemphigus vulgaris. The patient was recalled for further re-evaluation; she was a member of the auxiliary staff of the hospital, and returned quickly. Within days of the prior biopsy, it was found that the erosions and blisters of the cervix were now so extensive and so painful that a general anesthetic was required to visualize the cervix properly. Pressure on the cervix and vaginal wall elicited a positive Nikolsky sign. In addition, the patient had by this time developed extensive ulceration of the oral mucosa, with superimposed Candidiasis. There was no cutaneous involvement. Oral steroids were prescribed and within one month the patient showed complete regression of oral and genital lesions. Pemphigus Vulgaris presenting with genital ulceration, with cervical cytology Discussion: Pemphigus vulgaris is an autoimmune disease characterized by vesiculo-bullous lesions of skin and mucosal surfaces. The mucosal lesions have been described in esophagus, conjunctiva, larynx, urethra, vulva and cervix. Individual case reports exist in the cytologic literature; most current texts mention the entity and caution that the cytologic features may mimic malignancy. In almost all cases, however, the diagnosis of generalized or oral pemphigus vulgaris is known prior to involvement of the cervix. The case presented here is unusual in that the cervicovaginal changes preceded oral lesions, and also unusual in that no dermal lesions appeared. At the time this case was initially encountered, it appeared to be the first on record in which the diagnosis was made on cervicovaginal lesions prior to more usual oropharyngeal presentation. Pemphigus vulgaris is characterized by formation of suprabasal acantholytic vesicles and blisters (bullae). Recent evidence regarding pathogenesis points to an autoantibody against a Cadherin-like cell adhesion molecule on the surface of stratified squamous epithelial cells. The resulting flaccid blisters break easily, forming erosions and ulcers. The mere scraping of a cervix by a spatula is sufficient to break the overlying mucosal and obtain cellular samples from these lesions. The Nikolsky sign refers either to pressure applied to a Pemphigus blister leading to its easy extension and enlargement, or to pressure on adjacent normal mucosa or skin causing the epidermis to be dislodged. Cervical involvement may be more common than apparent, because Pemphigus is usually treated by dermatologists, who rarely examine the genitalia. The cytology of cervicovaginal smears is similar to that of scrapings from oral vesicles. The component cells have been termed "Tzanck cells"; they perfectly mirror the loose-lying intra-bullous cells seen on histology. Smears are typically hypercellular, with extremely active nuclear chromatin features including mitotic figures and large irregular nucleoli. Classically, the nucleoli are said to be "bullet-shaped", but this was not an obvious feature in the current case. Despite the highly "malignant" single cell exfoliation, and background blood, there is no true tumor diathesis. Immunocytochemistry using E-cadherin permits specific diagnosis. If this is not available, immunofluorescence for IgG and C3 is diagnostic. Finally, it should be noted that there have been three reports of patients with Pemphigus of the cervix in whom genital malignancy has been diagnosed. Two cases of micro-invasive squamous cell carcinoma of the cervix have been seen, as has one case of endometrial carcinoma. Cautious examination of the patient and screening of the smear are therefore required, even if the characteristic cytologic features of Pemphigus vulgaris are overwhelming. References: Mikhail GR, Drukker BH, Chow C. Pemphigus vulgaris involving the cervix uteri. Arch Dermatol 1967;95:496-498. Kaufman RH, Watts JM, Gardner HL. Pemphigus vulgaris: genital involvement. Report of two cases. Obstet Gynecol 1969;33:264-266. Libeke JH. The cytology of cervical pemphigus. Acta Cytol 1970;14:42-44. Krain LS, Rosenthal L, Newcomer VD. Pemphigus vulgaris involving the cervix associated with endometrial carcinoma of the uterus: a case report with immunofluorescent findings. Int J Dermatol 1973;12:220-228. Friedman D, Haim S. 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