Lymphedema and painless papules of the vulva

Case summary An 86-year-old woman with a history of urothelial bladder cancer currently on enfortumab and pembrolizumab presented with several months of painless papules on the bilateral labia majora, with the extension of induration to the lower abdomen. Computed tomography (CT) scan 2 months prior showed bladder wall thickening secondary to urothelial bladder cancer and subcutaneous edema in the anterior lower pelvis without enlarged lymph nodes or adnexal masses suggestive of metastatic disease. She had no history of transplant, abdominal surgery, or radiation. She wore incontinence garments for bouts of diarrhea. Physical examination revealed confluent firm and nontender pink plaques involving the bilateral labia majora, mons pubis, and lower abdomen (Fig. 1). There were 1–2 mm vesicles at the medial free margins of the clitoral hood. Punch biopsies of both the lower abdomen and right labium majus were performed with histopathologic features shown (Fig. 2).Fig. 1.: Bilateral labia majora, mons pubis, and lower abdomen with confluent indurated pink plaques. 1–2 mm vesicles at the medial free margins of the clitoral hood.Fig. 2.: 4 mm punch biopsies revealed pleomorphic cells with retraction artifacts and no contiguity with the epidermis. The cells demonstrated high mitotic activity and areas of lymphovascular invasion. The atypical cells were positive for GATA-3 and CK20.Question 1 What is the most likely diagnosis? A. Vulvar lymphedema B. Metastatic urothelial carcinoma C. Vulvar lymphangiomatosis D. Allergic contact dermatitis E. Drug-induced Crohn’s Disease Correct answer: B. Metastatic urothelial carcinoma. This diagnosis is supported by histopathologic findings of high mitotic activity, pleomorphism, lymphovascular invasion, and positive staining for GATA-3 and cytokeratin (CK) 20. The other answer choices would not demonstrate these histopathologic findings. Discussion Vulvar edema may be caused by infection, trauma, contact dermatitis, pregnancy, granulomatous inflammation, physical lymphatic obstruction, or malignancy.1 Edema pathophysiology involves an imbalance between fluid secretion and removal, resulting in excess interstitial fluid accumulation. This fluid imbalance may be from lymphatic obstruction, decreased plasma oncotic pressure, increased vascular permeability, or increased hydrostatic pressure. Most incidents of vulvar edema have been attributed to lymphatic obstruction.1 Given the patient’s history of urothelial bladder cancer, the vulvar lymphedema was initially attributed to physical obstruction from the pelvic tumor. A repeat CT scan of the abdomen/pelvis revealed unchanged asymmetric thickening of the urinary bladder wall, without lymphadenopathy or significant change from the CT scan 2 months prior. Dermatology was consulted for edema management, and a vulvar examination was performed with subsequent punch biopsies of the lower abdomen and right labium majus. Histopathologic examination demonstrated a malignant neoplasm with irregular nests of pleomorphic cells with retraction artifacts and no contiguity with the epidermis. The cells demonstrated pleomorphism and high mitotic activity and there were areas of lymphovascular invasion. The atypical cells were positive for GATA-3 and CK 20, which confirmed the diagnosis of urothelial cancer metastases to the vulva and lower abdomen. The clinical differential diagnosis included vulvar lymphangioma circumscriptum (LC), an uncommon condition characterized by benign dilation of lymphatic vessels in the skin and subcutaneous tissue which do not communicate with anatomic lymphatic vessels.2 Vulvar LC typically presents with multiple pseudovesicular lesions.2 Histopathologic examination helps differentiate this from other entities and shows acanthosis and epidermal hyperkeratosis, numerous dilated lymphatic channels, and eosinophilic proteinaceous material in the dermis and epidermis.2 Vulvar lymphedema secondary to Crohn’s disease was also considered but ruled out because of absent noncaseating granulomas on histology. Cutaneous metastasis of bladder urothelial carcinoma is an uncommon phenomenon, with an incidence of 0.84%.3 Metastasis can be hematogenous, lymphatic, iatrogenic, or from direct tumor invasion.3 The gross appearance of cutaneous metastasis can vary but is commonly associated with infiltrated plaques or nodularity of the genitals, suprapubic area, or lower abdomen.3 There are additional documented cases of cutaneous metastasis from urothelial carcinoma which manifested as edema of the lower extremities and umbilicus, erythematous and indurated plaques, and inguinal lymphadenopathy.3 These findings are nonspecific and may mimic other dermatologic conditions. Therefore, a biopsy with appropriate immunohistochemical staining is crucial for narrowing the differential diagnosis. CKs 7 and 20 are positive in approximately 89% of urothelial bladder cancers.3 This case highlights the importance of vulvar examination and a broad differential for vulvar edema. Patients with genital complaints should have a thorough genital and perianal examination, with the generation of a broad differential diagnosis and low threshold to biopsy for atypical or suspicious findings. Question 2 Which of the following is not a cause of inflammatory lymphedema? A. Allergic contact dermatitis B. Candidiasis C. Lymphatic filariasis D. Melkersson-Rosenthal syndrome E. Streptococcal infection Correct answer: C. Lymphatic filariasis.1 Lymphatic filariasis is the only answer choice that does not cause inflammatory lymphedema. All other answer choices can lead to inflammatory lymphedema. Question 3 Of the following, which is the most common cause of acquired vulvar lymphangiectases in all populations? A. Chronic bacterial cellulitis B. Crohn’s vulvitis C. Gynecologic malignancy D. Pregnancy E. Obesity Correct answer: C. Gynecologic malignancy.1 While the other or remaining answer choices are also sources of acquired vulvar lymphangiectasis, they are less common. Conflicts of interest None. Funding None. Author contributions All authors significantly contributed to the writing of this article. Patient consent Informed, written consent was received from all patients for whom photographs are present in the article.