Rajal Patel, MD

A 38-year-old nulligravid woman has experienced worsening itchy and uncomfortable vulvar lesions over seven years. Initially, the lesions were small and scant. She was clinically diagnosed with genital warts, but various topical agents failed to stop the growth and spread of the lesions. She had never tested positive for HPV. Her medical history is significant for obesity, polycystic ovary syndrome, and asthma. Exam showed thick, rough, pink, and white warty projections along the mons and labia majora with mild underlying edema. The rest of the vulvar exam was normal.

Lymphangioma circumscriptum (LC) or microcystic lymphatic malformation presents as clusters of pseudo-vesicles usually on the labia majora or mons pubis. The blisters contain serous or slightly-blood tinged fluid. In 1975, Moschelia et al. described the clinical presentation of this condition as one resembling “frog spawn.”

 LC can occur on the abdomen, axillae, genitalia, and mouth.

 In addition to the blistering, the vulva may be swollen and painful.

The diagnosis of LC is made by biopsy. A Keyes punch biopsy should be sufficient. We recommend an accompanying photograph for your pathologist to review as well. On histology, LC shows dilated lymphatics in the epidermis and the papillary dermis. The dilated lymphatics contain red and white blood cells.

When considering LC as a diagnosis, it is important to include infectious causes such as condylomata acuminata, molluscum contagiosum, and pelvic tuberculosis in your differential diagnoses. Similarly, lymphedema can manifest in patients with cutaneous Crohn disease and those with a history of pelvic cancers who have undergone surgery and pelvic radiation.

LC is a benign lymphatic malformation characterized by dilation of lymphatic vessels in the skin and subcutaneous tissue. There are two types of disease: congenital and acquired. Congenital LC usually appears soon after birth, whereas the acquired version occurs later in life. Acquired LC is found more commonly on the vulvar region.

 The exact etiology of either type is unknown. 

Interestingly, LC can be identified in patients with Klippel-Trenaunay syndrome (KTS). KTS is a relatively rare congenital vascular anomaly classically defined as the triad of vascular stain, venous varicosities, soft tissue, and/or bony hypertrophy. Many cases of KTS are mixed malformations with capillary, lymphatic, and venous elements.

Traditionally, the treatment of LC is surgical excision. We recommend 0.5 cm margins laterally around the disease. It is important to excise all of the tissue down to the fascia

 unless a skin graft is being performed. In this situation, a small amount of fat needs to remain for the skin graft to “take.” Often, a flap is required. 

Therefore, collaboration with a plastic surgeon and/or referral for management in these situations may be needed. Other treatments that have been proposed are laser therapy, sclerotherapy, and cryosurgery.

 The recurrence rate is directly proportional to the original lesion size. Surgical excision has a lower risk of recurrence compared to other methods.

 However, due to the nature of LC, it will tend to recur if the original lesion is not fully excised.

LC is not thought to have an isolated cancer risk but could be related to underlying cancer recurrence.

 However, Bae et al. identified a case series of 2 out of 16 patients with existing HPV-related cervical cancer who demonstrated new vulvar high-grade squamous intraepithelial neoplasia in vulvar LC.

 Appropriate evaluation with the patient’s oncologist should be considered in this setting.

Finally, patients may have some concerns about their personal appearance with this condition and any psychosocial concerns should be addressed. 

. Philadelphia, PA: WB Saunders Company; 1975.

2. James W, Berger T, Elston D, eds. Dermal and Subcutaneous Tumors. In: 

Andrew’s Diseases of the Skin: Clinical Dermatology

. 11th ed. Philadelphia, PA: Elsevier Inc; 2011:579.

3. Vlastos A, Malpica A, Follen M. Lymphangioma circumscriptum of the vulva: a review of the literature*1. 

. 2003;101(5):946-954. doi:10.1016/s0029-7844(03)00048-6

Lymphangioma Circumscriptum of the Vulva: Report of a Rare Case.

 Journal of Mid-life Health 6, 91-93 (2015). http://10.0.16.7/0976-7800.158968.

5. Maari C, Frieden IJ. Klippel-Trénaunay syndrome: The importance of “geographic stains” in identifying lymphatic disease and risk of complications. 

. 2004;51(3):391-398. doi:10.1016/j.jaad.2003.12.017

6. Haroon S, Hasan SH. Lymphangioma circumscriptum in the scrotum: A case report. 

7. Lai CH, Hanson SG, Mallory SB. Lymphangioma circumscriptum treated with pulsed dye laser. 

. 2001;18(6):509-510. doi:10.1046/j.1525-1470.2001.1862001.x

8. Browse N, Whimster I, Stewart G, Helm C, Wood J. Surgical management of ‘lymphangioma circumscriptum’’.’ 

9. Valente K, Montgomery K, Schultenover S, Desouki MM. Acquired vulvar lymphangioma circumscriptum after cervical cancer treatment: Case report. 

. 2016;16:31-33. doi:10.1016/j.gore.2016.03.006

10. Bae G, Yoon G, Song Y, Kim H. High-grade squamous intraepithelial lesion arising adjacent to vulvar lymphangioma circumscriptum: a tertiary institutional experience. 

Articles

Could you recognize this rare vulvar condition?

Lymphangioma circumscriptum

A 55-year-old woman presented to her hematologist/oncologist 56 days after a bone marrow transplant for acute myeloid leukemia (AML). 

The patient was immunosuppressed with methotrexate and tacrolimus to prevent graft versus host disease (GVHD). 

She complained of poor appetite, weight loss, and diarrhea. She was found to have elevated liver function tests and bilirubin and hospitalized for evaluation, which included esophagogastroduodenoscopy (EGD) and flexible sigmoidoscopy. 

The patient was diagnosed with GVHD of the colon and started on intravenous (IV) steroids for the treatment of acute GVHD. Chest x-ray was concerning for pneumonia. She was started on piperacillin/tazobactam. She was found to have cytomegalovirus viremia and was started on ganciclovir.

Two weeks after admission, the patient developed vulvar pain. 

Vulvar examination showed small ulcerations measuring 3 mm in the largest diameter. 

One day later, the lesions enlarged to 1 to 3 cm, with subepithelial hemorrhage on the labia majora and labia minora (Figure 1). The patient’s vulva was exquisitely tender. Her feet contained large bullae. Figure 2 shows a ruptured bulla in the medial aspect.

The patient was afebrile, with normal vital signs. Laboratory investigation revealed a normal white blood cell count.

 She was anemic (hemoglobin 8.8 g/dL) and thrombocytopenic with a platelet count of 20 K/µL, secondary to previous bone marrow transplant.

A yeast culture and aerobic culture were obtained. A punch biopsy of the vulva was performed for histologic evaluation and tissue culture. Two days later, the yeast culture grew Rhizopus. 

The organism also was identified on pathology staining from the patient’s punch biopsy, which showed abundant fungal elements morphologically consistent with Rhizopus infection (Figure 3).

The patient was placed on IV amphotericin B. Unfortunately, the appearance of her vulva worsened rapidly—becoming edematous, with subcutaneous hemorrhage progressing to necrotic tissue. 

A decision was made to proceed to the operating room secondary to rapid deterioration. A partial vulvectomy was performed and the excision was carried down to the fascia to remove all of the necrotic tissue (Figure 4). 

An adequate margin of normal tissue was taken to ensure that the area of disease was effectively debrided. Platelets were administrated intraoperatively for thrombocytopenia. 

The patient’s estimated blood loss was 100 cc. Pathology revealed abundant fungal elements morphologically consistent with the previously cultured Rhizopus specimen.

Postoperatively, the patient’s dressing was changed twice a day with 4x4 gauze soaked with amphotericin B. Her wound was healing well. 

However, on postoperative day 4, multiple new erythematous, tender lesions (similar in appearance to the initial vulvar lesions) were noted on the patient’s left upper extremity, left scapula, and bilateral lower extremities (Figure 5). 

A punch biopsy of her leg lesions was consistent with a deep fungal infection morphologically consistent with Rhizopus. 

A computed tomography scan indicated potential fungal infection in the kidneys and interval development of nodular opacities in the lungs. The dose of amphotericin B was increased to 10 mg/kg and micafungin was added secondary to the dissemination of Rhizopus, likely due to hematogenous seeding of the lesions. 

The patient’s condition continued to deteriorate and she died 9 days after surgery.

Rhizopus is the most common species of the order Mucorales.

 Mucormycosis occurs most often in immunocompromised patients, including individuals with hematological malignancies. It has also been associated with diabetes.

Epidemiological studies suggest that the incidence of mucormycosis has significantly increased in the past 30 years.

 A high mortality rate is reported across studies, which may be secondary to a lack of antifungal agents with adequate activity against the class zygomycetes. 

Vulvar mucormycosis is a rare entity; only three cases of Rhizopus infection on the vulva have been reported previously.

Hematopoietic stem cell transplant recipients run a high risk of developing invasive fungal infections during the immediate post-transplant and the pre- and post-engraftment periods, as well as up to 3 months after transplantation.

This was the case with our patient, who presented with Rhizopus infection of the vulva 56 days after a bone marrow transplant for AML. A review of 929 mucormycosis cases revealed skin as the third most common site infected, representing 19% of mucormycosis infections, whereas 39% were located in the sinuses and 24% in the lungs.

Cutaneous mucormycosis typically results from direct spore inoculation or exposure of compromised skin (e.g., burns or trauma). 

Cutaneous mucormycosis can present as pustules, bullae, nodules, ulcers, necrotizing cellulitis, granulomatous pyoderma, bulls-eye cutaneous infarcts, and, rarely, zosteriform lesions.

The hallmark of disease is tissue necrosis resulting from angioinvasion and subsequent thrombosis. Black necrotic eschars are common in affected tissues,

 which can extend into deep fascia and muscle layers. Necrotizing fasciitis has also been reported in association with this condition.

A high index of suspicion is required for rapid and timely diagnosis of invasive mucormycosis. 

Even if the cutaneous location observed upon mycological examination and/or pathologic analysis facilitates diagnosis, this rare condition is often not initially considered.

 Fungal growth alone is insufficient, as it may represent colonization or contamination; histopathological evidence of invasive disease is required. 

Related: Test your knowledge of Rhizopus with this quick quiz. 

So far, there has not been enough evidence that identification of mucormycosis to the genus and/or species level helps guide antifungal treatment.

 Rapid and exact diagnosis by both morphology and molecular techniques is crucial for starting early treatment of fungal infection.

Invasive disseminated Rhizopus infections develop in around 25% of patients who present with localized infection.

 Although hematogenous dissemination to the skin is rare, cutaneous infections are often complicated by deep extension or dissemination by secondary vascular invasion.

In a review by Roden et al., 78 of 176 cases (44%) of cutaneous mucormycosis showed extension to bone, tendon, or muscle—or even hematogenous dissemination.

Dissemination of infection resulted in an increase in overall mortality that approached 90%, compared to approximately 30% in localized cutaneous mucormycosis.

Due to the invasive aspect of the infection and the potential for disseminated disease, imaging should be performed promptly to detect other possible sites of infection independent of the initial location.

In our case, the later involvement of lung and kidneys classifies it as a case of disseminated infection.

The European Society for Clinical Microbiology and Infectious Diseases and the European Confederation of Medical Mycology have released comprehensive guidelines for the management of mucormycosis.

Whenever possible, early and aggressive surgical debridement is strongly recommended to be combined with immediate first-line antifungal treatment, because the procedure yields greater than a 1.5-fold increase in survival rates.

The rapid reversal of predisposing conditions, such as using granulocyte colony-stimulating factor in patients with ongoing neutropenia, controlling hyperglycemia and ketoacidosis in diabetic patients, and limiting glucocorticosteroids to the minimum dose required, may be useful.

This is an aggressive infection that targets and destroys local vasculature, preventing the delivery of systemic antimicrobial/antifungal therapy.

If treatment is delayed, proliferation and dissemination of angioinvasive Mucorales will result in thrombotic necrosis of tissues, thus limiting adequate delivery of antifungal agents to the sites of infection.

 This is especially true when the infected cutaneous site is highly vascularized, such as the vulva.

Multiple procedures may be necessary, and the need for skin grafting or other wound closure techniques should be individualized.

Zimmermann et al. presented a case of mucormycosis of decubitus ulcers, which demonstrated that intraoperative analysis of frozen section slides was a valuable tool for assessing skin and soft tissue margins for fungal infection (68.4 % sensitivity and 100% specificity).

However, in our case, surgical debridement in addition to amphotericin B resulted in local improvement, but the patient died 9 days after her surgery due to her underlying disseminated Rhizopus infection.

Amphotericin B is clinically effective for treatment of these infections, with response rates of 39% to 71%.

However, the potential for long-term nephrotoxicity remains a concern. 

The current guidelines from the European Conference on Infections in Leukemia state that first-line treatment should be initiated with lipid formulations of amphotericin B.

The recommended dose is 5 mg/kg/day for patients without central nervous system (CNS) involvement and 10 mg/kg/day for patients with CNS involvement, for at least 6 to 8 weeks.

 The optimal dose or duration of therapy remains debatable in the absence of prospective comparative studies. It can be continued for weeks until a positive clinical outcome and/or negative mycological culture results occur.

There is also some evidence to suggest that posaconazole and isavuconazole are best reserved for de-escalation, refractory cases, or patients intolerant to amphotericin B.

 A combination of amphotericin B and echinocandins may be beneficial after failure of first-line treatment.

Antifungal susceptibility testing is important in understanding susceptibility patterns, although most data come from morphologically identified isolates.

The prognosis of patients with mucormycosis is poor. Mortality rates up to 94% have been reported in patients with hematogenous dissemination.

 This underscores the importance of early aggressive therapy.

In our patient, early dissemination was present, which significantly lowered the chance of survival. 

Image credit: Courtesy of Dr. Hope Haefner

1.Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. 

2. Non L, Sta Cruz JP, Tuazon S. Sudden death in a patient with bone marrow transplant by a fungus among us. 

3.Bitar D, Lortholary O, Le Strat Y, et al. Population-based analysis of invasive fungal infections, France, 2001-2010. 

4.Jeong SJ, Lee JU, Song YG, Lee KH, Lee MJ. Delaying diagnostic procedure significantly increases mortality in patients with invasive mucormycosis. 

5.Nomura J, Ruskin J, Sahebi F, Kogut N, Falk PM. Mucormycosis of the vulva following bone marrow transplantation. Bone Marrow Transplant 1997;19:859-60.

6.Colon M, Romaguera J, Mendez K, Vilchez D, Navas EJ, Perez J. Mucormycosis of the vulva in an immunocompromised pediatric patient. 

 et al. Cutaneous mucormycosis in a patient with lupus nephritis: A case report and review of literature. 

8.Ye B, Yu D, Zhang X, et al. Disseminated Rhizopus microsporus infection following allogeneic hematopoietic stem cell transplantation in a child with severe aplastic anemia. 

9.Verma R, Nair V, Vasudevan B, Vijendran P, Behera V, Neema S. Rare case of primary cutaneous mucormycosis of the hand caused by Rhizopus microsporus in an immunocompetent patient. 

10.Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. 

11.Shivananda P, Mahabala C, Kausalya S, Suchitra S, Anand KU. Cutaneous mucormycosis with necrotising fasciitis in a young immunocompetent individual. 

12.Sharma D, Dahal K, Pathak B, Dahal U. Case of early-disseminated Rhizopus microsporus var. microsporus mucormycosis in a renal transplant patient. 

13.Tissot F, Agrawal S, Pagano L, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. 

14.Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. 

15.Spellberg B, Edwards J, Jr., Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. 

16.Delie A, Vlummens P, Creytens D, Steel E. Cutaneous mucormycosis as result of insulin administration in an AML patient: Case report and review of the literature. 

17.Riley TT, Muzny CA, Swiatlo E, Legendre DP. Breaking the mold: a review of mucormycosis and current pharmacological treatment options. 

18.Zahoor BA, Piercey JE, Wall DR, Tetsworth KD. A surgical approach in the management of mucormycosis in a trauma patient. 

19.Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. 

20.Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. 

21.Gardiner BJ, Simpson I, Khuu MH, Kidd SE, Lo CH, Jenkin GA. An unusual ulcer: A case of cutaneous mucormycosis caused by Rhizopus oryzae. 

22.Zimmermann N, Hagen MC, Schrager JJ, Hebbeler-Clark RS, Masineni S. Utility of frozen section analysis for fungal organisms in soft tissue wound debridement margin determination. 

23.Skiada A, Lanternier F, Groll AH, et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). 

24.Guinea J, Escribano P, Vena A, et al. Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: Epidemiology and microbiological characterization of the isolates. 

This vulvar infection rarely is seen but presents an intriguing case.

Vulvar infection in patient with acute myeloid leukemia

45-year-old female presents to her primary care physician complaining of changes in her vulvar skin with intermittent irritation and some bleeding. She had recently experienced severe pruritus and white discharge which she treated with an over-the-counter anti-fungal cream for vulvovaginal candidiasis. However, her symptoms were only partially alleviated. On examination, she was noted to have thickening and wrinkling of the skin of the labia majora.  Excoriations were seen (Figure 1).

The history and physical examination are consistent with the diagnosis of lichen simplex chronicus. Lichen simplex chronicus is a non-specific skin condition that results from repetitive scratching or rubbing of the skin in response to pruritus.

 Other terms that have been utilized for this condition include hyperplastic dystrophy, squamous cell hyperplasia, and pruritus vulvae.

 Lichen simplex chronicus is estimated to occur in the anogenital region in 5% of all Western European and American adults.

Patients with lichen simplex chronicus typically complain of intense pruritus which can be chronic or intermittent and exacerbated by heat, stress, or menstruation.

 On examination you will observe lichenification or hard thickened skin. You may also note wrinkling of the skin, hair loss in areas of scratching, excoriations, erosions, hyperpigmentation or white patches of skin.

The development of lichen simplex chronicus is often secondary to a trigger that causes pruritus. This would include infections such as candida which is likely the trigger in this case.  Other instigating factors include chemical or allergic irritants, underlying skin dermatoses such as eczema, psoriasis, lichen sclerosus, or lichen planus, and pre-cancers or cancers of the vulva.

It can also be provoked by metabolic conditions such as diabetes mellitus or iron deficiency anemia. These triggers then result in a cycle of itching and scratching that ultimately compromises the skin’s protective barrier and results in inflammation.

 The altered skin barrier also increases the risk for secondary infection.

The diagnosis is typically made based on history and physical examination. It is critical to obtain information about when the pruritus began, when the patient is scratching and rubbing and with what. We have had patients report using items as extreme as a wire brush. Patients will often report that there is temporary relief from the pruritus with scratching or rubbing.

In addition, patients may often complain of painful urination or defecation and sexual activity which is typically related to the excoriations that can occur as a result of repetitive scratching or rubbing.

   You should also collect information about potential inciting events as well as current vulvar hygiene practices such as the type of underwear, frequency of showers/baths, whether tight clothing is worn, and whether soaps or other feminine hygiene products are utilized on the vulvar skin as well as fragrance or dyes in detergents for clothing.

A wet mount or yeast culture should be performed to rule out candidiasis. You should also consider a biopsy if the patient does not improve with initial therapies, or the gross appearance is concerning.

 A tissue biopsy can help to rule out other causes of pruritus and skin changes such as lichen sclerosus, lichen planus, psoriasis, high grade squamous intraepithelial lesions, and cancers.

On histology, a tissue biopsy from a patient with lichen simplex chronicus will display thickening of epidermis (acanthosis) and hyperkeratosis.

 You may also see increased mitotic activity without cellular atypia in the hyperplastic epithelium and a lymphocytic infiltrate within the dermis.

At the University of Michigan Center for Vulvar Diseases, we utilize a multi-step approach to treat this diagnosis. It begins with education on appropriate vulvar care which includes keeping the area dry, avoiding potential irritants such as soaps, detergents, and fabric softener with dyes or fragrance, wearing cotton underwear, and avoiding tight clothing. We also recommend against using products with benzocaine given the risk of developing contact dermatitis from this medication.

In addition, we advise our patients to utilize vulvar comfort measures focused on reducing scratching or rubbing such as tap water soaks in tepid water followed by application of a barrier to protect the skin (e.g. petroleum jelly).  Patients are encouraged to wear cotton gloves at night to prevent scratching and wear a nightgown without underwear or cotton pajama pants with a string.

Our treatment protocol also includes using medications to help with nighttime pruritus such as amitriptyline or gabapentin or hydroxyzine. Of note, if the patient complains of more pruritus during the day as opposed to at night, citalopram can be utilized instead of the medications listed for nighttime use.

In addition, we also prescribe an antibiotic, such as cefadroxil, to decrease secondary inflammation. You may utilize clindamycin instead of a cefadroxil in the case of severe penicillin or cephalosporin allergy. Do not forget to utilize an antifungal medication, such as oral fluconazole, if candida is discovered as part of your work-up. However, caution should be exercised if you are utilizing amitriptyline for nighttime pruritus. In these cases, you should utilize a topical rather than oral antifungal to avoid drug-drug interactions.

Once the skin has had an opportunity to heal, typically over the course of 4-5 days, the patient may then start topical corticosteroids such as clobetasol propionate ointment followed by triamcinolone acetonide ointment. It is important to instruct the patient where to apply the topical corticosteroids.

 Only a thin film should be applied to avoid the side effects associated with overuse which include tissue thinning, striae and rebound dermatitis.

If the patient fails topical corticosteroids, a systemic corticosteroid burst may be needed. This can be achieved with an oral prednisone taper. If still no improvement with prednisone, an intramuscular injection of triamcinolone acetonide can be given into the gluteus muscle.

In some cases, a patient may require a longer course of topical corticosteroids for maintenance. In addition, recurrence is common even with complete resolution.

 Although, this inflammatory dermatitis does not increase the risk of malignancy, it can have significant ramifications for a patient’s quality of life.

 Thus if a patient is not responding to the treatment regimen, consider referral to a vulvar specialist.

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. 2017;44(3):379-388. doi:10.1016/j.ogc.2017.04.003

2. Ellenson LH, Pirog EC. The Female Genital Tract. In: Kumar V, Abbas AK, Aster JC, eds. 

. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:991-1042.

3. Thorstensen KA, Birenbaum DL. Recognition and management of vulvar dermatologic conditions: lichen sclerosus, lichen planus, and lichen simplex chronicus. 

4. Edwards L, Lynch P. Genital pruritus and the eczematous diseases. In: 

. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2011.

5. Nguyen HL, Yiannias JA. Contact Dermatitis to Medications and Skin Products. 

. 2019;56(1):41-59. doi:10.1007/s12016-018-8705-0

6. Weiss M, Mettang T, Tschulena U, Weisshaar E. Health-related quality of life in haemodialysis patients suffering from chronic itch: results from GEHIS (German Epidemiology Haemodialysis Itch Study). 

Would you be able to recognize this diagnosis in your practice?

Rajal Patel, MD

Articles

Lymphangioma circumscriptum

Vulvar infection in patient with acute myeloid leukemia

Multistep approach for lichen simplex chronicus