Natalie Saunders, MD

A 51-year-old patient presents for evaluation of possible vulvar lichen sclerosus. The patient describes a 12-month history of vulvar discomfort. The pain was initially intermittent but is now continuous. She describes “pinching and stretching” extending from the perineum spreading to the anus. She notes “ripping” with intercourse. She describes “raised clear blisters” on her inferior vulva. A biopsy done at the referring hospital demonstrated “stromal sclerosis, favor lichen sclerosus over amyloidosis.” 

Patient had no improvement with topical clobetasol ointment 0.05% for 1 month and therefore was referred to Michigan Medicine Center for Vulvar Diseases for further evaluation.

Examination showed tender, raised areas on the perineum approaching the perianal tissue.

Repeat vulvar biopsies were performed. Pathology showed amyloidosis (evaluated with Congo red histochemistry). Mass spectrometry for amyloid typing was performed at the Mayo Clinic, which revealed AL (kappa)-type amyloid deposition. This type of amyloid is usually associated with systemic disease due to an underlying clonal plasma cell proliferative disorder or a B-cell lymphoma.

The patient was referred to Michigan Medicine Hematology/Oncology clinic for further evaluation and management of the underlying disease. Bone marrow biopsy showed Kappa light chain myeloma with t(11;14). She was initially treated with cyclophosphamide, bortezomib, dexamethasone, followed by ixazomib and lenalidomide. 

She again presented to Michigan Medicine Center for Vulvar Diseases 6 months after initial presentation. She was still suffering from vulvar discomfort. Examination of the vulva was unchanged. 

After extensive review of the literature, she was offered laser ablation of the amyloidosis of the vulva. Risk of recurrence, pain after surgery, prolonged recovery time with healing, and inability to remove all of the affected tissue were reviewed. At that time, the amyloidosis extended to the anus but did not appear to go into the anus. 

Risk of injury to surrounding tissue, especially anus/rectum given proximity of disease was reviewed. We reviewed concern for hemostasis given the friable nature of the tissue.

The patient was taken to the operating room for laser ablation of amyloidosis of the vulva. The area of concern was carefully demarcated with a 0.5 cm border using a marking pen. 

We first followed the border outlined preoperatively using a CO2 silk touch laser. We then filled in our outline working to create a surgical plane. As expected, the tissue was highly friable and bled easily. 

The lesions required multiple cautious passes with laser and subsequent cautery. We varied between a 4 mm and 6 mm spot size and power of 20-25 watts. Despite our efforts with the laser, mechanical dissection was ultimately needed in order to separate the planes of disease and normal tissue. We used gentle scraping with the Bovie cautery in order to separate the planes. 

A tactical difference could be appreciated between the abnormal and normal tissue. 

We repeated our mixed method approach through the entire affected area. We eventually cleared all grossly visible disease and achieved excellent hemostasis.

Ultimately, the patient underwent bone marrow transplant for treatment of her systemic disease with excellent results. At 9 months post-operative evaluation there was no evidence of recurrence of amyloidosis on the vulva.

Amyloidosis is a term used to describe fibril deposition of proteins.AL amyloidosis is due to deposition of protein from immunoglobulin light chain fragments. A monocolonal protein is detected in the urine and or blood of more than 95% of patients with amyloidosis.

Amyloidosis can be present by itself or associated with underlying systemic disease such as plasma cell dyscrasias (multiple myeloma, Waldenström macroglobulinemia). These are malignant disorders of plasma cells or lymphoplasmacytic cells.

Since AL amyloidosis is a clonal cell disorder, it is treated with chemotherapy to destroy the underlying clone. In our patient, diagnosis of AL amyloidosis (deriving from a light chain fragment) was confirmed by mass spectrometry. This differentiates AL from other types of amyloidosis such as AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis. These types are not neoplasms and therefore not susceptible to chemotherapy.

AL amyloidosis is a very rare disease. It is estimated that in the United States the incidence is 9 to 14 cases per million person-years. 

 Patients present in a variety of ways. Since AL amyloidosis is often associated with plasma cell dyscrasias such as multiple myeloma, it can present as a myeloma defining event such as bone pain that is shown to be an osteolytic bone lesion.

Some common symptoms on presentation include unintentional weight loss and fatigue.

 It can also present in a variety of organ systems. 

Common presentations include nephrotic syndrome, cardiomyopathy, peripheral neuropathy, hepatosplenomegaly, and bleeding diasthesis. It can also present with skin manifestations such as thickening of the skin, easy bruising, and infiltration of subcutaneous fat.

Diagnosis is made through biopsy that demonstrates amyloid fibrils. It can be confirmed with Congo Red staining that demonstrate green birefringence under polarized light.

 The amyloid is then typed using a variety of techniques (in our patient’s case using mass spectrometry). This can identify the amyloid type with 100% specificity.

The Mayo Clinic and the International Myeloma Working Group have established diagnostic criteria for AL amyloidosis. All 4 must be met to confirm diagnosis.

An amyloid-related systemic syndrome. Organ damage must be confirmed to be related to amyloid protein deposition;

Confirmation that amyloid is light chain (mass spectometry);

Confirmation of monoclonal plasma cell proliferative disorder.

For treatment of our patient’s vulvar amyloidosis she was offered laser ablation to the affected areas. Case reports suggest CO2 laser is successful in managing nodular disease, satisfactory cosmetic results and no recurrences at follow-up. There is no consensus on particular settings/technique, especially with gynecologic lesions.

It is imperative that AL amyloidosis is differentiated from other forms because treatment and prognosis is markedly different. Our patient ultimately underwent bone marrow transplant to cure her underlying multiple myeloma. 

She continues to do well without evidence of recurrence of multiple myeloma and with no recurrence of vulvar amyloidosis.

In conclusion, systemic AL amyloidosis can manifest as atypical nodular lesions on the vulva. Extensive amyloid deposits can cause significant discomfort, warranting surgical management. A combination of ablative therapy and mechanical dissection may be needed to create the necessary surgical plane for successful treatment. 

Maintenance of hemostasis and avoidance of sensitive structures are key operative concern. 

Vulvar amyloidosis is a rare, but important clinical entity. Its diagnosis can facilitate the recognition of a potentially life-threatening systemic condition. Proper treatment provides symptomatic relief without significant disfigurement or loss of function.

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2. Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood 1992; 79:1817.

3. Quock TP, Yan T, Chang E, et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv 2018; 2:1046.

4. Kyle RA, Larson DR, Kurtin PJ, et al. Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015. Mayo Clin Proc 2019; 94:465.

5. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15:e538.)

6. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45.)

7. Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses (first of two parts). N Engl J Med 1980; 302:1283.

8. Dasari S, Theis JD, Vrana JA, et al. Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples. Mayo Clin Proc 2020; 95:1852).

9. Kourelis TV, Kumar SK, Gertz MA, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013; 31:4319.

10. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23:3.

11. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016; 91:719.)

12. Quddus, M. R., Sung, C. J., Simon, R. A., & Lawrence, W. D. (2014). 

Articles

A case study on diagnosis and management. Could you recognize this rare condition?

Vulvar amyloidosis

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. 

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

Andrew’s Diseases of the Skin: Clinical Dermatology

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

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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. 

Could you recognize this rare vulvar condition?

Lymphangioma circumscriptum

A 44-year-old woman presents to your clinic in consultation due to issues with vaginal itching and irritation. She has noted yellowish discharge on her pad on a daily basis. No odor noted. 

Previously, she underwent treatment with intravaginal clindamycin for 1 week that somewhat helped her symptoms. On examination with a speculum, she is noted to have copious thin yellow discharge on her vaginal mucosa. A wet mount was obtained, with a pH of 6.0. 

, clue cells, hyphae, trichomonads. Parabasal cells and white blood cells were seen and the whiff test is negative.

This patient is presenting with signs and symptoms of vaginitis. There is a broad differential, including candidiasis, bacterial vaginosis, trichomoniasis, gonorrhea or chlamydia infection, lichen planus, atrophic vaginitis, desquamative inflammatory vaginitis (DIV), or a less commonly discussed condition, cytolytic vaginosis. Based on her presentation and her wet mount results, a diagnosis of DIV is made and the patient is treated with intravaginal clindamycin for 3 weeks with resolution of her symptoms.

Gray and Barnes first introduced the DIV condition with their 1965 case series of six women with a “reddened” vagina and “numerous pus cells…with oval and round parabasal cells.”

 The etiology is unclear but this condition is consistent with a loss of the normal vaginal flora and increase in inflammation. 

 and an increase in the concentration of obligate or facultative anaerobic flora.

 There is limited literature available about this condition but available studies suggest a prevalence of 2 to 20%.

 It tends to occur more commonly in perimenopausal women but can occur at any age.

Classically, the patient presents complaining of vaginal discharge, itching, vaginal discomfort or dyspareunia.

 Externally, the patient may have vulvar erythema (Figure 1). 

On speculum examination, yellow discharge will be apparent, as well as vaginal petechaie.

The patient may have mucosal erythema with bruising or erosions. Approximately 27% ofpatients with DIV will have colpitis macularis or small erythematous macules on their ectocervix.

The diagnosis is made based on clinical symptoms and physical examination. You should obtain a complete medical history, including sexual history, associated symptoms, and failed treatments. The physical exam consists of placing a vaginal speculum, obtaining a pH from the lateral sidewall of the vagina, and microscopic evaluation of vaginaltions.

On examination, be sure to evaluate the color, consistency, amount, and odor of vaginal discharge.

In addition, perform an examination for cutaneous, oral, and vulvovaginal changes to rule out lichen planus.

 Vaginal atrophy needs to be excluded, as atrophic vaginitis and DIV appear similar on microscopic evaluation.

To obtain a sample of the discharge, use a cotton-tipped applicator or sterile 10-microliter plastic loop from the vaginal side wall. A pH of the discharge should also be obtained. The cotton swab is placed directly on the pH paper without adding any saline or potassium hydroxide (KOH), since these will alter the pH. Typically, the pH is greater than or equal to 4.7 in DIV. 

Of note, a gram stain alone cannot discriminate between bacterial vaginosis and DIV, and thus, will not be useful.

Another cotton swab containing vaginal secretions should be placed in a glass tube to which a few drops of saline are added. Spread the sample on two locations on a slide. 

On one of the locations, add a drop of KOH. Place coverslips over each sample. Then examine the slide under a microscope at low power (10x) and high power (40x). 

On wet mount, there will be an absence of clue cells, hyphae, trichomonads and 

. Immature vaginal epithelial cells or parabasal cells will be seen. Parabasal cells are typically round or oval in shape with a high nuclear/cytoplasmic ratio.

You will also see an increase in inflammatory cells (e.g. the ratio of leukocytes to epithelial cells is greater than 1:1).

 No amine odor will be detected on the KOH specimen, in contrast to bacterial vaginosis and trichomonas, which often have this feature. 

One might also consider obtaining a yeast culture with speciation as part of the evaluation for vaginal discharge. Nucleic acid amplification tests should also be obtained to rule out other infectious etiologies of vaginitis if indicated.

As with any vulvovaginal condition, it is important to reinforce appropriate vulvar care measures, including keeping the area dry, avoiding constricting clothing, irritants in detergents, soaps, or over-the-counter medications like benzocaine, and wearing cotton underwear.

Initial treatment for DIV should begin with topical intravaginal clindamycin or intravaginal hydrocortisone. There are a variety of regimens that may be used. For the intravaginal clindamycin, 5g of 2% cream is inserted vaginally once a night for 3 weeks. 

Alternatively, 200 mg clindamycin can be inserted intravaginally at night for 3 weeks. For both of these regimens, consider maintenance therapy twice a week, for 2 months, since DIV frequently recurs. Another treatment is intravaginal hydrocortisone. The dosing regimens for intravaginal hydrocortisone are 25 mg suppositories twice a day, for 3 weeks. 

Consider maintenance therapy, three times a week for 2 months, following this treatment. At times, a higher dose of hydrocortisone may be required. Hydrocortisone, 300 to 500 mg, is inserted vaginally at night for 3 weeks. 

Maintenance therapy, twice a week for 2 months, should be considered with this regimen

; other causes of purulent vaginitis should be excluded. 

The main symptoms include purulent discharge, vestibulo-vaginal irritation, and dyspareunia. Examination of vaginal walls will show signs of inflammation with increased erythema and petechiae. 

These recommendations are based on an observational study published by Sobel et al in 2011 that looked at the prognosis of 98 patients meeting diagnostic criteria for DIV and a publication by Reichman and Sobel in2014.9,10

In this same 2011 series by Sobel et al, almost a third of patients who had initial resolution of symptoms relapsed within 6 weeks of stopping therapy and approximately 40% relapsed within 26 weeks off therapy.

 Thus, maintenance therapy should be considered as mentioned.

Regular assessments of signs and symptoms with microscopy and measurement of pH are critical to assess for improvement or remission, as many patients will require maintenance therapy for longer than 2 months.

 In Sobel et al’s 2011 observational study, 58% of the women diagnosed with DIV were still on treatment or had required maintenance therapy 1 year from initial treatment.

Of note, there do not appear to be systemic effects from prolonged intravaginalsteroid use. However, clindamycin or intravaginal corticosteroids can increase the risk of vulvovaginal candidiasis.

 Thus, an antifungal may be warranted, such as oral fluconazole, for patients more likely to get symptomatic candida infections. 

 should occur when choosing a treatment regimen in order to weigh the pros and cons of maintenance therapy, including the risk of vulvovaginal 

For challenging cases in which there is no improvement, and in which the patient may have atrophic vaginitis as well, adding intravaginal estrogen may be beneficial.

 The presence of estrogen facilitates colonization of the vaginal microbiome with 

which helps to decrease the pH to less than 4.7.

1. Gray L, Barnes M. Vaginitis in women, diagnosis and treatment. 

2. Gardner H. Desquamative inflammatory vaginitis: a newly defined entity. 

3. Donders GGG, Bellen G, Grinceviciene S, Ruban K, Vieira-Baptista P. Aerobic vaginitis: no longer a stranger. 

. 2017;168(9-10):845-858. doi:10.1016/j.resmic.2017.04.004

4. Sobel JD. Desquamative inflammatory vaginitis: a new subgroup of purulent vaginitis responsive to topical 2% clindamycin therapy. 

5. Mitchell L, King M, Brillhart H, Goldstein A. Cervical Ectropion May Be a Cause of Desquamative Inflammatory Vaginitis. 

. 2017;5(3):e212-e214. doi:10.1016/j.esxm.2017.03.001

6. Paavonen J, Brunham RC. Bacterial vaginosis and desquamative inflammatory vaginitis. 

. 2018;379(23):2246-2254. doi:10.1056/NEJMra1808418

7. Sherrard J, Wilson J, Donders G, Mendling W, Jensen JS. 2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge. 

. 2018;29(13):1258-1272. doi:10.1177/0956462418785451

8. Mason MJ, Winter AJ. How to diagnose and treat aerobic and desquamative inflammatory vaginitis. 

. 2017;93(1):8-10. doi:10.1136/sextrans-2015-052406

9. Sobel JD, Reichman O, Misra D, Yoo W. Prognosis and treatment of desquamative inflammatory vaginitis. 

. 2011;117(4):850-855. doi:10.1097/AOG.0b013e3182117c9e

10. Mills BB. Vaginitis: Beyond the Basics. 

. 2017;44(2):159-177. doi:10.1016/j.ogc.2017.02.010

11. Hasteh F. Parabasal cells. Pathology Outlines. http://www.pathologyoutlines.com/topic/cervixcytologyparabasalcells.html. Published 2020.

12. Reichman O, Sobel J. Desquamative inflammatory vaginitis. 

. 2014;28(7):1042-1050. doi:10.1016/j.bpobgyn.2014.07.003

The etiology of this condition is unclear but is consistent with a loss of the normal vaginal flora and increase in inflammation.

Desquamative inflammatory vaginitis

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 vulvar infection rarely is seen but presents an intriguing case.

Natalie Saunders, MD

Articles

Vulvar amyloidosis

Lymphangioma circumscriptum

Desquamative inflammatory vaginitis

Vulvar infection in patient with acute myeloid leukemia