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Vulvar Cancer as a Result of GATA2 Deficiency, a Rare Genetic Immunodeficiency Syndrome

Toboni, Michael D., MD, MPH; Bevis, Kerri S., MD, MSPH

doi: 10.1097/AOG.0000000000002905
Contents: Cancer: Case Reports

BACKGROUND: Vulvar cancer has become more prevalent, and its causes include chronic dermatoses and human papillomavirus (HPV)–mediated disease. Younger immunocompromised women can also be affected. We describe a case of vulvar carcinoma as a result of GATA2 deficiency.

CASE: A 19-year-old woman presented to our gynecologic oncology clinic for management of a large vulvar mass. She was diagnosed with stage IB vulvar carcinoma after vulvectomy. GATA2 deficiency was the contributing factor causing vulvar carcinoma.

CONCLUSION: GATA2 deficiency causes immunodeficiency in young women, and patients with early-onset HPV–related disease, a family or personal history of leukemia, recurrent infection, or immune irregularities should be screened. Health care providers for these women are often obstetrician–gynecologists, who can provide diagnosis, treatment, referral, and prevention of HPV–related diseases.

GATA2 deficiency causes immunodeficiency syndromes, and women with this mutation need to be identified to prevent human papillomavirus–related cancers.

Department of Obstetrics & Gynecology and the Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama.

Corresponding author: Michael D. Toboni, MD, MPH, University of Alabama at Birmingham, 619 19th Street South, 176F Room 5329, Birmingham, AL 35249; email:

Financial Disclosure The authors did not report any potential conflicts of interest.

Each author has indicated that he or she has met the journal's requirements for authorship.

Received May 18, 2018

Received in revised form July 10, 2018

Accepted July 26, 2018

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Teaching Points

  1. GATA2 mutation and the resulting immunodeficiency syndrome can predispose young women to human papillomavirus (HPV)–related disease.
  2. Patients with family history of early-onset HPV-related disease, leukemia, recurrent infection, or immune irregularities should be screened.
  3. Early screening and vaccination should be encouraged in this population to prevent HPV-related cancers.

In the United States, almost 5,000 women are diagnosed with vulvar cancer each year, with more than 20% of those eventually dying from the disease.1 Additionally, 2.86 per 100,000 women are diagnosed with vulvar intraepithelial neoplasia (VIN) 3 every year.2 From 1973 to 2004, incidence of vulvar invasive tumors and in situ tumors increased by an average of 1.0% and 3.5%, respectively, each year3; however, it is still rare in young populations. Estimated incidence of vulvar cancer is 0.1% in those younger than 20 years, 1.7% in those 20–34 years, and 5.2% in those 35–44 years old, meaning 93% of vulvar cancer is diagnosed in those older than 44 years of age.4 Etiology of vulvar cancer includes chronic dermatoses, typically in elderly populations, and human papillomavirus (HPV)–mediated disease, seen often in younger populations. Immunocompromised patients are an exception to this generalization,5 including those with history of an organ transplant, human immunodeficiency virus (HIV) infection, chronic steroid use, and an extensive smoking history.6–8 We describe a case of vulvar carcinoma in a 19-year-old woman who previously presented with extensive vulvar condyloma. This was the result of a previously undiagnosed inherited immunodeficiency syndrome, GATA2 deficiency.

The mutation in the GATA2 gene recently has been implicated as the cause in a number of previously described clinical syndromes, namely familial myelodysplastic syndromes and acute myeloid leukemia9; monocytopenia and mycobacteria infection syndrome10; and dendritic cell, monocyte, B and NK lymphoid deficiency.11 The mutation is thought to be the result of haploinsufficinecy,12 meaning a gene has a mutation or absence of one diploid copy. In this case, the haploinsufficiency is caused by a monoallelic mutation that is inherited autosomal-dominant with incomplete penetrance.9,13,14 There is a wide array of presentations, but the GATA2 deficiency is characterized by two separate syndromes that can overlap: Emberger syndrome and MonoMAC syndrome. These syndromes can cause immune regularities and lymphoid deficiency, which causes susceptibility to infection.10,13 In one study of 57 patients with GATA2 deficiency, the majority had symptoms by age 20 years and 75% had symptoms by age 30 years with the overwhelming majority (82%) of patients having infection as their presenting symptom. Of the 82% of patients whose presenting symptom was infectious in nature, 70% were viral, and 63% of those were caused by the HPV in the form of condylomata, warts, or dysplasia. Human papillomavirus–related dysplasia was observed in 35% of study participants ranging from intraepithelial lesions and Bowenoid papulosis to invasive squamous cell carcinoma.15 This poses a significant morbidity and mortality risk in young, sexually active women who are subjected to these immune deficiency syndromes caused by the GATA2 deficiency.

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A 19-year-old nulliparous white woman presented to our gynecologic oncology clinic for evaluation and management of a large vulvar mass. She initially presented to an obstetrician–gynecologist (ob-gyn) reporting a thin, yellow, foul-smelling vaginal discharge; vulvar irritation; and worsening menstrual symptoms. Physical examination revealed a large fungating mass replacing the right labia majora, which then extended across the mons pubis to include a portion of the left labia majora. The mass was friable, bleeding, and was noted to have a foul-smelling drainage. Biopsy revealed condyloma acuminatum with mild-to-moderate squamous dysplasia. Review of systems revealed a 20-pound weight loss over the previous several months but no other abnormalities. The patient had a medical history of chronic anemia and arthritis, no surgical history, and a family history significant for breast cancer in her maternal aunt, colon cancer in her father, and childhood leukemia in her younger sister. Her social history was significant for smoking 10 cigarettes per day for a year but was otherwise negative. Gynecologic history was significant for regular monthly menstrual cycles beginning at age 12 years. To her knowledge she had never received an HPV vaccination. She was sexually active with one male partner with no history of sexually transmitted diseases and no prior pregnancies. Her preoperative laboratory work was notable for a white blood cell count of 2.8 and negative HIV serology.

Three weeks after her initial presentation, the patient underwent a total vulvectomy with clitoral sparing and CO2 laser ablation of clitoral condyloma. Surgical pathology returned large condyloma and VIN with areas concerning for invasion and positive surgical margins. After a 2-month recovery, she had further CO2 laser ablation of the residual and progressive vulvar condyloma. After the second procedure, she enjoyed a symptom-free period where she regained the weight she had lost and stated she felt like herself. She subsequently reported increasing symptoms of pain and burning on the left side of her vulva and ultimately was diagnosed with stage IB squamous cell carcinoma of the vulva (Fig. 1). She underwent a radical partial vulvectomy, including resection of the clitoris and bilateral inguinal lymphadenectomy. Her pathology returned with no evidence of residual invasive disease and negative lymph nodes. The patient did well postoperatively, with no residual pain, and was able to return to work. She was also able to resume normal sexual activity despite resection of the clitoris.

Fig. 1

Fig. 1

Shortly after her final surgery, the patient's mother was diagnosed with leukemia, prompting evaluation and confirmation of a GATA2 deficiency. Although the patient initially refused testing, she did consent and tested positive for GATA2 mutation 4 years after her initial consultation; as of this writing, she is undergoing evaluation for a bone marrow transplant.

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The mutation in the GATA2 gene, inherited in an autosomal-dominant pattern, is a newly described cause of two syndromes, which often overlap and manifest with systemic malignancies, pulmonary infections, and multiple different hematologic findings. However, the vast majority of early-onset GATA2 deficiency cases presents as immunodeficiency in young individuals. The afflicted individuals present with symptoms of infection 82% of the time, with the majority of those infections being HPV-related. For females, their primary care provider during this time is often an ob-gyn, who has the capability to diagnose, treat, and refer these patients to the appropriate physicians.

This patient presented with early-onset and severe HPV-related disease and has a sister who was diagnosed with childhood leukemia at the age of 8 years. Initially, the clinical significance of her familial history went unrecognized by her medical care team, likely as a result of the fact that this is a newly described mutation. It was not until her mother was diagnosed with the GATA2 deficiency that the clinical syndrome in her first-degree relatives was elucidated.

Special attention must be paid to the population of young women who present with extensive condyloma, VIN, or vulvar cancer. Ob-gyns have an opportunity to diagnose these patients with a GATA2 deficiency, especially if the clinical or familial history correlate. Early diagnosis of this disease would have implications on the health of her family members as well as on the patient's future health including the possible prevention of future disfiguring surgical procedures. Additionally, in young women who do not have severe HPV-related disease but have elements in the clinical or familial history consistent with this disease, a GATA2 mutation should be considered. These elements of history include relatives or a personal history of leukemia (adult and childhood), unexplained leukopenia, unexplained immunodeficiency, or myelodysplastic syndromes. Early diagnosis of these familial syndromes is paramount because it can allow an ob-gyn to aggressively counsel these patients on administration of the HPV vaccine, smoking cessation, and safe sexual practices to combat the ubiquitous prevalence of the HPV and avoid development of severe HPV-related disease as described in this patient. One cannot help but wonder whether administration of the HPV vaccine in this individual could have prevented the multiple morbid and disfiguring surgical procedures.

If a GATA2 deficiency is diagnosed, patients should undergo increased surveillance, earlier Pap testing, and physical examinations at decreased intervals as a result of the high likelihood for dysplasia and malignancy. Additionally, consideration should be given for referral to a hematologist because of the increased likelihood of developing acute myeloid leukemia, consideration of Azithromycin prophylaxis as a result of the susceptibility to mycobacterial infections,14 and the possibility of necessitating a bone marrow transplant, for which this patient is currently undergoing evaluation. The goal of a bone marrow transplant is to treat her severe pancytopenia caused by the myelodysplasia syndrome, which effectively will eliminate future recurrent infections.

This demonstrates a rare case of vulvar carcinoma in an otherwise low-risk adolescent with GATA2 deficiency. An extensive English language search did not yield any cases described in gynecologic journals. Although this deficiency was discovered in the past 6 years, one small study, namely Spinner et al,15 described a high incidence of cervical dysplasia related to HPV in their study participants. Referral for diagnostic testing of the GATA2 deficiency based on clinical history, familial history, or HPV-related disease is important because those women who have the mutation are more likely to present with vulvar and cervical dysplasia and invasive cancers at younger ages and with increasing prevalence when compared with the general population.

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© 2018 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.