Abstract
A 7-year-old girl presented with painful genital enlargement, which was first believed to be clitoromegaly of hormonal origin. However, on the physical exam the clitoris was not visible and the prepuce and labia minora were enlarged and tender. Magnetic resonance imaging demonstrated an infiltrative abnormal signal with restricted diffusion involving the enlarged clitoris and adjacent soft tissues of the prepuce and labia minora, confirming a nonhormonal infiltrative malignancy. The same abnormal signal was present in enlarged inguinal lymph nodes, the kidneys, and an anterior mediastinal mass. The pathologic diagnosis was T-cell acute lymphoblastic leukemia.
Keywords: Clitoris, clitoromegaly, leukemia, magnetic resonance imaging, malignancy
Clitoromegaly, abnormal enlargement of the clitoris, may be congenital or acquired and is usually the result of elevated androgens. Congenital clitoromegaly from hormonal disturbances is often noticeable at birth. Acquired clitoromegaly develops later in life. Clitoromegaly can be divided into two causal categories, hormonal (endocrinopathies, masculinizing tumors, exposure to androgens, and virilization syndromes) and nonhormonal (neurofibromatosis, epidermoid cysts, infection, and tumors).1 While acute lymphoblastic leukemia is the most prevalent childhood cancer, accounting for 20% of all cancers diagnosed in the pediatric population,2 a presenting complaint of clitoromegaly is unique.
CASE PRESENTATION
A previously healthy 7-year-old girl presented to her pediatrician with severe anterior vulvar and clitoral pain with erythema and enlargement, in addition to bilateral inguinal lymphadenopathy on exam. With no change in symptoms after topical nystatin and a trial of oral amoxicillin-clavulanate, she was referred to pediatric gynecology and pediatric surgery.
Gynecologic exam of the perineum revealed a sexual maturity rating 1 female with swollen prepuce and labia minora forming a mass 3.5 cm long and 2 cm wide (Figure 1). The clitoris was not visible under the prepuce or within this mass, as the hood could not be retracted due to discomfort. There were tender inguinal masses. A working diagnosis of virilization vs disorder of sexual differentiation was entertained, though other causes including infection, clitoral vein thrombosis, or other inflammatory processes could not be ruled out. Laboratory evaluation for endocrinopathies was negative.
Figure 1.
Clinical photograph demonstrating massive enlargement of the clitoral hood and labia minora. The clitoris is not identified.
Ultrasound identified a normal left ovary, inguinal adenopathy, and hypoechoic renal masses bilaterally. Computed tomography showed soft tissue thickening of the external genitalia, inguinal lymphadenopathy, bilateral renal hypodensities, and a left chest mass. Magnetic resonance imaging confirmed a normal prepubertal uterus and bilateral ovaries, ruling out a disorder of sexual differentiation. The enlarged clitoris measured 7.6 mm wide. Most of the genital mass consisted of the clitoral hood and labia minora (Figure 2a). The mass had intermediate T2 signal, hypointense T1 signal, and restricted diffusion (Figure 2b) with mild enhancement, demonstrating identical signal to renal lesions, pelvic and retroperitoneal adenopathy, and the mediastinal mass. The signal and distribution were most consistent with leukemia/lymphoma.
Figure 2.
Magnetic resonance imaging of the pelvis. (a) Axial T2-weighted image showing mild enlargement and intermediate signal of the clitoris (double-headed arrow) and surrounding soft issues (arrow). (b) Axial apparent diffusion coefficient map showing hypointense signal (arrow) confirming restricted diffusion that is commonly seen in tumors with a high nuclear to cytoplasmic ratio and is the typical signal for lymphoma/leukemia. Bilateral renal lesions, retroperitoneal adenopathy, and the chest mass demonstrated identical signal characteristics (not shown).
Laboratory findings included a white blood cell count of 38.9 109/L, hemoglobin of 13.2 g/dL, platelet count of 472,000/L, and absolute neutrophil count of 22,600/L. Inguinal lymph node biopsy and bone marrow biopsy and aspiration were performed. Bone marrow showed 90% lymphoblasts, and peripheral flow cytometry revealed small amounts of lymphoblasts; a lymph node biopsy and molecular testing were performed (Table 1), resulting in a diagnosis of high-risk T-cell acute lymphoblastic leukemia. Her central nervous system status was 3.
Table 1.
Initial oncological evaluation laboratory results
| Test | Result |
|---|---|
| CBC | White blood cell count, 38.9 109/L; hemoglobin, 13.2 g/dL; platelets, 472,000/L; absolute neutrophil count, 22,600/L |
| Peripheral blood smear |
Leukocytosis with circulating blasts (7%/200 white blood cells) |
| Bone marrow | 90% lymphoblasts |
| CSF studies | 36 white blood cells in the CSF with 55% lymphoblasts |
| Flow cytometry |
Immunophenotype with an immature T lymphoid population positive for CD7, CD5, CD2, CD38, CD13, cytoplasmic CD3, and TdT, representing approximately 50% of the total number of events analyzed |
| Lymph node biopsy |
Immunophenotype with a predominant immature T cell population positive for CD2, CD5, CD7, CD4/CD8, cytoplasmic CD3, and TdT |
| Cytogenetics/ FISH |
45,X,-X,del(6)(q21q25), add(7)(q32), del(9)(p10)[6]/46,XX[11] NOMENCLATURE: nuc ish (D6Z1x3 ∼ 4,MYBx3 ∼ 4) [44/200], (RELNx4,TESx4) [36/200], (CDKN2Ax0 ∼ 2,D9Z3x2 ∼ 4) [129/200], (ABL1x2 ∼ 4,BCRx3 ∼ 4) [47/200], (KMT2Ax4) [28/200], (TRDx3 ∼ 4) [43/20 0] |
| DNA FISH | Positive for loss of CKDN2A (9p21) and for gains of D6Z1 (6 centromere), MYB (6q23), RELN (7q22), TES (7q31), D9Z3 (9q12), ABL1 (9q34), KMT2A (11q23), TRA/D (14q11.2), BCR (22q11.2) |
CBC indicates complete blood count; CSF, cerebrospinal fluid; FISH, fluorescence in situ hybridization.
Treatment included four-drug induction including vincristine, daunorubicin, dexamethasone, and pegaspargase. She had weekly lumbar punctures during the induction phase and had clearance of her central nervous system disease and mediastinal mass by day 8. Her end of induction marrow was <0.01% by flow cytometry, and end of induction cytogenetics were normal. Eight months after diagnosis, she had an early combined relapse involving bone marrow and cerebrospinal fluid. Her cerebrospinal fluid remains positive despite numerous rounds of chemotherapy.
DISCUSSION
Clitoromegaly is defined by width >6 mm in females from 4 to 8 years of age, >5 mm in ages 8–12, and >8 mm in children ≥13.3 Tumors of the clitoris are rare, often benign, and are described primarily in case reports, including genital neurofibromatosis in young children with neurofibromatosis 1,4–6 an epidermoid cyst in a 22-year-old woman after female circumcision from genital mutilation,7 a congenital cyst of the clitoral hood in a newborn,8 and pseudoclitoromegaly in a 3-year-old girl with an aggressive vulvar angiomyxoma.9 There has been one other case reporting clitoromegaly in a child due to malignancy in a 2-year-old girl with mediastinal non-Hodgkin’s lymphoma and clitoromegaly in 1987.10
Careful physical exam is critical to determine if clitoromegaly is truly present and will guide the differential diagnosis and workup. In this rare case, the clitoris was not externally visible, and imaging determined that the abnormality was due to an infiltrative process involving the clitoris and surrounding soft tissues. Imaging confirmed involvement of lymph nodes, kidneys, and an anterior mediastinal mass, leading to the diagnosis. This rare case highlights the importance of meticulous evaluation of presumed clitoromegaly and keeping a broad differential diagnosis including tumors if there is potential pseudoclitoromegaly.
Disclosure statement/Funding
The authors report no funding or conflicts of interest. The parents of the patient gave permission for the publication of this case.
References
- 1.Iezzi ML, Lasorella S, Varriale G, Zagaroli L, Ambrosi M, Verrotti A.. Clitoromegaly in childhood and adolescence: behind one clinical sign, a clinical sea. Sex Dev. 2018;12(4):163–174. doi: 10.1159/000489385. [DOI] [PubMed] [Google Scholar]
- 2.Ward E, DeSantis C, Robbins A, Kohler B, Jemal A.. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):83–103. doi: 10.3322/caac.21219. [DOI] [PubMed] [Google Scholar]
- 3.Brodie KE, Grantham EC, Huguelet PS, Caldwell BT, Westfall NJ, Wilcox DT.. Study of clitoral hood anatomy in the pediatric population. J Pediatr Urol. 2016;12(3):177.e1-5–177.e5. doi: 10.1016/j.jpurol.2015.12.006. [DOI] [PubMed] [Google Scholar]
- 4.Rabley A, Bayne CE, Shenoy A, DeMarco RT.. Genital neurofibromatosis presenting as painful clitoromegaly. Urology. 2019;133:219–221. doi: 10.1016/j.urology.2019.07.016. [DOI] [PubMed] [Google Scholar]
- 5.Darcy C, Ullrich NJ.. A 15-month-old girl presenting with clitoromegaly and a chest mass. Semin Pediatr Neurol. 2018;26:128–131. doi: 10.1016/j.spen.2017.03.020. [DOI] [PubMed] [Google Scholar]
- 6.Thakur DS, Yerawar CG, Phiske M, Bhagwat NM.. Clitoromegaly: beyond testosterone. BMJ Case Rep. 2018;2018:bcr-2018-225350. doi: 10.1136/bcr-2018-225350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Karaci S, Kulaksiz D, Sekerci CA.. A rare cause of clitoromegaly: epidermoid cyst. Arch Ital Urol Androl. 2019;91(2):137–138. doi: 10.4081/aiua.2019.2.137. [DOI] [PubMed] [Google Scholar]
- 8.Hiers PS, Abi Younes RT, Haller MJ.. Apparent clitoromegaly in healthy female newborn. Pediatr Rev. 2021;42(Suppl 2):173–176. doi: 10.1542/pir.2020-0043. [DOI] [PubMed] [Google Scholar]
- 9.Kawamura M, Matsumoto F, Matsui F, Yazawa K, Shimada K.. Aggressive angiomyxoma of the vulva mimicking clitoromegaly in a young child. Urology. 2017;101:142–144. doi: 10.1016/j.urology.2016.10.034. [DOI] [PubMed] [Google Scholar]
- 10.Ludwig R, Heinrich U, Brandeis WE.. Clitoromegaly and abdominal tumour as leading signs of a mediastinal non-Hodgkin lymphoma. Eur J Pediatr. 1987;146(1):70–71. doi: 10.1007/BF00647290. [DOI] [PubMed] [Google Scholar]