Fumarate hydratase (FH)-deficient uterine leiomyoma mimicking malignancy: A diagnostic challenge

Abstract

Fumarate hydratase (FH) deficient uterine leiomyomas account for only 0.4 % of all uterine leiomyomas. They have some unique histological characteristics and can be linked to renal cell carcinoma (HLRCC) syndrome and hereditary leiomyomatosis. Only pathologic investigation can identify the uncommon subtype of uterine fibroids known as fumarate hydratase-deficient (FH-d) fibroids. The earliest sign of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome could be FH-d uterine fibroids. A young female in her 30s presented to the endocrinology clinic at a tertiary care hospital for a subfertility consultation. She had a history of poorly controlled hypertension. She reported having regular menstrual cycles lasting 28 days, with no complaints of menstrual irregularity or weight loss. Additionally, she had no prior pregnancy or history of spontaneous abortions. Imaging demonstrated a large subserosal fibroid with normal ovaries. After a loss of follow-up for approximately 2 years, the patient presented to the emergency department with a complaint of non-radiating epigastric pain for 1.5 months which was aggravating with time and became the cause of her acute presentation. Additionally, she also complained of interval development of a cutaneous nodule in the right inguinal region and a soft bulge around the umbilicus. This time imaging redemonstrated subserosal fibroid but with atypical features. The lesion showed ill-defined margins and heterogenous enhancement. Associated mild ascites which seems to be increased in magnitude from prior examination, mild omental stranding, and right-sided pleural effusion. Based on these findings, the possibility of malignant transformation was raised. Patient after a multidisciplinary consensus was scheduled for surgical resection. Post-surgical biopsy revealed a FH-deficient leiomyoma with no evidence of necrosis. The excised skin lesion showed features of fibroepithelial growth. Due to the lack of specific radiographic features, a FH enzyme-deficient fibroid, also known as an FH-deficient uterine leiomyoma, usually appears as a normal-looking uterine fibroid on imaging. However, clinical presentations such as early onset, multiple large fibroids, skin lesions, or a family history of renal cell carcinoma may raise suspicion for additional investigation and genetic testing to confirm FH deficiency.

Introduction

The most prevalent benign tumors of the female reproductive system are uterine leiomyomas, typically presenting with abnormal uterine bleeding, pelvic pain, or infertility. The rare autosomal dominant disease known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is typified by uterine and cutaneous leiomyomas as well as a higher risk of aggressive type 2 papillary renal cell carcinoma. Germline mutations in the FH gene, which codes for fumarate hydratase (FH), a crucial enzyme in the tricarboxylic acid cycle (TCA cycle), are the cause of the syndrome [1,2].

Cutaneous leiomyomas often preceded or coincided with the development of uterine leiomyomas, typically at a younger age and in larger numbers compared to sporadic cases [2,3]. These tumors may be mistaken for leiomyosarcoma or other malignancies due to their atypical morphology and rapid growth [4,5].

The loss of FH protein expression, detectable by immunohistochemistry, and the accumulation of aberrantly succinate proteins (eg, S-(2-succino)-cysteine or 2SC) are important diagnostic markers for FH deficiency [6,7]. Identifying FH-deficient leiomyomas has critical implications, as they may represent the initial clinical manifestation of HLRCC, warranting genetic evaluation and surveillance for renal cancer [4,8].

In this report, we present a case of an FH-deficient uterine leiomyoma in a young woman whose clinical and radiologic presentation closely mimicked malignancy, highlighting the importance of integrating histopathologic and molecular features in diagnosis and management.

Case presentation

A young female in her 30s presented to the endocrinology clinic at a tertiary care hospital for a subfertility consultation. She had a history of poorly controlled hypertension but no history of diabetes mellitus, thyroid dysfunction, or other endocrine disorders. She reported regular menstrual cycles lasting 28 days, with no complaints of menorrhagia, dysmenorrhea, dyspareunia, or significant weight loss. She had no prior pregnancies or history of spontaneous abortions. Other than that, her prior medical and surgical history was ordinary.

On physical examination, the patient was alert and hemodynamically stable. She weighed 109 kg and measured 156 cm in height, resulting in a body mass index (BMI) of 44.8, consistent with Class III obesity. Her blood pressure was elevated at 160/107 mm Hg. Abdominal examination revealed a firm, nontender mass palpable in the lower abdomen and pelvis, extending up to the umbilicus. There was no shifting dullness, other palpable masses, or visceromegaly. She was advised to undergo a baseline workup, including a pelvic ultrasound.

Transabdominal ultrasound of the abdomen revealed a large exophytic soft tissue mass arising from the uterus, consistent with a subserosal uterine fibroid (Fig. 1). Complementary transvaginal ultrasound was also performed, which demonstrated dilated myometrial vessels around the uterus in a subserosal location (Fig. 2), along with dilated adnexal vessels. The maximum diameter of the dilated vessels measured 9 mm, suggesting associated pelvic congestion syndrome. Further evaluation was performed using contrast-enhanced MRI due to the limited acoustic window of ultrasound.

Fig. 1.

Grayscale transabdominal ultrasound image demonstrating a large exophytic soft tissue mass (arrowheads) arising from the uterus (arrows), suggestive of a subserosal uterine fibroid. The mass appears well-defined with a heterogeneous echotexture. No signs of cystic degeneration or calcifications are observed.

Fig 2.

Grayscale and color Doppler transvaginal ultrasound images demonstrating dilated and tortuous myometrial vessels around the uterus in a sub-serosal location (arrows). The grayscale image highlights the abnormal vascular structures, while the color Doppler image confirms increased blood flow, suggestive of pelvic congestion syndrome.

MRI demonstrated a large, heterogeneously enhancing exophytic mass with mixed T2 signal intensity and isointensity on T1-weighted images. No diffusion restriction was observed (Fig. 3). The mass arises from the uterine fundus, extends into the abdominal cavity, and displaces adjacent bowel loops, consistent with a large subserosal fibroid. It measures approximately 168 × 118 × 176 mm in the transverse, anteroposterior (AP), and craniocaudal (CC) dimensions, respectively. Both ovaries appeared normal. No pelvic lymphadenopathy was noted; however, mild ascites was seen.

Fig. 3.

MRI images of the pelvis. (A) Sagittal T2, (B) Coronal T2, and (C) Axial postcontrast T1 fat-saturated images demonstrate a large heterogeneous exophytic mass arising from the uterus (arrows). The mass appears heterogeneous, with both solid and cystic components on T2-weighted imaging (A, B) and shows heterogeneous enhancement on postcontrast images (C). Additionally, mild ascites is noted (arrowheads).

After a loss to follow-up for approximately 2 years, the patient complained of nonradiating epigastric pain when they arrived at the emergency room.

Persisting for 1.5 months. The pain was not associated with food intake, vomiting, constipation, diarrhea, fever, or weight loss. Due to a sudden increase in the intensity of pain and the known history of a uterine fibroid, a CT scan of the abdomen was performed.

On the subsequent CT examination, a large, solid-cystic pelvic lesion—previously considered a subserosal fibroid—was noted, now approximately 30% larger in size compared to the prior MRI. The lesion exhibited ill-defined margins and heterogeneous enhancement. Additional findings included mild ascites which increased in magnitude, omental stranding, mild right-sided pleural effusion, and a few prominent pelvic lymph nodes (Fig. 4). These imaging features raised concern regarding the previous diagnosis of a subserosal fibroid. Furthermore, there was interval development of an umbilical cyst and a skin lesion in the right inguinal region. The remainder of the CT examination was unremarkable.

Fig. 4.

Contrast-enhanced CT images. (A) Coronal and (B, C) Axial images demonstrate a large heterogeneous mass with ill-defined margins and heterogeneous enhancement (arrow). Mild ascites increased in interval and omental stranding are observed (arrowheads). Additionally, pleural effusion indicated by double arrow.

After clinical evaluation and multidisciplinary consensus, the patient was advised to undergo surgical resection. Postsurgical biopsy revealed a FH-deficient leiomyoma without evidence of necrosis. Increased mitotic activity was observed, along with benign reactive changes in the pelvic lymph nodes. The dermal lesion was skin covered polypoidal fragment comprising of fibro collagenous core and abundant blood vessels. Areas of adipose tissue without evidence of malignancy. These features favor fibroepithelial growth, and the umbilical cyst was benign lined by squamous cells with underlying stroma showing chronic inflammation and histocytes representing epidermal cyst as shown in (Fig. 5).

Fig. 5.

Contrast-enhanced CT images. (A) Sagittal and (B) axial images showing a cutaneous lesion in the right inguinal region marked by an arrow. (C) Axial image showing an umbilical cyst marked by an arrowhead.

Discussion

A young female patient in her early thirties was initially evaluated for subfertility and was found to have a large uterine fibroid. She also had morbid obesity and poorly controlled hypertension. Imaging revealed a subserosal fibroid with degenerative features. Histopathological analysis following surgical removal confirmed that the uterine leiomyoma was FH-deficient. Rare uterine smooth muscle tumors as FH-deficient leiomyomas are linked to the autosomal dominant condition known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, which is brought on by mutations in the FH gene. However, these tumors can also occur sporadically, even in the absence of a germline mutation [[1], [2], [3], [4],8].

Histologically, FH-deficient leiomyomas frequently exhibit distinguishing characteristics that facilitate their recognition. These include enhanced cellularity, staghorn-shaped arteries and veins, eosinophilic cytoplasmic inclusions, and conspicuous nucleoli with perinucleolar halos. There is usually no indication of overt cancer, despite the possibility of aberrant mitotic figures on occasion [5,6,9].

In this patient, the large tumor size, cystic degeneration, and mass effect on adjacent structures are consistent with the known behavior of FH-deficient leiomyomas, which tend to grow more aggressively than typical leiomyomas.

Given its correlation with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, which entails a higher risk of aggressive renal cell carcinoma, the diagnosis of an FH-deficient leiomyoma has clinical importance. Therefore, even if a patient does not have a family history of cutaneous leiomyomas or kidney cancers, they are frequently recommended to have genetic counseling and FH germline mutation testing when they are diagnosed with FH-deficient leiomyomas.

Importantly, the MRI findings in this case—including a large heterogeneous mass with post-contrast enhancement and cystic changes—align with the imaging characteristics commonly observed in FH-deficient tumors. However, definitive diagnosis requires histopathological and immunohistochemical confirmation, such as the loss of FH expression or detection of 2-succinocysteine (2SC) accumulation [7].

Fortunately, our patient was followed with a CT scan of the abdomen and pelvis, which not only helped to see the extension and changes in the fibroid but also helped to evaluate the genitourinary tract and skin lesions. The patient had an umbilical cyst and a small dermal outgrowth in her right inguinal region, which these syndromic patients have a propensity to develop in the form of skin leiomyomas but in our case the histopathology of the skin lesion in right inguinal region showed a fibroepithelial lesion, and the umbilical cyst was benign.

Given the patient's age, clinical presentation, and the rare nature of this tumor subtype, a multidisciplinary approach involving gynecologists, geneticists, and oncologists is critical for comprehensive care, including surveillance for associated malignancies if a germline mutation is detected. In conclusion, FH-deficient leiomyomas represent a distinct clinical and pathological entity with implications beyond benign gynecologic disease, emphasizing the importance of early recognition and appropriate genetic evaluation.

The identification of FH-deficient leiomyoma highlights the importance of close monitoring for atypical fibroids, particularly those displaying unusual growth patterns, rapid development, extensive degeneration, or peculiar imaging characteristics. It also highlights the significance of immunohistochemical studies and histology in differentiating benign from pathologic or potentially malignant entities.

Our patient was advised for genetic testing but declined by family due to financial constraints.

There are a few case reports and some case series in the literature describing the unique presentation and features of this rare leiomyoma. A strong emphasis on the patient's family history evaluation should be made as soon as possible after diagnosis, supported by immunohistochemistry, to initiate proper screening and surveillance, especially due to the risk of renal malignancy.

Meenakshi Kamboj et al reported a case series described the diagnostic challenges of her five patients who underwent myomectomy and histopathologic diagnosis ranged from smooth muscle tumor of uncertain malignant potential to leiomyosarcoma [10].

Another report by Bužinskienė D highlights the challenges in diagnosis, thorough investigations, and describes treatment option depending upon clinical history, medical and surgical findings for the best of patient care in patients with FH-deficient leiomyoma [11].

For proper risk assessment and long-term surveillance, referral for genetic counseling and evaluation of FH germline mutation testing are crucial due to the possible systemic manifestations. Early detection of FH deficiency affects patient prognosis and family counseling by guiding treatment of the uterine tumor itself and facilitating proactive screening for related cancers. To ensure thorough evaluation and follow-up, this case also highlights the importance of a multidisciplinary approach that involves teams from gynecology, genetics, oncology, and radiology.

Conclusion

This case highlights the importance of diagnosing leiomyomas with atypical features, especially in young patients who present with progressively increasing abdominal masses. After surgical removal and histological analysis, the unusual FH-deficient subtype was definitively diagnosed, despite the initial clinical and radiological features being consistent with a benign subserosal uterine fibroid undergoing cystic degeneration. Given that FH-deficient leiomyomas can occasionally arise or as a component of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, a genetic disorder linked to an elevated risk of severe renal malignancies.

Patient consent

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