DISCUSSION
Uterine smooth muscle tumors (USMTs) include a wide spectrum of benign, atypical/uncertain malignant potential, and fully malignant tumor types. Each tumor type has variants with distinct cytohistologic and molecular profiles. Recent advances in next-generation sequencing (NGS) identify driver gene mutations and genomic alterations in many USMT types, allowing further tumor classification and more accurate diagnosis. ULMs account for the most common USMT type in reproductive-age women[3]. Many ULMs and their variants are driven by MED12 and HMGA2 mutations/alterations, while a small fraction are caused by alterations in FH and COL4A5-COL4A6[4-6].
FH gene is associated with different types of ULMs, among which hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is the only well-defined syndrome, also known as Reed’s syndrome. HLRCC is a rare autosomal dominant syndrome caused by germline mutations in the FH gene with increased risks of cutaneous leiomyomas (CLMs) and uterine leiomyomas (ULMs) and renal cell carcinoma (RCC)[7, 8]. Previously, the incidence may have been underestimated due to insufficient awareness of the disease. In 2016, HLRCC-associated RCC is recognized as a separate category in the World Health Organization (WHO) classification of renal tumors, it has been widely recognized[9]. Although CLMs frequently precede ULMs, cutaneous nodules may be inconspicuous, and therefore symptomatic ULMs may be the primary reason to seek medical care[8]. Diagnosis that begins with a thorough personal and family history, and a thorough skin examination, and if applicable, a gynecologic examination should be performed[8]. Although genetic testing is currently considered the criterion standard to diagnose, immunohistochemistry (IHC) could be used as a screening method in tumors with features suggestive of FH alterations[10, 11], newer IHC markers may have a role in provide rapid and cost effective testing[8, 12], an expert pathologic assessment will facilitate the clinical identification of FH mutation cases[13]. FH mutation associated ULMs have been shown to demonstrate distinctive pathological features delineating them from ULMs in the general population. They are well circumscribed, fascicular tumors with increased cellularity, nuclear atypia, and occasional mitoses[8, 14]. Fibrillary cytoplasm, eosinophilic globules, and staghorn vessels may also be found[8, 15]. A characteristic finding is tumor nuclei with orangiophilic (ie, eosinophilic) inclusion-like nucleoli with a perinuclear halo. This finding is the hallmark of FH mutation ULMs, and should prompt additional workup if clinical features or history suggests HLRCC[8, 16]. when patient’s medical history and/or histopathologic tumor characteristics indicate potential FH-deficiency, the tumor’s FH status is determined by 2SC staining. When aberrant staining is observed, the patient can be directed to genetic counseling and mutation screening[12].
Mutations in the FH gene are not uniquely associated with HLRCC syndrome. The great majority of HLRCC patients’ ULMs are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur[17]。FH inactivation can also occur in sporadic ULMs[10]. No cutaneous or renal cell tumors were reported when it was referred to genetic analyses in a family with closely related women with ULMs, and a novel germline FH mutation was detected[18]. A recent study showed that a relatively high rate of FH germline mutation in FH-negative ULMs from patients aged up to 30 years[19]. Some cases describe in young patient who was originally diagnosed with atypical leiomyoma (ALM) from a myomectomy specimen and experienced recurrence many years later,suggestive of FH mutations[20]. WHO (2014) classification defines ALM as leiomyoma with bizarre nuclei (LBN). Another study showed that FH gene mutations were a common finding only in LBN, but not in ULMs and leiomyosarcoma (LMS)[11]. There are also data demonstrate that HLRCC-related morphological features, abnormal FH/2SC staining, and somatic FH mutations/deletions can be seen in a subset of sporadic tumors in LBN[21]. Inactivation of FH can occur in nonsyndromic ULMs but is rare in other tumors[22].
The patient had a family history of ULMs, but neither the patient nor her family members had CLMs and RCC. At the age of 19, the patient presented with menstrual changes as the first symptom and was found to have early onset and multiple ULMs. After the onset of the disease, twice myomectomy and drug treatment were performed in a short period of time, and then it recurred again, until genetic testing identifies the FH germline mutation. What is lacking is that gynecologists failed to think of genetic testing to confirm the diagnosis at an early stage, resulting in repeated treatment and recurrence in a short time, failure to do reproductive guidance.