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.