Leiomyosarcoma of the uterus is a rare soft-tissue tumor of the female pelvis with <1% of uterine tumor. It usually arises from the uterine myometrium de novo or is very rarely transformed from a preexisting benign leiomyoma. These tumors are found mainly in females 40–60 years of age. Leiomyomas are commonly seen in the reproductive age group, and a strong suspicion of leiomyosarcoma should be kept in mind in cases of fibroid with postmenopausal bleeding. The World Health Organization classification of tumors of female genital organs classifies leiomyosarcoma into three types – conventional (spindle cell), epithelioid, and myxoid variant. Conventional leiomyosarcoma is the most common one. Myxoid and epithelioid variants of leiomyosarcoma are rare. World Health Organization classification of female genital tract tumors in the latest 5th edition recommends a diagnosis of epithelioid leiomyosarcoma if there are >50% cells showing epithelioid morphology with tumor cells showing moderate-to-severe atypia along with tumor cell necrosis or ≥1.6 mitoses/mm2. There are very few cases of epithelioid leiomyosarcoma reported in the past. This case is being reported because of its diagnostic challenge apart from its rarity. To the best of our knowledge, ours is the first case of lymph node metastasis of epithelioid leiomyosarcoma. It also highlights the need for complimentary newer IHCs such as p53, p16, and WT1 which are helpful in the diagnosis and they have a prognostic significance also.
A 46-year-old postmenopausal female presented to the gynecology outpatient department at our hospital with symptoms of postmenopausal bleeding for the past 3 months along with abdominal obstruction. There was a history of significant weight loss and loss of appetite. There were no bladder or bowel complaints. Ultrasound abdomen revealed multiple ill-defined hypodense lesions in the anterior and posterior myometrium. Contrast-enhanced computed tomography abdomen–pelvis showed a large solid cystic mass of 7.2 cm × 9.5 cm × 7.6 cm with significant contrast enhancement in the posterior uterine wall suggestive of a sarcomatoid change in leiomyoma [Figure 1]. The rest of the uterus and adnexa appeared normal. There were multiple heterogeneous enhancing lesions in bilateral common and internal iliac and other mesenteric lymph nodes (metastatic).
On abdominal examination, a large, nontender, solid, mobile abdominopelvic mass of 22 weeks gravid uterus size was felt. On per speculum examination, the cervix could be visualized, and no abnormal discharge was seen. On vaginal examination, a nontender mass was felt. Routine blood analysis was within normal limits. An explorative laparotomy was performed and it was found that the tumor was arising from the uterus with normal bilateral fallopian tubes and ovaries lying separately from the mass. The biopsy from the lesion was sent for histopathological examination. H and E sections revealed a tumor mass composed of round to spindle to epithelioid cells in sheets and nests separated by delicate vasculature. The tumor cells had eosinophilic to granular cytoplasm, irregular nuclear contour, and granular to vesicular chromatin with variably prominent nucleoli. Abnormal mitotic figures and necrosis were present Figure 2. On immunohistochemistry, the tumor cells were positive for estrogen receptor (ER), progesterone receptor (PR), vimentin, cytokeratin, WT1, p53, and a very high Ki67 labeling index. They were negative for smooth muscle actin (SMA), desmin, CD117, CK7, CK20, HMWCK, MyoD1, S100, p16, and HMB45. Therefore, a histological diagnosis of an epithelioid leiomyosarcoma was made Figure 3.
According to the 2020 WHO classification, uterine sarcoma consists of leiomyosarcoma, low- and high-grade endometrial stromal sarcoma, and undifferentiated sarcoma. Epithelioid leiomyosarcomas have very rarely been reported in the literature and can be very unpredictable. They can remain dormant for long periods or recur after years. The most frequent presenting symptoms are abnormal vaginal bleeding and pelvic or abdominal pain. Two rare variants of leiomyosarcomas, epithelioid and myxoid leiomyosarcoma, can be difficult to diagnose, as their pathologic and diagnostic features are different from those of usual spindle cell leiomyosarcomas. The diagnosis of epithelioid leiomyosarcoma requires the presence of predominantly epithelioid morphology with a round-to-polygonal cell with eosinophilic cytoplasm and round-to-ovoid nuclei comprising most (≥50%) of the tumor cells. In both these subtypes of leiomyosarcomas, nuclear atypia is mild and the mitotic rate is usually <3 mitotic figures/10 HPF. Further, in myxoid leiomyosarcomas, cellularity is usually low and in epithelioid leiomyosarcoma is very scant or absent. Hence, a differential diagnosis has to be made, also with a variety of benign smooth muscle tumors that exhibit atypical histologic features and unusual growth patterns.
The differential diagnosis of epithelioid leiomyosarcoma includes entities with epithelioid and round cell morphology. This includes perivascular epithelioid cell tumor (PEComa), uterine tumor resembling ovarian sex cord-stromal tumor (UTROSCT), rhabdomyosarcoma, and another undifferentiated uterine sarcoma. PEComa is a challenging mimicker. It is excluded if there is the presence of clear epithelioid cells which is rare and focally present in PEComa with the presence of expression of melanocytic markers. UTROSCT is positive for smooth muscle markers, expression of ovarian sex cord-stromal markers, and keratins. Sex cord-like morphology can occur in epithelioid leiomyosarcoma but sex cord-like areas should be positive for desmin, SMA, and WT1, but negative for inhibin, calretinin, and CD10, suggesting morphologic mimicry rather than true sex cord-stromal differentiation. ER and PR positivity show the highly variable result in cases of leiomyosarcoma, unlike the leiomyoma uterus. WT1 is a transcription factor needed for the development of the genitourinary tract and is seen in both uterine and soft-tissue LMS. The presence of WT1 shows an adverse prognostic indicator in soft-tissue sarcomas. WT1 may also serve as a potential therapeutic target. Coosemans et al. studied the role of WT1 and found WT1 positivity was seen in 12/27 carcinosarcoma, 29/38 leiomyosarcoma, 7/15 endodermal stromal tumor, and 4/7 undifferentiated sarcoma. They concluded that WT1 is overexpressed in uterine sarcomas. Molecular testing can be helpful in cases where morphology alone is not confirmatory. The molecular alterations include ATRX, TP53, CDKN2A, and PTEN.
These are highly metastatic malignancies with 5-year overall survival varying between 0% and 73%. FIGO stage is the most important deciding feature of recurrence-free, overall, and disease-free survival in patients. Other prognosis factors such as age, race, tumor grade, size of the tumor, mitotic count, and lymphovascular invasion. Uterine leiomyosarcoma has a strong metastatic potential to distant sites even many years after hysterectomy. The most common sites of distal metastases are the lungs, followed by the liver. Metastases to the kidney, brain, bones, heart, thyroid, parotid gland, and oral cavity have also been reported. Ours is a case of lymph node metastases. Surgery is the treatment of choice, but the patient should be closely followed up for recurrences and metastasis. Since it is a highly aggressive tumor and can metastasize to various organs, a proper diagnosis, management, and follow-up of the patient
Uterine epithelioid leiomyosarcoma is a very rare and aggressive sarcoma of the uterus. It is difficult to diagnose on microscopy alone at times and a panel of IHCS especially the additional IHCs such as WT1, P53, CD117, and p16 are helpful where molecular investigations are not feasible. WT1 has diagnostic as well as prognostic importance. Surgery is the treatment of choice, but the patient should be followed up for recurrences or metastasis.
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