A case of ruptured epithelioid uterine leiomyosarcoma

In this study, we investigated HMB-45 expression in epithelioid uterine leiomyosarcomas with clear cell areas. From 12 epithelioid leiomyosarcomas, we selected 5 that had: 1) clear cell areas and 2) spindle cell areas that were at least focally positive for desmin and caldesmon. The patients' ages ranged from 47 to 82 years (mean 64 years). Presenting symptoms were uterine bleeding (three), abdominal pain (one), and a pelvic mass (one). There was no history of tuberous sclerosis or lymphangioleiomyomatosis. One patient had stage II disease, one stage III, and three stage IV. All were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Two received radiotherapy, and three were also treated with chemotherapy. The tumors ranged in size from 4 x 3 x 3 cm to 10 x 7 x 6 cm; all had significant cellular atypia, areas of coagulative necrosis, and between 10 and 90 mitoses per 10 high power fields. Vascular invasion was seen in three cases. The epithelioid component varied from 50% to 90% in each case; and the percentage of clear cells was < 1% in one case, 5% in one case, and 10% to 80% in three cases. Smooth muscle actin and desmin were positive in all cases. Four cases were positive for HMB-45 only in the clear cell areas. The tumor with < 1% of clear cells was negative for HMB-45. All were negative for S-100 and c-kit. Three patients died of disease at 9, 30, and 32 months; one patient is alive with progressive disease at 6 months, and one patient (stage II disease) is alive with no evidence of disease at 8 months. Unequivocal uterine epithelioid leiomyosarcomas may have clear cells positive for HMB-45. These tumors might belong to the group of lesion designated as PEComas; however, it is advisable to designate them as uterine leiomyosarcomas. In uterine smooth muscle tumors, some epithelioid cells most likely undergo clear cell changes and become positive for HMB-45. It would be advisable to perform this stain in all epithelioid smooth muscle tumors of the uterus.

Epithelioid Leiomyosarcoma Arising in the Subcutis—A New Case Report of a Rare Variant

Uterine epithelioid and myxoid leiomyosarcomas and inflammatory myofibroblastic tumors are rare mesenchymal neoplasms. Next-generation sequencing recently detected novel PGR fusions in uterine epithelioid leiomyosarcomas that demonstrate characteristic rhabdoid and spindled morphology. PLAG1 gene fusions have also been identified in a subset of myxoid leiomyosarcomas and are associated with PLAG1 overexpression. ALK rearrangements underpin the vast majority of uterine inflammatory myofibroblastic tumors, which demonstrate morphologic, and immunohistochemical features similar to those of inflammatory myofibroblastic tumors elsewhere. This review summarizes the morphologic, immunophenotypic, and molecular genetic features of PGR fusion-positive epithelioid leiomyosarcoma, PLAG1 fusion-positive myxoid leiomyosarcoma, and inflammatory myofibroblastic tumors of the uterus.

Epithelioid leiomyosarcoma of the uterus is rare and poorly understood. Herein, we characterize a large institutional series of epithelioid leiomyosarcomas aiming to define outcome-determinant diagnostic pathologic features. We also retrieved epithelioid smooth muscle tumors of unknown malignant potential and evaluated a consecutive cohort of leiomyomas for epithelioid subtypes. Of a total of 1177 uterine leiomyosarcomas, 81 (7%) were categorized as epithelioid after review. Epithelioid leiomyosarcoma was strictly defined as having round to polygonal cells with visible pink cytoplasm and round to ovoid nuclei in ≥50% of the tumor volume. Average age was 55 years (range: 26 to 81 y). Median tumor size was 11 cm; tumor was >5 cm in 93% of subjects; 47% were stage 1 at presentation. An infiltrative tumor border was observed, grossly and/or microscopically, in 89% of cases; necrosis was noted in 80%, and vascular invasion in 47%. Mitotic count in 2.4 mm2 (totalling 10 high-power fields, each field 0.55 mm in diameter) ranged from 3 to 100 (median: 26). All cases had moderate, severe or highly pleomorphic atypia. All cases had 2 or 3 of the following: necrosis, at least moderate atypia and ≥4 mitoses in 2.4 mm2. Immunohistochemistry revealed frequent expression of smooth muscle markers including SMA (96%), desmin (95%), and caldesmon (81%). HMB45 and Melan-A were negative in 92% and 100% of cases, respectively. Estrogen and progesterone receptors were expressed by 65% and 54% of tumors, respectively. Follow-up information was available in 68 subjects (median: 23 mo, range: 1 to 254); cancer-related death occurred in 63%, and an additional 15% had recurrent or metastatic disease at last follow-up. Disease-specific survival was shorter in epithelioid leiomyosarcoma patients (median: 44 mo; 35% at 5-y) than in a matched cohort of nonepithelioid leiomyosarcoma (median: 55 mo; 46% at 5-y) (P=0.03). Three epithelioid smooth muscle tumors of unknown malignant potential were evaluated, all <5 cm in size and with atypia and/or irregular borders but mitotic count below the threshold for malignancy. Two of these had follow-up available, which was uneventful. Of 142 consecutive leiomyomas assessed, none had epithelioid morphology as defined. Epithelioid leiomyosarcoma is an aggressive neoplasm, sometimes with a remarkably low mitotic count. In the setting of an epithelioid smooth muscle tumor of the uterus, we postulate that the diagnosis of malignancy is made in the presence of ≥2 of the following: moderate or severe atypia, ≥4 mitoses/2.4 mm2 and tumor cell necrosis. In their absence, the finding of tumor size ≥5 cm, vascular invasion, infiltrative edges or atypical mitoses should be treated with caution, and designation as of at least uncertain malignant potential is warranted.

Genetic aberrations among uterine epithelioid leiomyosarcomas are unknown. Following identification of an index case with NR4A3-PGR fusion demonstrating monomorphic morphologic features, we interrogated additional uterine tumors demonstrating similar histology and sought to describe the morphologic and immunohistochemical characteristics of PGR-rearranged sarcomas. Targeted next-generation RNA sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue of the index case. Fluorescence in situ hybridization using custom probes flanking PGR and NR4A3 genes was applied to 17 epithelioid leiomyosarcomas, 6 endometrial stromal tumors, and 3 perivascular epithelioid cell tumors. NR4A3-PGR fusion (n=4) and PGR rearrangement (n=2) were detected in 6 (35%) epithelioid leiomyosarcomas. Median patient age was 45 years, and all presented with FIGO stage I or II tumors, 2 being alive with disease at 75 and 180 months. All tumors were centered in the cervical stroma or myometrium and consisted of cells with abundant eosinophilic cytoplasm (epithelioid), including many displaying dense intracytoplasmic inclusions (rhabdoid). Myxoid matrix and hydropic change imparted a microcystic growth pattern in 4 tumors. Five also showed a minor spindle cell component which was low-grade in 3, consisting of bland spindle cells with low mitotic activity. High-grade spindle cell morphology was seen in 2 tumors, exhibiting a storiform pattern of atypical spindle cells associated with brisk mitotic activity. Desmin, estrogen receptor, and progesterone receptor were positive in all 6 tumors, while CD10 and HMB45 were negative. PGR rearrangements define a genetic subset of epithelioid leiomyosarcomas with often biphasic morphology consisting of epithelioid and rhabdoid as well as spindle cell components.

Patient: Female, 58-year-oldFinal Diagnosis: LeiomyosarcomaSymptoms: Abdominal painClinical Procedure: Hysterectomy • salpingo-oophorectomySpecialty: PathologyObjective:Rare diseaseBackground:Leiomyosarcoma is the most common uterine sarcoma. Leiomyosarcoma is classified into conventional leiomyosarcoma, epithelioid leiomyosarcoma, and myxoid leiomyosarcoma. Leiomyosarcomas with rhabdoid features have been rarely reported. Herein, we report a case of uterine leiomyosarcoma with rhabdoid features.Case Report:A 58-year-old Korean woman presented with acute abdominal pain. Computed tomography and magnetic resonance imaging of the pelvis revealed a large solid mass in the posterior wall of the uterus that extended to the uterine cervix. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy and tumor-ectomy. Microscopic and immunohistochemical examination of the tumor revealed leiomyosarcoma with rhabdoid features and high proliferation rate. Next-generation sequencing showed PI3K amplification and ERBB2 amplification. Postoperative abdominal and pelvic computed tomography performed 3 weeks after the operation showed a mass at the vaginal stump that was attached to the urinary bladder and rectum. The patient underwent pelvic exenteration of remnant vaginal stump, rectum, and urinary bladder with loop ileostomy, and was diagnosed with recurrent leiomyosarcoma. One month later, after the second operation, a 13-cm recurrent mass was noted on the computed tomography. Chemotherapy was not done and the patient died during supportive treatment 7 months after diagnosis.Conclusions:This case, which is a uterine leiomyosarcoma with rhabdoid features and high proliferation rate, recurred very fast, within 1 month, and showed an aggressive clinical course. The molecular classification and postoperative therapy are not well established in uterine leiomyosarcomas. Further studies are required to clarify the clinical and pathological characteristics of leiomyosarcomas.

BackgroundUterine sarcoma is a rare tumor that is often difficult to classify based on morphological and immunohistochemical analysis alone. Limited access to molecular biological analysis in routine practice would hinder making a definitive diagnosis.Case PresentationIn this report, we describe a case of a mesenchymal tumor arising from the uterine cervix in a 52-year-old woman. From microscopic morphology of the resected specimen, epithelioid leiomyosarcoma, high-grade endometrial stromal sarcoma, or uterine gastrointestinal stromal tumor (GIST) were considered as differential diagnoses. The immunophenotype of the tumor featured smooth muscle differentiation and hormone receptor expression. The cell membrane and cytoplasm were positive for c-kit, although no mutation was found in the c-kit or PDGFRA gene. Fluorescence in situ hybridization (FISH) analysis revealed a relatively low frequency of YWHAE rearrangement, whereas there were few NUTM2A and NUTM2B split signals.ConclusionsIn this case, the tumor was not typical of any three of the differential diagnoses mentioned above. However, insufficient frequency of YWHAE, NUTM2A, and NUTM2B gene rearrangement and absence of mutation in both the c-kit and PDGFRA genes suggested that this tumor should be categorized as epithelioid leiomyosarcoma. This is an instructive case showing a potential diagnostic pitfall of uterine sarcoma. Comprehensive approaches including molecular biological techniques are required for definitive diagnosis.

Small intestinal malignant tumor accounts for about 3% of all malignant tumors in the gastrointestinal tract, among which 13% are leiomyosarcoma (LMS). In addition, epithelioid LMS is of very rare occurrence. As small intestinal malignant tumors are initially asymptomatic and nonspecific, diagnosis is often delayed, and this can lead to large tumor at the time of detection and lead to intussusception. We observed ileocolonic intussusception in an 80-year-old male patient who was admitted to the hospital with a complaint of abdominal pain and palpable mass on right lower quadrant. The laparoscopic ileocecectomy was performed by the emergency operation because of obstruction. The pathologic examination revealed that the epithelioid LMS developed in the terminal ileum was the leading point of intussusception. To the best of our knowledge, laparoscopic surgery for ileocolonic intussusception with epithelioid LMS has not yet been reported.

Leiomyosarcomas (LMS) are the most common type of uterine sarcoma. Most LMS have typical histologic features, and variants such as epithelioid LMS, myxoid LMS, LMS with osteoclast-like giant cells and LMS with rhabdoid features occur only rarely. Rhabdoid cells were first described in rhabdoid tumor, a distinctive renal neoplasm of infancy. Such tumors are composed of diffuse proliferation of rhabdoid cells that are round or polygonal in shape with eccentric nuclei, prominent nucleoli and glassy eosinophilic cytoplasm containing hyaline-like inclusion bodies. In the literature, extrarenal localizations of malign rhabdoid tumors have been described in a variety of primary sites such as the central nervous system, liver, skin and soft tissues. These characteristic rhabdoid cells have been reported in sarcomas and carcinomas of various types and in a few cases of uterine sarcomas. The presence of rhabdoid cells in tumors is considered to be a predictor of aggressive tumor behavior. Our case is that of a 56-year-old woman who was admitted to the state hospital with left inguinal mass. Microscopically the tumor was admixed of three different types of cell with spindle, epithelioid or rhabdoid features. Immunopositive cytoplasmic staining for myoglobulin and desmin was seen in rhabdoid cells, and cytokeratin immunopositivity was observed in epithelioid and some rhabdoid cells. Epithelioid cells and spindle cells were also SMA positive. The histopathologic and immunohistochemical findings support the diagnosis of epithelioid LMS with rhabdoid features. We report this very uncommon LMS variant; to the best of our knowledge there are only a few cases in the English literature.

Uterine sarcomas.

Uterine Leiomyosarcomas and Benign Smooth Muscle Tumors: Usefulness of Nuclear DNA Patterns Studied by Flow Cytometry

To better define the cytological features of various leiomyosarcoma (LMS) variants, we reviewed the fine-needle aspiration material and the corresponding histologic sections of 96 tumors in 68 patients. Histological variants of LMS were as follows: 80 (83.3%) were of the classical/usual, seven (7.3%) were epithelioid, and nine (9.4%) were myxoid. Review of original cytology reports showed that 23 (24%) tumors were diagnosed as LMS and 69 (71.8%) as other types of malignancies. Two (2.1%) cases were reported as suspicious and two (2.1%) were unsatisfactory. The classical variants of LMS were characterized cytologically by various proportions of spindle-shaped, cohesive, small- or large-sized cells arranged in parallel alignment. Large spindle, round, binucleated, giant cells with intracytoplasmic granulations were frequently seen. Blunt-ended nuclei, intranuclear inclusions and mitotic figures were occasionally seen, as well as stromal fragments. The epithelioid tumors were composed of an admixture of small and large, spindle-shaped and round cells, also arranged in parallel alignment. Tumor cells with granular cytoplasm, blunt-ended nuclei, intranuclear inclusions, mitotic figures, fibrous or myxoid stroma were not observed. The myxoid tumors disclosed large amounts of background myxoid matrix containing large spindle-shaped and giant cells. Entities such as leiomyoma, malignant peripheral nerve sheath tumor, monophasic synovial sarcoma, and malignant fibrous histiocytoma should be considered in the differential diagnosis of LMS of the classical type. Epithelioid leiomyoma may share similar cytological features with epithelioid LMS. The cytological features of the myxoid variant of LMS can be easily confused with other types of benign and malignant mesenchymal tumors depicting degenerative myxoid changes and/or a myxoid matrix component.

A diagnosis of parathyroid hormone-related protein (PTH-rP)-secreting metastatic uterine epithelioid leiomyosarcoma was made in a 61-year-old woman with humoral hypercalcemia of malignancy. A primary uterine tumor had been removed 10 years previously, which had been associated with a short history of hypercalcemia. The original uterine tumor was diagnosed as a smooth muscle tumor of uncertain malignant potential. To the best of our knowledge, this is the first reported case of a PTH-rP-secreting uterine leiomyosarcoma. We demonstrate the dramatic changes in serum calcium, phosphorus, PTH, and PTH-rP levels after tumor resection. Extensive biochemical analysis and detailed immunohistochemical and ultrastructural characterization demonstrate several features of this tumor.

A uterine leiomyosarcoma that became positive for HMB45 in the metastasis

Uterine mesenchymal tumors are a heterogeneous group of neoplasms that can be diagnostically challenging. Thorough investigations and histopathological findings are highly significant to arrive at the correct diagnosis, thus ensuring appropriate and prompt treatment to the patient. Leiomyosarcoma (LMS) is an uncommon uterine malignancy, which arises from the smooth muscle of the uterine wall. They usually present in postmenopausal women with abnormal uterine bleeding. It follows an aggressive clinical course with an extremely poor prognosis. Surgical management followed by adjuvant chemotherapy is usually the treatment for such cases. Here, we report the case of a 57-year-old menopausal female who presented with a large abdominal swelling that was seen infiltrating the adjacent structures. On resection and histopathological evaluation, a diagnosis of epithelioid LMS was made, which was confirmed by immunohistochemistry.