Undifferentiated Embryonal Sarcoma of the Liver with Epithelioid Features: A Case Report of an Exceptional Histological Heterogeneity among Rare Diseases.

INTRODUCTION: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignant tumor, with nonspecific clinical symptoms and radiological features. Less than 150 cases have been reported in adults across the world. PRESENTATION OF CASE: We report a case of an extremely rare subtype of UESL with epithelioid features in a 29-year-old woman, presenting as a cystic lesion of 27 × 17 cm, completely subverting the right hepatic lobe. She underwent a right hepatectomy with anterior approach, complete hilum lymphadenectomy and partial diaphragmatic resection for local infiltration, followed by systemic chemotherapy. She remains with no evidence of disease and liver mass has been restored after 6 months. DISCUSSION: The present case report represents the second case of UESL with epithelioid features described across the world. The immunohistochemical expression pattern, cytokeratin (CK)19 + and CK7 -, strongly suggests an origin of this epithelioid component from native biliary cells and not from a reshaped ductal plate. Due to the rarity of this form, to date it is impossible to define the prognostic impact of this subtype of UESL, and treatment remains challenging. CONCLUSION: UESL is associated with a poor prognosis, especially in adults, but a comprehensive and multidisciplinary treatment based on radical resection and adjuvant therapy may provide a survival benefit. Surgical excision with negative margins remains mandatory to diagnose and treat UESL.

Intra-Abdominal Epithelioid Neoplasm With EWSR1::CREB Fusions Involving the Kidney: A Clinicopathologic and Molecular Characterization With an Emphasis on Differential Diagnosis.

Soft tissue neoplasms, harboring fusions between EWSR1 and FUS with genes encoding CREB transcription factors family (ATF1, CREB1, and CREM), are an emerging heterogeneous group of mesenchymal tumors that differ significantly in morphology, immunophenotypes, and behavior. Recently, EWSR1/FUS::CREB fusions have been recognized to define a group of aggressive neoplasms of epithelioid morphology with multiple growth patterns and a striking predilection for mesothelial-lined cavities. These neoplasms presenting as a primary neoplasm of intra-abdominal visceral organs are rare, which could elicit a wide range of differential diagnoses because of their diverse morphologies and immunohistochemical profiles. We report 3 cases of intra-abdominal epithelioid neoplasms with EWSR1::CREB fusions involving the kidney. This study included 2 female patients and 1 male patient, with age at presentation ranging from 17 to 61 years (mean: 32 years). All the patients underwent radical nephrectomy without adjunctive therapies. Grossly, the tumors were large, and all were solitary masses with sizes ranging from 5.6 to 30.0 cm (mean: 14.5 cm). Histologically, the neoplasms showed infiltrating and indistinct borders and were composed predominantly of monomorphic round-to-epithelioid cells with variable amounts of pale-to-clear cytoplasm, arranged in cords, nests, and sheets and embedded in a sclerotic hyalinized stroma with variable lymphoid cuffing either intermixed or at the periphery. Notably, a hemangiopericytomatous growth pattern was commonly seen. Nuclear atypia was mild, and mitotic activity was scarce. Immunohistochemically, all 3 cases were at least focally positive for epithelial membrane antigen and keratin AE1/AE3, with 2 tumors showing focal MUC4 expression and 1 case displaying diffuse CD34 and focal CAIX positivity. Targeted RNA sequencing identified EWSR1::CREM fusion in 2 cases and EWSR1::ATF1 fusion in 1 case. Subsequent fluorescence in situ hybridization analysis confirmed the RNA sequencing results. On follow-up, 1 patient developed multiple spinal bone metastases 5 months after the surgery while the other 2 patients were free of disease 9 and 120 months after diagnosis, respectively. Our findings demonstrate that intra-abdominal epithelioid neoplasms with EWSR1::CREB fusions may rarely occur primarily in the kidney and should be included in the differential diagnosis of primary renal epithelioid mesenchymal neoplasms.

Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Primary gallbladder melanoma: A systematic review of literature.

Primary gallbladder melanoma (PGM) is a rare malignancy with only sporadic cases reported in the English literature. We performed a systematic review of the cases published in the PubMed, Science Direct and Google Scholar databases with the aim of describing the reported clinicopathologic features of PGM. Thirty-six articles reporting on 39 patients were reviewed. There was a male predominance, with 23 (64 %) of 36 patients being males. The mean age at presentation was 55 ±16 years. Pain in the right upper quadrant was reported in 20/27 (74 %). The average size of the tumor was 3.5 × 1.9 × 1.4 cm. Gallbladder calculi were reported in 7/27 (26 %). A cholecystectomy was performed in 34/38 (89.5 %). Grossly, the tumor mostly (96.5 %) had polypoid appearances and on microscopic examination, the tumor were predominantly comprised of epithelioid cells 12/17 (70.6 %). Mitotic figures and prominent nucleoli were reportedly found in 8/8 (100 %) and 3/3 (100 %) respectively. Junctional melanocytic components were present in 13/21 (61.9 %). Tumor cells were reportedly immunoreactive for S-100 and HMB-45 in all tested cases. Metastasis were reported in 25/36 (69.4 %), with lymph nodes being the most common site (n = 8), followed by brain (n = 6) and liver (n = 4) for metastasis. At a mean follow-up period of 19 +/- 3 months, 16 (48.5 %) of the 33 patients with available survival data were alive and 17/33 (51.5 %) were dead of disease. There is a lack of unified criteria for the diagnosis of PGM, and future studies should aim to resolve this.

Molecular Characterization of Malignant Renal Epithelioid Angiomyolipoma: A Review of Two Cases.

OBJECTIVES: Epithelioid angiomyolipoma (EAML, perivascular epithelioid cell tumor) is an uncommon primary renal tumor that may recur or metastasize, although there remain limited data for prediction of these outcomes. Here, we report two cases of renal EAML with molecular testing, adding to the existing literature of potential alterations associated with malignant behavior. METHODS: Tumors diagnosed as malignant renal EAML were identified, and clinical data, radiology, histology, immunohistochemistry, and molecular testing results were reviewed. RESULTS: Two cases of malignant renal EAML were identified, both of which demonstrated TSC2 and TP53 mutations. In ATRX, one had a mutation and the other had a variant of uncertain significance. In addition, one patient had a synchronous classic angiomyolipoma that lacked TP53 and ATRX alterations. CONCLUSIONS: These findings highlight the molecular landscape of malignant renal EAML and expand on the existing literature suggesting a role for TP53 and ATRX alterations in malignant progression of these tumors. The presence of synchronous benign and malignant tumors within the same patient offers a unique opportunity to directly compare the molecular alterations, further supporting the association with aggressive behavior.

Epithelioid Trophoblastic Tumor Presenting as an Adnexal Mass: Report of a Diagnostically Challenging Case.

Epithelioid trophoblastic tumor (ETT) is a rare neoplasm derived from chorionic intermediate trophoblast cells, representing less than 2% of all gestational trophoblastic neoplasms. Classically, ETT presents as a uterine mass in women of reproductive age following a term pregnancy. The time from pregnancy to tumor development varies from months to several years. ETT most often arises in the endometrium, followed by the cervix. Extrauterine ETT are extremely infrequent, with few cases reported in the literature. We report a case of a 41-year-old woman, with history of three term pregnancies who presented with abdominal pain and elevated beta human chorionic gonadotropin (ß-hCG) level, ten years after her last pregnancy. Imaging reported a 3.5 cm adnexal mass, suspicious for ectopic pregnancy. Hysterectomy and mass resection revealed a 4.7 cm, tan-yellow, necrotic mass adjacent to the broad ligament. Histologic evaluation in conjunction with immunohistochemical stains revealed a tumor consistent with ETT. No connection to the endometrium was found grossly or microscopically. DNA fingerprinting analysis revealed the tumor to have two copies of paternal alleles, as seen in molar gestations. One of the primary differential diagnoses for ETT is squamous cell carcinoma due to similar morphologic features. In challenging cases, genetic analysis demonstrating paternally derived genes can establish the diagnosis. In this report, we discuss the challenges in the diagnosis of extrauterine ETT, due to its rarity and highly variable presentation, given that appropriate diagnosis is critical for correct patient management.

Malignant Pigmented Epithelioid Angiomyolipoma of the Kidney in a Child with Tuberous Sclerosis Complex.

INTRODUCTION: Pigmented epithelioid angiomyolipoma is a variant of epithelioid angiomyolipoma (EAML) that has not previously been described in children with tuberous sclerosis. CASE PRESENTATION: A 15-year-old boy with tuberous sclerosis had a rapidly enlarging renal mass associated with a left lung nodule. Microscopically it was a pigmented EAML, confirmed by immunohistochemistry. DISCUSSION/CONCLUSION: The pigmented variant of EAML can arise and metastasize from the kidney of a teenager with tuberous sclerosis.

Primitive pituitary perivascascular epithelioid cell tumor: A challenging diagnosis of melanocytic pituitary lesion.

BACKGROUND: Perivascular Epithelioid cell tumors (PEComa) are rare mesenchymal tumors. They generally occur in the gynecologic or digestive tract. The diagnosis of Central Nervous System PEComa is exceptional and challenging. CASE DESCRIPTION: We report the case of a 46-year-old woman, with no particular medical history, who presented a secondary amenorrhea and a slight hyperprolactinemia. She was diagnosed on MRI with a pituitary tumor showing spontaneous hypersignal in T1-weighted images. After failure of medical treatment with cabergoline, surgical resection was required due to progressive tumor growth. Macroscopic aspect and initial immunohistochemical features were in favor of a primitive hypophyseal melanocytoma. However, molecular and transcriptional study through targeted exome- and RNA-sequencing led to the exceptional diagnosis of pituitary Perivascular Epithelioid Cell Tumor (PEComa). Three-years of postoperative radio-clinical follow-up showed an asymptomatic non-evolutive small remnant. CONCLUSION: PEComa is an exceptional diagnosis among pituitary tumors. It should be evoked as a potential differential diagnosis in case of primitive melanocytic lesion of the pituitary gland. Specific molecular analysis is mandatory to confirm the diagnosis and exclude differential diagnosis.

A rare case of primary cutaneous malignant perivascular epithelioid cell tumor and review of the literature.

A 77-year-old female presented with a 6-month history of a 2-cm pink exophytic tumor on the right anterior shin, which had grown rapidly and began to bleed over the last 4 weeks. A shave biopsy showed a dermal proliferation of epithelioid spindled cells, arranged in nests and trabeculae associated with thin-walled capillary vessels. The cells showed pleomorphic nuclei with vacuolated nuclear chromatin and occasional prominent nucleoli. Mitotic figures (7/10 high-power fields [HPFs]), including atypical forms, were present in the specimen. Immunohistochemical staining was negative for SOX10 and stained positive for MiTF. The histopathologic findings were consistent with a malignant perivascular epithelioid cell tumor (PEComa). A malignant PEComa is a rare entity of mesenchymal-derived cells with both melanocytic and myocytic differentiation. A PEComa is considered to be malignant by fulfilling two of the following criteria: size greater than 5 cm, vascular invasion, necrosis, mitotic figures greater than 1 per 50 HPF, infiltrative growth pattern, high nuclear grade, and hypercellularity. PEComas show immunohistochemical positivity to myocytic markers such as SMA, pan-muscle actin, muscle myosin, calponin, and h-caldesmon as well as melanocytic markers such as HMB-45, Melan-A, tyrosinase, and MiTF.

Advancements in the diagnosis and treatment of renal epithelioid angiomyolipoma: A narrative review.

Renal epithelioid angiomyolipoma (EAML) is a unique subtype of angiomyolipoma that contains a variety of cytoplasmic-rich, eosinophilic cytoplasm epithelioid cells in addition to mature adipocytes, hyaline thick-walled vessels, and smooth muscle-like spindle cells. In recent years, increasing evidence has shown that EAML is a potentially malignant tumor. Due to the lack of typical clinical manifestations and imaging features, it is difficult to diagnose before surgery, and the diagnosis mainly depends on postoperative histopathological examination. With the advancement of pathological diagnostic techniques, more EAML cases has been discovered, but clinicians still lack a comprehensive understanding of EAML. This review comprehensively describes some pathological and clinical features of EAML, with special attention to the pathogenesis and treatment of malignant EAML in order to assist with clinical diagnosis and treatment.

♣Evaluation of clinicopathological profiles and development of a risk model in renal epithelioid angiomyolipoma patients: a large-scale retrospective cohort study.

BACKGROUND: To identify the malignant potential and prognostic indicators of renal epithelioid angiomyolipoma (eAML), clinicopathological and molecular features as well as the drug efficacy of 67 eAML cases were analyzed. MATERIALS AND METHODS: Sixty-seven renal eAML patients were enrolled and the immunohistochemical features of these patients were examined. FFPE slides of all patients were re-examined. 21 patients with metastasis received Everolimus 10 mg orally once daily. Responses were evaluated with RECIST criteria by three authors. A risk stratification model was constructed using the following factors: pT3 and pT4, presence of necrosis, mitotic count ≥ 2; the presence of atypical mitoses; severe nuclear atypia, SMA negative, Ki-67 ≥ 10%. RESULTS: The average percentage of the epithelioid component was 85.6% (range 80-95%). Immunohistochemically, Ki-67 ≥ 10% and negative SMA staining were significantly correlated with malignant characteristics (Ki-67: p < 0.001; SMA: p = 0.001). Survival analysis suggested that pT3-pT4 stage, presence of necrosis, severe nuclear atypia, presence of atypical mitoses, mitotic count ≥ 2, Ki-67 ≥ 10% and negative SMA expression were significantly associated with poorer PFS and OS (p < 0.05). The risk model sufficiently discriminated recurrence/metastasis (AUC = 0.897) and cancer-specific mortality (AUC = 0.932) of renal eAML patients in different risk groups. 21 patients had received Everolimus targeted therapy after recurrence/metastasis. The best response for Everolimus treatment was 8/21 (38.1%) partial responses (PR), 9/21 (42.9%) stable disease (SD) and 4/21 (19.0%) progressive disease (PD). CONCLUSION: The risk stratification model could well distinguish eAML patients at high risk of recurrence/metastasis. Everolimus targeted treatment showed good efficacy in patients with recurrence/metastasis.

Primitive Cutaneous (P)erivascular (E)pithelioid (C)ell Tumour (PEComa): A New Case Report of a Rare Cutaneous Tumor.

Perivascular epithelioid cell tumours (PEComas) are a growing family of tumours composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. Cutaneous primitive PEComas (cPEComas) are very rare, with 65 cases described in the English literature, and occur as a painless lesion predominantly in female patients, with a wide age range. We present a new case of cPEComa found on the left thigh of a 53-year-old patient with histopathological, immunohistochemical, and molecular information. The lesion was positive for HMB-45 and focal for smooth muscle actin and desmin but negative for melan-A, S-100 protein, CD31, and CD34. Next generation sequencing (NGS) analysis demonstrated the presence of genomic aberration for baculoviral IAP repeats containing BIRC3 splice site 1622-27_1631del37. Although there are little molecular data regarding this entity, our case adds to this knowledge, considering the importance of detecting genomic aberrations in the context of specific therapies such as mTOR inhibitors.

Trends of lymph node sampling and metastasis in pediatric and young adult patients with clear cell, epithelioid, and synovial sarcomas.

BACKGROUND: Clear cell sarcoma of soft tissue (CCS), epithelioid sarcoma, and synovial sarcoma are rare tumors historically identified as high risk for lymph node metastasis. This study investigates incident nodal metastasis and associated survival in children and young adults with these subtypes. PROCEDURE: Using the National Cancer Database (2004-2015), we created a retrospective cohort of 1303 patients (aged ≤25 years) who underwent local control therapy for CCS, epithelioid sarcoma, and synovial sarcoma. Kaplan-Meier curves estimated overall survival (OS) by subtype. Stratifying on subtype, Cox regressions assessed OS by lymph node sampling status and nodal metastasis. RESULTS: There were 103 (7.9%) patients with CCS, 221 (17.0%) with epithelioid sarcoma, and 979 (75.1%) with synovial sarcoma. Lymph node sampling was more frequent in patients with CCS (56.3%) and epithelioid sarcoma (52.5%) versus synovial sarcoma (20.5%, p < .001). Synovial sarcoma metastasized to lymph nodes less frequently than CCS or epithelioid sarcoma (2.1% vs. 14.6% and 14.9%, p < .001). Across all subtypes, lymph node metastasis was associated with inferior OS (HR 2.02, CI 1.38-2.95, p < .001). Lymph node sampling was associated with improved OS in CCS (HR 0.35, CI: 0.15-0.78, p = .010), inferior OS in synovial sarcoma (HR 1.60, CI: 1.13-2.25, p = .007), and no statistical association with OS in epithelioid sarcoma. CONCLUSIONS: Lymph node metastasis is rare in children and young adults with synovial sarcoma. Lymph node sampling procedures were not consistently performed for patients with CCS or epithelioid sarcoma, but improved OS supports routine lymph node sampling in children and young adults with CCS.

Superficial CD34-positive fibroblastic tumor (SCPFT): A review of pathological and clinical features.

Superficial CD34-positive fibroblastic tumor (SCPFT) is a recently described rare mesenchymal tumor of borderline malignancy. It generally involves superficial soft tissue, with a predilection to the lower extremities. Microscopically this tumor is characterized by a fascicular and storiform growth pattern, spindled to epithelioid cells, nuclear atypia with pleomorphism, and eosinophilic granular, and fibrillar to glassy cytoplasm. Strong diffuse immunoreactivity for CD34 is very characteristic of this entity. Due to under-recognition, this tumor is generally underreported. Additionally, cases of recurrence are rarely reported in the literature. We will comprehensively review the English language literature on all reported cases of SCPFT, with emphasis on recurrence.

Diagnostic Challenges of Intra-operative Frozen Consultation for Mammary Epithelioid Myofibroblastoma.

Myofibroblastoma (MFB) of the breast is a rare benign neoplasm that exhibits several morphologic variants and presents diagnostic challenges for pathologists, especially in recognizing intra-operative frozen sections. In order to raise awareness of this tumor and avoid misdiagnosis, we describe a case of a 38-year-old female patient diagnosed as epithelioid MFB. This painless tumor was well-circumscribed, found in the left breast and was physically examined over a period of six months. Histologically, this tumor was predominantly composed of epithelioid cells, which arranged as single cells, small clusters or nests. Tumor stroma was collagenized with spindle cells, adipose and focal myxoid areas. This case was misinterpreted as invasive carcinoma in the frozen section. The immunohistochemical profile demonstrated positivity for Vimentin, desmin, SMA, calponin, CD34, ER, PR and AR, whereas pan-keratin, keratin 7, keratin 34ßE12, keratin 5/6, EMA, p63 and S100 were negative. RB1 was abnormally negative, confirming the diagnosis of epithelioid MFB. Making a correct diagnosis is primarily dependent on awareness by the pathologist of this unusual variant of MFB and careful integration of clinicopathologic findings to avoid potential diagnostic pitfalls.

Expanding the spectrum of mesenchymal neoplasms with NR1D1-rearrangement.

Undifferentiated mesenchymal neoplasms can be morphologically subclassified based on cell shape; epithelioid tumors may be diagnostically challenging, particularly since they can show morphologic and immunohistochemical overlap with epithelial neoplasms. Following the recent report of an NR1D1::MAML1 gene fusion in an undifferentiated pediatric neoplasm, we performed a retrospective archival review and identified four additional cases of undifferentiated mesenchymal neoplasms with NR1D1-rearrangement. All four tumors occurred in adult women. The tumors involved superficial and/or deep soft tissues of the extremities or abdomen. Morphologically, they showed a spectrum of overlapping features. In addition to epithelioid cells, two cases also had a prominent spindle cell component. Two cases also had admixed polygonal cells containing prominent cytoplasmic vacuoles with amorphous debris. The immunophenotype was nonspecific but all cases had at least focal keratin expression; this was extensive in two tumors. Targeted RNA-sequencing revealed two cases each with NR1D1::MAML1 and NR1D1::MAML2 gene fusions. One patient developed lung and liver metastases, and one patient required amputation due to multifocal disease and underlying bone involvement. This study confirms undifferentiated NR1D1-rearranged sarcoma represents a distinct mesenchymal neoplasm with an epithelioid morphology and potential for aggressive behavior. Further, we offer new insight into the spectrum of clinical, morphologic, immunohistochemical, and molecular findings possible in these rare neoplasms. An awareness of this entity is especially important given the potential for misclassification as a carcinoma.

GLI1-altered epithelioid soft tissue tumor: A newly described entity with a predilection for the tongue.

A novel subset of epithelioid soft tissue tumors with GLI1 gene fusions or amplifications has recently been characterized. Histologically, these tumors typically exhibit multinodular or plexiform growth of ovoid, round to epithelioid neoplastic cells, with a distinctive nested architecture separated by a rich delicate arborizing vascular network. The immunoprofile is variable and nonspecific, indicating no definitive line of differentiation. GLI1-altered epithelioid soft tissue tumor is considered to be a low-grade sarcoma; however, with a limited number of cases reported, the biologic behavior of this entity is unclear. Interestingly, these tumors frequently occur in the head and neck, with a clear predilection for the tongue. To date, 11 cases of lingual GLI1-altered epithelioid soft tissue tumors have been reported in the English literature, and none showed evidence of recurrence or metastasis. Herein, we report an additional case of lingual GLI1-altered epithelioid soft tissue tumor harboring GLI1 fusion in a 56-year-old man with regional nodal metastasis and distant metastasis to increase the awareness of this entity among oral pathologists and clinicians. An accumulation of similar cases is mandatory to clarify biological behaviors and also for the development of new therapeutic strategies.

Snot what you think: Mucus or myxoid matrix with epithelioid cells and bubbly cytoplasm?

A case of progressive nasal obstruction in a 63 year old man is described. FNA cytology yielded dominant myxoid matrix with charateristic epithelioid cells, round nuclei with nucleoli, and eosinophilic, granular or vacuolated cytoplasm to allow a diagnosis tto be made.