Fritchie, Karen

AimsPRRX1–NCOA1‐rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis.Methods and resultsThe six cases were from three females and three males (age, 20–49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow‐growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent‐shaped or staghorn‐like thin‐walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA‐sequencing revealed PRRX1–NCOA1 fusions in all cases. Of the four cases with limited follow‐up (1.5–4 months), none recurred following local surgical excision.ConclusionsThe morphological features of PRRX1–NCOA1‐rearranged fibroblastic tumour overlap with those of RB1‐deficient soft‐tissue tumours, solitary fibrous tumour, and low‐grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1–NCOA1‐rearranged fibroblastic tumour appears to be quite favourable, although longer‐term study of a larger number of cases is warranted.

Aims . Fibrous dysplasia (FD) is a benign fibro-osseous neoplasm that most commonly arises in the ribs, femur, and craniofacial bones. We analyzed features of FD arising in the spine/short tubular/small bones of the hands/feet (STSBHF), specifically assessing for pattern of bone formation (conventional, complex/anastomosing, psammomatoid/cementum like), myxoid change, and presence of osteoclast-type giant cells. Materials and methods . A total of 1958 cases of FD were reviewed, of which 131 arose in the spine/STSBHF representing 2.5% of institutional and 10% of consultation cases, respectively. Eighty-six cases had material available for review. Anatomic sites included vertebrae ( n = 58, 67%), short tubular bones ( n = 20, 23%), and small bones of the hands/feet ( n = 8, 9%). The most common morphologic pattern of bone identified was conventional ( n = 77, 90%), followed by complex/anastomosing ( n = 22, 26%) and psammomatoid/cementum like ( n = 22, 26%). Eighteen cases (21%) had matrix-poor areas. Hypercellular areas were identified in 6 cases, 2 cases of which showed matrix-poor areas. Osteoclast-type giant cells were noted in 9 cases and myxoid change was present in 3 cases. Radiologic imaging studies available for 41 cases nearly all demonstrated features typical of FD, but the diagnosis was not predicted due to the unexpected location. Conclusions . FD arising in the spine/STSBHF is rare and frequently results in expert consultation. A significant number of cases exhibited less commonly recognized patterns of bone formation, and stromal changes including osteoclast-type giant cells, and matrix poor areas. Furthermore, imaging features in the STSBHF are often less specific. Awareness of the morphologic spectrum at these locations coupled with radiologic correlation should aid in accurate classification.

Abstract One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell–cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression. Significance: Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma. See related commentary by Menard, p. 2815

AbstractA novel group of S100‐ and CD34‐positive spindle cell tumors with distinctive stromal and perivascular hyalinization harboring recurrent gene fusions involving kinases includingRAF1,BRAF,NTRK1/2/3, andREThave been recently reported. To our knowledge, no such cases harboringALKrearrangements have been identified. We report a previously healthy 41‐year‐old male with a 12‐cm intramuscular shoulder mass. The tumor was composed of bland‐appearing spindled to epithelioid cells, arranged in a patternless pattern in a background of loose myxoid stroma containing striking amianthoid‐like stromal collagen and perivascular rings. In accordance with the previously reported tumors, the tumor cells showed diffuse immunopositivity with S100 and CD34, while lacking SOX10 expression. Targeted RNA‐based next‐generation sequencing identified a novel serine/threonine‐protein phosphatase PP1‐beta‐catalytic subunit (PPP1CB)‐ALKfusion gene. Although ALK break‐apart was not detected by FISH, likely due to a paracentric inversion of chromosome 2, the presence of the fusion was confirmed by Sanger sequencing showing a 10‐bp linker between exon 6 ofPPP1CBand intron 19 ofALKwhile maintaining reading frame. Subsequent ALK‐1 immunostain exhibited diffuse cytoplasmic staining in the tumor cells. Our case expands the molecular genetic spectrum of the distinctive group of spindle cell tumors with CD34/S100+ immunophenotype, supporting the important role of various kinases as drivers of oncogenesis. Awareness of this entity including its unique morphologic and immunophenotypic features as well as its interchangeable kinase gene fusions is crucial for correct classification and potential targeted therapy, particularly in aggressive subsets.

AbstractCIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC‐DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45‐years‐old, range 14‐65) superficial CIC‐rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next‐generation sequencing was positive for CIC‐DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC‐DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow‐up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC‐rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC‐rearranged sarcomas are aggressive.

Objective. We explore the clinicopathologic features of Ewing sarcoma (ES) presenting in older adulthood. Methods. Cases of molecularly confirmed ES arising in patients aged ≥40 years were evaluated. Results. Fifty patients were identified (33 males/17 females; 41-86 years). The majority of tumors (41) arose at extraskeletal sites, while 9 were bone primaries. Twenty-eight cases showed nested architecture, while the remaining cases showed sheet-like growth. Tumor cytology was categorized as conventional (n = 39), crushed (n = 5), clear cell (n = 4), rhabdoid (n = 3), and epithelioid (n = 2). Fifty percent had necrosis, while rosettes were noted in 1 case. Immunostains performed ranged from 1 to 28 (median = 10). Follow-up (n = 43, 1-147 months) revealed 15 patients with metastasis. Conclusion. Although rare, ES should be considered in the differential diagnosis for round cell malignancies in older adult patients. In this cohort, ES is most often extraskeletal, and may show unusual morphologic features, closely simulating more common neoplasms in this age group.

Calcification and ossification are uncommon in schwannomas; however, when present these findings may cause diagnostic confusion with other mesenchymal tumors which more frequently harbor these features. We sought to better characterize the type and rate of calcification and ossification in schwannomas. Cases of schwannoma diagnosed at our institution from 2005 to 2019 were reviewed to determine the type and amount of calcification and ossification present. Of 2116 total cases of schwannoma reported during the study period, 38 cases harbored calcification or ossification per the pathology report. Thirty‐two of the 38 cases had slides available for review, of which 27 (84.3%) showed calcification, nine showed ossification (28.1%), and four (12.5%) cases demonstrated both. Foci of ossification typically occurred adjacent to large vessels. Of the 27 cases showing calcification, coarse dystrophic calcification was seen in 22 cases, psammomatous calcification in nine cases, and combined dystrophic and psammomatous calcification was seen in four cases. Cases with psammomatous calcification predominantly occurred in spinal roots and cerebellopontine angle of a younger age group with almost equal gender distribution. All four cases tested for protein kinase cyclic adenosine monophosphate‐dependent type I regulatory subunit alpha immunohistochemical stain demonstrated retained expression. We confirm that calcification and ossification are rare findings in schwannoma. Awareness that these features may be present in these tumors will prevent misdiagnosis and ensure appropriate clinical management.

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and spindle cell lipoma are lipomatous tumors with distinct clinical, molecular, and prognostic features. Although histological and immunophenotypic features can overlap between ALT/WDL and spindle cell lipoma, the oncogenesis and clinical behavior are markedly different. In borderline cases, molecular analysis for MDM2 or CDK4 amplification can aid in distinguishing ALT/WDL from spindle cell lipoma. Although dedifferentiated liposarcoma has been reported to harbor both MDM2 amplification and loss of the RB1 region, we are not aware of a reported RB1 loss in well-differentiated ALT/WDL. In this article, we present a 69-year-old woman with a lipomatous tumor in the gluteal region that histologically, immunohistochemically, and molecularly mimicked spindle cell lipoma (with positive immunohistochemical staining for CD34 and loss of the RB1 gene region), yet harbored amplification of MDM2 and CDK4 confirmed by fluorescence in situ hybridization, supporting classification as ALT/WDL. This case strengthens the argument that in atypical clinical contexts, molecular studies for MDM2/CDK4 should be considered in tumors resembling spindle cell lipoma.

Aims Limited data exist on atypical lipomatous tumour (ALT)/well‐differentiated liposarcoma (WDL) and de‐differentiated liposarcoma (DDLPS) in children and young adults. Methods and results Cases of ALT/WDL/DDLPS arising in patients aged ≤ 40 years were collected from multiple institutional and consultation archives. A total of 116 cases of ALT/WDL (75) and DDLPS (41) were identified, representing fewer than 5% of these tumours seen at our institutions during this time‐period. The patients (59 male/57 female) ranged in age from 8 to 40 years. Sites included deep central (abdomen/retroperitoneum/pelvis/groin) ( n = 60), extremity ( n = 42), trunk ( n = 5), head/neck ( n = 8) and mediastinum ( n = 1). De‐differentiated patterns included: high‐grade pleomorphic sarcoma, myxofibrosarcoma‐like, heterologous rhabdomyoblastic differentiation, low‐grade spindle cell sarcoma and homologous lipoblastic differentiation. Forty‐one patients experienced a local recurrence and 11 patients with DDLPS developed metastasis. ALT arising in the extremities had lower recurrence rates than deep central WDL (5‐year recurrence‐free survival 88.9% versus 59.0%; P = 0.002), while patients with deep central DDLPS experienced significantly more adverse events compared to WDL at this site (5‐year event‐free survival 11.9% versus 59.0%) ( P < 0.0001). Seven (of eight) head/neck tumours had follow‐up available; five recurred, and one patient (DDLPS) with recurrence also experienced a metastasis. The single mediastinal tumour (DDLPS) recurred and metastasised. Conclusion ALT/WDL and DDLPS occurring in patients aged ≤ 40 years is rare, but exhibits similar morphological features to its counterparts in older adults, including potential for heterologous and homologous de‐differentiation in the latter. Although case numbers are limited, tumours arising in the head and neck exhibit high rates of adverse events, suggesting that classification as WDL rather than ALT is more appropriate.