Search

Background Ewing sarcoma (ES) is a round cell sarcoma that can be challenging to diagnose on cytologic material given its significant overlap with numerous mesenchymal, epithelial, and lymphoid cytomorphologic mimics. The objective of this study was to assess the utility of a novel marker, NKX2.2, in the diagnosis of ES in cytologic material and its ability to distinguish ES from its mimics. Methods NKX2.2 immunohistochemistry was performed on cell blocks from 107 fine-needle aspirations, and nuclear expression was scored semiquantitatively for extent and intensity. The study cohort included ES (n = 10), well differentiated neuroendocrine tumor (n = 20), melanoma (n = 11), Merkel cell carcinoma (n = 10), small cell carcinoma (n = 10), alveolar rhabdomyosarcoma (n = 2), spindle cell/sclerosing rhabdomyosarcoma (n = 2), synovial sarcoma (n = 12), solitary fibrous tumor (n = 2), chronic lymphocytic leukemia (n = 10), lymphoblastic lymphoma (n = 11), adenoid cystic carcinoma (n = 6), and CIC-rearranged sarcoma (n = 1). Results NKX2.2 had high sensitivity (100%) and moderate specificity (85%) for the diagnosis of ES in cytologic material. NKX2.2 expression also was present in a subset of mesenchymal and epithelial mimics, and staining was most commonly observed in small cell carcinoma (80%) and well differentiated neuroendocrine tumor (45%). Among mesenchymal mimics, 42% exhibited NKX2.2 expression. NKX2.2 staining was absent in melanoma, adenoid cystic carcinoma, and lymphoproliferative neoplasms. Conclusions NKX2.2 is a highly sensitive but only moderately specific marker for ES. Neuroendocrine neoplasms exhibit variable NKX2.2 expression and remain a significant potential diagnostic pitfall. Thus, NKX2.2 expression should be interpreted in the context of an appropriate immunohistochemical panel (and often with confirmatory molecular testing) for the accurate diagnosis of ES.

Aims Rhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harbouring a FUS-TFCP2 fusion and involving both soft tissue and bone locations has been reported very recently. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma. Material and results A previously well 72-year-old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA-seq, RT-PCR and FISH confirmed the presence of the FUS-TFCP2 fusion. Conclusions Spindle cell rhabdomyosarcomas carrying the FUS-TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/sclerosing rhabdomyosarcoma are discussed.

Background Clinical characteristics and optimal treatment strategies for spindle cell/sclerosing rhabdomyosarcoma (ssRMS) have not been well established because of its rarity. Procedure Retrospective re-evaluation of sarcoma specimens (1997–2014) identified 16 ssRMSs (median age 20 years, range 7–39 years). Clinicopathological features, clinical course, and outcome were analyzed. Results Primary disease sites were the head and neck (10 cases) and other regions (6 cases). Nine cases were at Intergroup Rhabdomyosarcoma Study preoperative stage 3. The primary tumors were >5 cm in 13 cases. Two patients had lymph node metastases, but none had distant metastases at presentation. At follow-up (median period 39 months, range 4.6–201), seven patients were alive without disease. Among nine patients treated with the vincristine, actinomycin, and cyclophosphamide (VAC) regimen, five responded well, with four surviving free of disease. Among ten patients with recurrent or progressive disease, three experienced local recurrence, four had distant metastases, and three had both. None exhibited bone marrow invasion. Eight of the ten patients died in median time from relapse to death of 18 months (range 11–56). Conclusions Although most ssRMSs present as a bulky tumor, nodal or distant metastases are rare at presentation. ssRMSs initially show good response to VAC, but >50% of tumors recur or progress; these data suggest a worse prognosis of ssRMS compared to the pediatric embryonal variant. As relapse typically occurs as local or distant solitary lesion without bone marrow invasion, localized treatment combined with chemotherapy would contribute to improve the prognosis of recurrent ssRMS. Pediatr Blood Cancer 2015;62:1011–1016. © 2014 Wiley Periodicals, Inc.

Sclerosing and spindle cell rhabdomyosarcoma (RMS) are rare types of RMS recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS (ERMS). Although sclerosing and spindle cell RMS share clinical and morphologic features, a pathogenetic link based on shared molecular alterations has not been established. Spindle cell RMS in children have been associated with a less aggressive clinical course compared to adults. Recently, recurrent MYOD1 mutations were described in 44% of adult spindle cell RMS, but no pediatric tumors or sclerosing RMS were studied for comparison. Thus, we investigated 16 RMS (5 sclerosing and 11 spindle cell) in children and adults for the presence of MYOD1 mutations by targeted Polymerase Chain Reaction (PCR). Remarkably, all 5 sclerosing RMS and 4 of 11 spindle cell RMS showed the MYOD1 p.L122R hot-spot mutation. Of the five pediatric tumors, 2/2 sclerosing RMS and 2/3 spindle cell RMS showed MYOD1 mutations. Three of nine MYOD1-mutant RMS showed coexistent PIK3CA mutations, while no MDM2 amplifications were identified. All four pediatric MYOD1-mutated RMS patients died of the disease at 12-35 months following diagnosis. In conclusion, spindle cell and sclerosing RMS show recurrent MYOD1 mutations, in keeping with a single pathologic entity, regardless of age at presentation. This group however, is distinct from the infantile RMS associated with NCOA2 fusions. Although our study suggests that pediatric MYOD1-mutant RMS follow an aggressive behavior with high mortality, further studies are required to confirm this finding.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and adolescents, being characterized by expression of genes and morphological and ultrastructural features of sarcomeric differentiation. The spindle cell variant of rhabdomyosarcoma (spindle cell RMS) in adults has been defined as an entity, separated from embryonal rhabdomyosarcoma (ERMS), with unfavourable clinical outcome. So far, no recurrent genetic alteration has been identified in the adult form of spindle cell RMS. We studied a case of adult spindle cell RMS using next-generation sequencing (NGS) after exome capture. Using this approach, we identified 31 tumour-specific somatic alterations and selected four genes with predicted functional relevance to muscle differentiation and growth. MYOD1, KIF18A, NOTCH1, and EML5 were further tested for mutations using Sanger sequencing on DNA from FFPE samples from 16 additional, adult spindle cell RMS samples. The highly conserved sequence homology of MYOD1 with other myogenic transcription factors prompted us to screen the basic DNA-binding domains of MYF5, MYF6 and MYOG for mutations. From the investigated 17 samples, seven (41%) showed homozygous mutation of MYOD1, indicating a critical role in this rare subtype of adult spindle cell RMS, while no mutations were found in any of the other genes involved in myogenic differentiation. The p.L122R mutation occurs in the conserved DNA binding domain in MYOD1 and leads to transactivation and MYC-like functions. MYOD1 homozygous mutations are frequent, recurrent and pathognomonic events in adult-type spindle cell RMS.

Spindle cell rhabdomyosarcoma (RMS) is a rare form of RMS with different clinical characteristics and behavior between children and adult patients. Its genetic hallmark remains unknown and it remains debatable if there is pathogenetic relationship between the spindle cell and the so-called sclerosing RMS. We studied two pediatric and one adult spindle cell RMS by next generation RNA sequencing and used FusionSeq for data analysis to detect novel fusions. An SRF-NCOA2 gene fusion was detected in a spindle cell RMS from the posterior neck in a 7 month-old child. The fusion matched the tumor karyotype and was further confirmed by fluorescence in situ hybridization (FISH) and by RT-PCR, which showed fusion of SRF exon 6 to NCOA2 exon 12. Additional 14 spindle cell (from 8 children and 6 adults) and 4 sclerosing (from 2 children and 2 adults) RMS were tested by FISH for the presence of abnormalities in NCOA2, SRF, as well as for PAX3 and NCOA1, identifying NCOA2 rearrangements in two additional spindle cell RMS from a 3 month-old and a 4 week-old child, both arising in the chest wall. In the latter tumor, TEAD1 was identified by rapid amplification of cDNA ends (RACE) to be the NCOA2 gene fusion partner. None of the adult tumors were positive for NCOA2 rearrangement. Despite similar histomorphology in adults and young children, these results suggest that spindle cell RMS is a heterogeneous disease genetically as well as clinically. Our findings also support a relationship between NCOA2-rearranged spindle cell RMS occurring in young childhood and the so-called congenital RMS, which often displays rearrangements at 8q13 locus (NCOA2).

Recently, spindle cell/sclerosing rhabdomyosarcoma (RMS) has been recognized as another distinct variant of a RMS. We evaluated clinicopathological features of 21 cases of spindle cell and sclerosing RMS and performed fluorescent in situ hybridization (FISH) testing in 10 (47.6%) tumours. Twenty-one tumours occurred in 16 males and 5 females (mean age, 19.7 years); commonly in the head and neck region (8) (38%) and extremities (7) (33.3%), followed by paratesticular region (2) (9.5%), chest wall (1), abdomen (1), pelvis (1) and paraspinal region (1). Average tumour size was 7.9 cm. Histopathologically, tumours that were spindle cell type (8) (38%) mostly occurred in the head and neck region, while sclerosing type (10) (47.6%) mostly occurred in the extremities. Remaining three (14.2%) tumours were mixed (sclerosing with spindle cell type). Tumour areas resembling embryonal RMS (ERMS) and alveolar RMS (ARMS) were noted in eight and three tumours respectively. Immunohistochemically, tumour cells were positive for desmin (21/21) (100%), MyoD1 (19/19) (100%), myogenin (13/15) (86.6%), SMA (2/3) and MIC2 (1/8) (12.5%). On FISH testing, none of the 10 tumours exhibited RMS1 (PAX3-FOXO1) or RMS 2 (PAX7-FOXO1) fusion. Eighteen patients underwent surgical resection and were offered adjuvant chemotherapy (CT) (4 cases), adjuvant CT + radiotherapy (RT) (4 cases) and adjuvant RT (1 case). Two patients underwent CT and a single patient received CT + RT. On follow-up (16 cases) (2-36 months), six tumours recurred and nine metastasized. Spindle/sclerosing RMSs are aggressive tumours and occur commonly in the head and neck and extremity sites. These tumours are histopathologically interrelated. Their immunohistochemical and cytogenetic profile is closer to ERMS than ARMS.

Objectives/Hypothesis: Sclerosing rhabdomyosarcoma is a newly described variant of rhabdomyosarcoma with a predilection for the head and neck. Little has been written on the topic, because of the scarcity of the disease and its recent recognition as a distinct entity. The present report describes the fifth confirmed case of sclerosing rhabdomyosarcoma and is the first report in the otolaryngology literature. Study Design: Case report. Methods: The authors have reported the case of a 66-year-old woman with a 35-year history of heavy cigarette smoking and daily alcohol consumption and a 2-month history of progressive dysphagia and dysarthria secondary to an enlarging tongue mass. Urgent tracheotomy was performed for impending respiratory embarrassment. Direct laryngoscopy revealed a bulky, exophytic mass involving the base of tongue. Specimens were obtained and submitted for analysis. Results: Initial frozen-section analysis of the specimens favored carcinoma, although subsequent immunohistochemical analysis disproved this. The diagnosis of sclerosing rhabdomyosarcoma was based on microscopic appearance and patterns of gene expression, including the expression of desmin and myogenin. A search of the literature revealed only four confirmed cases of sclerosing rhabdomyosarcoma. With the inclusion of the oropharyngeal tumor in the present report, three of the five confirmed cases have occurred in the head and neck. Conclusion: Sclerosing rhabdomyosarcoma is a rare variant of rhabdomyosarcoma that has a predilection for the head and neck. The clinical presentation may mimic carcinoma. The otolaryngologist-head and neck surgeon must be familiar with this disease entity.

Background. There is a need to develop a single prognostically significant classification of rhabdomyosarcomas (RMS) and other related tumors of children, adolescents, and young adults which would be a current guide for their diagnosis, allow valid comparison of outcomes between protocols carried out anywhere in the world, and should enhance recognition of prognostic subsets. Method. Sixteen pathologists from eight pathology groups, representing six countries and several cooperative groups, classified by four histopathologic classification schemes 800 representative tumors of the 999 eligible cases treated on Intergroup Rhabdomyosarcoma Study II. Each tumor was classified according to each of the four systems by each of the pathologists. In addition, two independent subsamples of 200 of the 800 patients were reviewed according to the new system, so that 343 distinct patients were reviewed once, and 57 of these twice. Results. A study of the survival rates of all subtypes in the sample of 800 patients led to the formation of a new system. This was tested on two independent subsets of 200 of the original cases and found to be reproducible and predictive of outcome by univariate analysis. A multivariate analysis of the 343 patients classified according to the new system indicated that a survival model including pathologic classification and known prognostic factors of primary site, clinical group, and tumor size was significantly better at predicting survival than a model with only the known prognostic factors. Conclusion. This new classification, termed International Classification of Rhabdomyosarcoma (ICR) by the authors, was reproducible and predictive of outcome among patients with differing histologies treated uniformly on the Intergroup Rhabdomyosarcoma II protocols. We believe it should be utilized by all pathologists and cooperative groups to classify rhabdomyosarcomas in order to provide comparability among and within multi-institutional studies. Cancer 1995;76:1073-85.

Adult sclerosing rhabdomyosarcoma (ASRMS) is a rare variant of rhabdomyosarcoma with a characteristic histological appearance of small, round cells in a dense, hyalinized stroma. Although nodal metastases of soft-tissue sarcomas are considered uncommon, up to 5% overall are associated with lymph node metastases. Nonetheless, there is little literature on the cytologic characteristics of metastatic soft-tissue sarcomas in lymph nodes, and to our knowledge, there are no reports of nodal metastasis of ASRMS diagnosed by fine-needle aspiration (FNA) cytology. We report here a 55-year-old woman who presented with a right thigh mass and associated ipsilateral inguinal lymphadenopathy. Biopsy of the mass revealed a uniform population of small, round cells in a dense, sclerotic background. A diagnosis of ASRMS was rendered. Subsequently, the patient underwent FNA of an enlarged inguinal lymph node, which revealed an identical population of small, round cells in a dense, myxoid background. This case highlights the cytologic features of a rare form of rhabdomyosarcoma, and emphasizes the utility of FNA in the assessment of lymphadenopathy in the setting of a soft-tissue sarcoma. Diagn. Cytopathol. 2010;38:761–764. © 2010 Wiley-Liss, Inc.