May 2021 – Bone and Soft Tissue Pathology

The correct answer is: near haploidization (LOH for all autosomes except for 5, 20, and 22)

The pattern of near haploidization with retention of disomic chromosomes 5, 20, and 22 is a highly characteristic genetic feature of inflammatory rhabdomyoblastic tumor (IRMT). This is an uncommon skeletal muscle tumor of borderline malignancy (locally recurring, rarely metastasizing) (1, 2). Cases of IRMT have previously been reported as both “inflammatory leiomyosarcoma” (ILMS) (3) and “histiocyte-rich rhabdomyoblastic tumor” (HRRMT) (1) .

IRMT occurs most often in young to middle-aged adults in the soft tissues of the extremities and trunk. Microscopically, it is characterized by a circumscribed growth pattern, often with features of chronicity, including a fibrous capsule, peripheral lymphoid aggregates, calcifications, and cholesterol deposition. The lesional cells themselves are often largely obscured by a striking infiltrate of foamy macrophages and multinucleated giant cells. Close inspection, however, disclosed small aggregates of pleomorphic, eosinophilic, spindled to epithelioid cells, sometimes with enlarged, hyperchromatic, bizarre-appearing nuclei. Mitotic activity is extremely low and tumor cell necrosis is absent. The lesional cells are diffusely desmin-positive, much more variably MyoD1-positive, and may be largely negative for myogenin. Smooth muscle actin expression may be seen, but caldesmon is negative. The non-neoplastic histiocytes are diffusely CD163/CD68-positive.

At the genetic level, IRMT are characterized by a near haploid genotype with or without subsequent genome doubling (2). Identical changes are seen in cases previously reported as “ILMS” and “HRRMT,” strongly supporting the concept that tumors reported under these different names represent the same entity. Some cases harbor pathogenic inactivating NF1 mutations (1, 4).

Based on relatively limited data, the prognosis for patients with IRMT is quite favorable, with only a low risk for metastases. To date, all reported patients are alive and without disease (1, 2). An exceptionally unusual example of a morphology and genetically typical IRMT showing progression to high-grade rhabdomyosarcoma has recently been reported, however (in press).

Incorrect answers

1. t(12;22)(q33;q12) translocation resulting in an EWSR1-CREB1 fusion
   
   This rearrangement is seen in the majority of angiomatoid fibrous histiocytomas (AFH), in addition to a variety of other mesenchymal and non-mesenchymal neoplasms (see below). Less often, AFH harbor EWSR1-ATF1 or FUS-ATF1 fusions (7, 8). AFH is a rare mesenchymal tumor of borderline malignancy that typically occurs in the superficial soft tissues of the extremities, trunk, head, and neck in children. It follows an indolent clinical course (3). These tumors share several histologic features with IRMT, including a thick fibrous pseudocapsule, lymphoid aggregates, and variably pleomorphic, desmin-positive tumor cells. However, AFH usually show a distinctive whorling pattern of growth and lack expression of MyoD1 and myogenin. The finding of EWSR1/FUS-CREB1/ATF1 fusions is diagnostic in the appropriate morphologic context (1, 7, 8). These fusions are also, however, found in wholly dissimilar tumors (e.g., clear cell sarcoma of soft tissue, malignant gastrointestinal neuroectodermal tumor, clear cell salivary gland carcinoma, others).

2. MYOD1 pLeu122Arg gene mutation
   
   Spindle cell/sclerosing rhabdomyosarcoma (S/SCRMS) harbors mutations in the DNA-binding domain of MYOD1, leading to a reduced transcriptional activation at MYOD1 sites with enhanced binding to MYC (9-12). Similarly to IRMT, S/SCRMS tends to occur in the head and neck as well as in the extremities. It affects infants, children and adults and has an equal sex distribution. However, S/SCRMS is morphologically quite different from IRMT, consisting of clearly malignant spindled and round cells, arranged in fibrosarcoma-like fascicles, and unusual nests of cells surrounded by vaguely chondroid, hyalinized stroma. S/SCRMS are typically diffusely positive for MyoD1, with much more limited expression of desmin and myogenin (3).

3. Loss of function mutations in PTCH1
   
   These mutations are characteristic of adult rhabdomyoma. PTCH1 encodes for a sonic hedgehog signaling pathway member and loss of function mutations result in inactivation of the pathway (3). These tumors are slow growing and frequently occur in the head and neck of older males. However, microscopically they are quite different from IRMT, being composed of sheets of polygonal or round cells with abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli. So-called “spider cells” may be prominent. Mitotic activity is absent. Adult rhabdomyomas express various skeletal muscle markers, as expected (1, 3).

References

1. Martinez AP, Fritchie KJ, Weiss SW, Agaimy A, Haller F, Huang H-Y, et al. Histiocyte-rich rhabdomyoblastic tumor: rhabdomyosarcoma, rhabdomyoma, or rhabdomyoblastic tumor of uncertain malignant potential? A histologically distinctive rhabdomyoblastic tumor in search of a place in the classification of skeletal muscle neoplasms. Modern Pathology. 2019;32(3):446-57.
2. Cloutier JM, Charville GW, Mertens F, Sukov W, Fritchie K, Perry KD, et al. “Inflammatory Leiomyosarcoma” and “Histiocyte-rich Rhabdomyoblastic Tumor”: a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as “Inflammatory Rhabdomyoblastic Tumor.” Modern Pathology. 2020.
3. WHO Classification of tumors of soft tissue and bone. 4 ed. Board WCoTE, editor. Lyon, France 2020.
4. Bourgeau M, Martinez AP. Histiocyte-rich rhabdomyoblastic tumor: a report of two cases and a review of the differential diagnoses. Virchows Archiv. 2020.
5. Nord KH, Paulsson K, Veerla S, Wejde J, Brosjö O, Mandahl N, et al. Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma. Neoplasia. 2012;14(9):807-12.
6. Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352).
7. Fanburg-Smith JC, Miettinen M. Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype. Hum Pathol. 1999;30(11):1336-43.
8. Smith ME, Costa MJ, Weiss SW. Evaluation of CD68 and other histiocytic antigens in angiomatoid malignant fibrous histiocytoma. Am J Surg Pathol. 1991;15(8):757-63.
9. Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, Antonescu CR. Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer. 2014;53(9):779-87.
10. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, et al. A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases. Am J Surg Pathol. 2016;40(2):224-35.
11. Szuhai K, de Jong D, Leung WY, Fletcher CD, Hogendoorn PC. Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol. 2014;232(3):300-7.
12. Rekhi B, Upadhyay P, Ramteke MP, Dutt A. MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod Pathol. 2016;29(12):1532-40.