—  SHORT COURSE #59  —

In Situ Hybridization in Diagnostic Pathology

Case 8 - Malignant Rhabdoid Tumor of Soft Tissue, Congenital

Ricardo V. Lloyd and Arie Perry


Clinical History
This 7-day old girl presented with a large soft tissue neck mass.

Gross Description
Two incisional biopsy specimens were received, each measuring roughly 1.5 cm in greatest dimension.


Case 8 - Figure 1

Case 8 - Figure 2
VIM


Case 8 - Figure 3
CD99
Case 8 - Figure 4
BCR-22q11 (green); NF2-22q12 (pink)

Microscopic Description
Sections revealed a highly cellular neoplasm composed of varying proportions of two cell types, one consisting of small undifferentiated cells and another of large epithelioid cells with eccentrically placed vesicular nuclei, prominent nucleoli, and an eosinophilic, fibrillar paranuclear inclusion (i.e. rhabdoid cells). Numerous mitotic figures and karyorrhectic nuclei were seen throughout the tumor. Zones of necrosis and calcification were also evident. Immunostains revealed strong, diffuse vimentin positivity, which highlighted the rhabdoid morphology. Subsets of tumor cells expressed EMA, smooth muscle actin, NSE, O13 (CD99), and cytokeratin, whereas synaptophysin and desmin were essentially negative. FISH demonstrated a 22q11 deletion involving the BCR region, near the INI1 gene.

Discussion (Modified from Reference [1])
Since its initial description as a unique renal neoplasm of early childhood with an unfavorable prognosis [2], the malignant rhabdoid tumor (MRT) has been the source of considerable debate. Originally thought to be restricted to the kidney, this highly malignant neoplasm has subsequently been reported as an apparent primary tumor in a variety of other anatomic sites, from the skin and soft tissues to the central nervous system [1, 3, 4, 5, 6] . A disseminated congenital form of MRT is also recognized [7], similar to the current case. As a group, MRTs may exhibit striking histologic and immunohistochemical variability. In the central nervous system, the term atypical teratoid / rhabdoid tumor (AT/RT) has been applied to antigenically polyphenotypic tumors of childhood composed of varying mixtures of rhabdoid, epithelial, mesenchymal, and/or primitive neuroectodermal tumor (PNET)-like elements, often misdiagnosed as medulloblastoma or central PNET [8]. Adding to some of the semantic complexity, extrarenal MRTs are divided into "pure" forms with the various morphologic and phenotypic attributes of classic renal MRT (i.e. rhabdoid tumor entity) versus "composite" extrarenal rhabdoid tumors (CERTs) or neoplasms containing rhabdoid elements admixed with an underlying differentiated neoplasm, such as a carcinoma, sarcoma, or melanoma (i.e. rhabdoid morphologic phenotype). Due to the wide histogenetic variability of these CERTs, some authors have challenged the concept of extrarenal-MRT as a distinct entity, proposing alternate terms such as "pseudorhabdoid" or "poorly differentiated neoplasm with rhabdoid features" [3, 4] .

Classic cytogenetic, FISH, and molecular genetic studies have shown that the majority of MRTs (both renal and extrarenal-"pure" type) and AT/RTs exhibit abnormalities involving chromosome 22, particularly monosomy 22 and 22q deletions [8, 9, 10, 11, 12] . Subsequently, a candidate tumor suppressor gene, INI1 (hSNF5), was mapped to the region of 22q11.2, in close proximity to the BCR region, for which a FISH probe is commercially available [13, 14, 15, 16, 17] . The presence of deletions and/or mutations of the INI1 gene in the majority of AT/RTs and pure MRTs has served to support the argument that the MRT is a distinct neoplastic entity, regardless of its primary site [14, 17] . In the CNS, it also helps to distinguish AT/RTs from medulloblastomas, which infrequently harbor 22q deletions, but often manifest instead with another FISH-detectable alteration, isochromosome 17q [10]. Utilizing FISH, we also found these 22q deletions to be rare in CERTs, suggesting alternate genetic pathways in this heterogeneous group of tumors [1].

References

  1. Fuller CE, Pfeifer J, Humphrey P, Bruch LA, Dehner LP, Perry A (2001) Chromosome 22q dosage in composite extrarenal rhabdoid tumors: clonal evolution or a phenotypic mimic? Hum Pathol 32:1102-1108

  2. Beckwith JB, Palmer NF (1978) Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study. Cancer 41:1937-1948

  3. Weeks DA, Beckwith JB, Mierau GW (1989) Rhabdoid tumor. An entity or a phenotype? Arch Pathol Lab Med 113:113-114

  4. Parham DM, Weeks DA, Beckwith JB (1994) The clinicopathologic spectrum of putative extrarenal rhabdoid tumors. Am J Surg Pathol 18:1010-1029

  5. Wick MR, Ritter JH, Dehner LP (1995) Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol 12:233-248

  6. Ogino S, Ro JY, Redline RW (2000) Malignant rhabdoid tumor: A phenotype? An entity?- A controversy revisited. Adv Anat Pathol 7:181-190

  7. White FV, Dehner LP, Belchis DA, Conard K, Davis MM, Stocker JT, Zuppan CW, Biegel JA, Perlman E (1999) Congenital disseminated malignant rhabdoid tumor: a distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11. Am J Surg Pathol 23:249-256

  8. Rorke LB, Packer RJ, Biegel JA (1996) Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85:56-65

  9. Biegel JA, Rorke LB, Packer RJ, Emanuel BS (1990) Monosomy 22 in rhabdoid or atypical teratoid tumors of the brain. J Neurosurg 73:710-714

  10. Bruch LA, Hill A, Cai DX, Levy BK, Dehner LP, Perry A (2001) A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumors. Hum Pathol 32:156-62

  11. Burger PC, Yu I-T, Tihan, T, Friedman HS, Strother DR, Kepner JL, Duffner PK, Kun LE, Perlman EJ (1998) Atypical teratoid/rhabdoid tumor of the central nervous system: A highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma- A pediatric oncology group study. Am J Surg Pathol 22:1083-1092

  12. Douglass EC, Valentine M, Rowe ST, Parham DM, Wilimas JA, Sanders JM, Houghton PJ (1990) Malignant rhabdoid tumor: A highly malignant childhood tumor with minimal karyotypic changes. Genes Chromosom Cancer 2:210-216

  13. Biegel JA, Allen CS, Kawasaki K, Shimizu N, Budarf ML, Bell CJ (1996) Narrowing the critical region for a rhabdoid tumor locus in 22q11. Genes Chromosom Cancer 16:94-105

  14. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74-79

  15. Rousseau-Merck MF, Versteege I, Legrand I, Couturier J, Mairal A, Delattre O, Aurias A (1999) hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors. Cancer Res 59:3152-3156

  16. Schofield D, Beckwith JB, Sklar J: Loss of heterozygosity at chromosome regions 22q11-12 and 11p15.5 in renal rhabdoid tumors. Genes Chromosom Cancer 15:10-17, 1996

  17. Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O (1998) Truncating mutation of hSNF5/INI1 in aggressive paediatric cancer. Nature 394:203-206