Silver Spring, MD
A twenty-four year old female presented with back pain. She was found to have a left posterior chest wall mass, primarily involving the L1 vertebra and the adjacent rib. The mass extended into soft tissue. A biopsy of the mass was performed that measured 3.5 cm (see slide). A definitive resection was performed elsewhere. Despite report that the patient received chemotherapy and radiation therapy, the patient died of disease one year later.
Case 1 - Slide 1
This case represents a rare chondrosarcoma subtype that was first described by Lichtenstein and Bernstein, half a century ago. Since then, this enigma has been studied by many great bone and soft tissue pathologists. Mesenchymal chondrosarcoma is primarily an intraosseous tumor of the second and third decades, with a predilection for the head and neck over the extremities. Rare extraskeletal cases are notoriously found in the brain and meninges and orbit more than other soft tissue sites. There is overall poor prognosis, with late recurrences, metastases, and the current 10-year survival rates are below 50%. The recommended treatment is resection with wide margins; the effectiveness of chemo- and radiotherapy remain poorly defined.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The known morphology includes biphasic zones of undifferentiated small cells with a hemangiopericytoid vascular pattern admixed with hyaline cartilage islands. New features include the observation of centrally located hyaline cartilage islands and a metaplastic or benign- appearing linear maturation of hyaline carilage, representing all stages of chondrogenesis, which undergoes endochondral ossification to bone. The presence of bone has been underrecognized, but can be observed grossly and radiologically. Supportive features include SOX9 reactivity in small cells and hyaline cartilage areas, supporting cartilage phenotype, newly observed nuclear beta-catenin in the cells adjacent to the hyaline carilage. Beta catenin is involved in osteogenesis and inhibition of chondrogenesis, representing a coupling effect between Sox9 (master regulator of chondrogenesis) and Beta-catenin during the endochonral ossification occuring in mesenchymal chondrosarcoma. Osteocalcin supports the aquired osteblastic phenotype and bone formation of the mature chonrocytes, during endochondral ossification; osteocalcin is negative in round tumor cells. Mesenchymal chondrosarcoma has myoid phenotype in 50% of case, but fails to support rhabdomyoblastic or smooth muscle differentiation. Additionally INI-1 is retained and ER and EMA are negative in tumor cells.
High grade chondrosarcoma De-differentiated chondrosarcoma Small cell osteosarcoma Atypical teratoid tumor/Extrarenal rhabdoid tumor with small round cells Malignant SFT/ hemangiopericytoma Neuroblastoma Primitive neuroectodermal tumor/Ewing sarcoma Synovial sarcoma (poorly differentiated-type) Rhabdomyosarcoma Round cell liposarcoma Desmoplastic small round cell tumor
The clinical and morphologic features and immunohistochemical stains against molecular events are key to the diagnosis. Intraosseous, head and neck and brain/meninges location, round cell with hemangiopericytoid vascular pattern and linearly progressive chondrogenesis undergoing endochondral ossification to bone aid in recognition of this tumor. The sox 9 reactivity (master regulator of chondrogensis), osteocalcin negativity in round tumor cells, and aberrant desmin and EMA, as well as retention of INI-1, support this diagnosis over the tumors discussed in the differential diagnosis above.
Review of the Literature/Treatment Options:
"Well-differentiated" or "bland" appearance of hyaline cartilage
Nakashima Y, Unni Kk, Shives TC, Swee RG, Dahlin DC Cancer 1986;57:2444.
Guccion JG, Font RL, Enzinger FM, Zimmerman LE Arch pathol 1973;95:336.
Fletcher CD, KrauszT. Appl Pathol 1988;6: 208.
"Reactive" or "metaplastic"
Salvador AH, Beabout JW, Dahlin DC. Cancer 1971;28:605.
"Array of cartilage in various stages of differentiation"
Dabska M, Huvos AG. Virchows Arch A Anat Histopathol 1983;399:89.
"Small-cell areas were negative for collagen II A and vimentin. Small cells closer to cartilage expressed collagen type IIA. Fully differentiated chondrocytic cells expressed collagen type II. The focal expression of type X collagen in cartilage indicated hypertrophic differentiation of the neoplastic chondrocytes. Arise from undifferentiated chondroprogenitor cells and have the potential to undergo all steps of chondrocytic differentiation. Finally, evidence was found for transdifferentiation of the neoplastic chondrocytes to osteoblast-like cells in areas of neoplastic bone formation."
Aigner T, Loos S, Muller S, Sandell LJ, Unni KK, Kirchner T. Am J Pathol 2000;156:1327.
"Presence of bone in mesenchymal chondrosarcoma:"
Nakashima Y et al. Salvador AH et al. Guccion JG et al. Lockhart R et al. Fletcher CD et al.
"Small punctuate calcifications are apparent in 57% of cases by radiographs or CT."
Shapeero LG, Vanel D, Couanet D, Contesso G, Ackerman LV. Extraskeletal mesenchymal chondrosarcoma. Radiology 1993;186:819-26.
"Roentgenographically, the lesions in bone frequently resembled ordinary chondrosarcomas, showing osteolytic and destructive appearances with stippled calcification. Tumors in extraskeletal sites were almost always identified as calcified masses."
Nakashima Y, Unni KK, Shives TC, Swee RG, Dahlin DC. Mesenchymal chondrosarcoma of bone and soft tissue. A review of 111 cases Cancer. 1986 Jun 15;57(12):2444-53.
Gengler C, Letovanec I, Taminelli L, Egger JF, Guillou L.Desmin and myogenin reactivity in mesenchymal chondrosarcoma: a potential diagnostic pitfall. Histopathology. 2006 Jan;48(2):201-3.
Hoang MP, Suarez PA, Donner LR, YRo J, Ordonez NG, Ayala AG, Czerniak B. Int J Surg Pathol. 2000 Oct;8(4):291- 301. Mesenchymal Chondrosarcoma: A Small Cell Neoplasm with Polyphenotypic Differentiation.
Dobin SM, Donner LR, Speights VO Jr. Mesenchymal chondrosarcoma. A cytogenetic, immunohistochemical and ultrastructural study. Cancer Genet Cytogenet. 1995 Aug;83 (1):56-60.
"sox9 specific to mesenchymal chondrosarcoma"
Wehrli BM, Huang W, De Crombrugghe B, Ayala AG, Czerniak B. Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors. Hum Pathol. 2003;34(3):263-9.
"Nuclear beta-catenin has been found in some chondrosarcoma subtypes"
Ng TL, Gown AM, et al. Nuclear beta-catenin in mesenchymal tumors Mod Pathol 2005;333:1300-8.
"Wnt signaling is crucial in bone formation and remodeling (osteogenesis)"
Issack PS, Helfet DL, Lane JM. Role of Wnt signaling in bone remodeling and repair. HSSJ 2008;4: 66-70
Topol L, Chen W, et al. Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus. J Biol 2009;284: 3323-33
Hill TP, Spater D, et al. Canonical Wnt betacatenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cel 2005;8:727-38.
"Beta-catenin inhibited by Sox 9 during chondrogenesis"
Bi W, Deng JM, Zhang A et al. Sox 9 is required for cartilage formation. Nat Genet 1999;22:85-9.
Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004 May 1;18(9):1072-87.
"Complicated process of coupling of chondrogensis and osteogensis"
Fanburg-Smith et al. McCarthy TL, Centrella M. Novel links among Wnt and TCF- beta signaling and Runx2 Mol Endocrinol. 2010. [Epub ahead of print]
Milat F, NY KW. Is Wnt signalling the final common pathway leading to bone formation? Mol Cell Endocrinol. 2009;310(1- 2):52-62.
Miclea RL, Karperien M et al. Adenomatous polyposis coli- mediated control of beta-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors. BMC Dev Biol. 2009;9:26.
Mesenchymal chondrosarcoma is a malignant small round cell tumor that undergoes benign-appearing linear chondrogeneis and endochondral ossification to bone. The morphologic appearance of the cartilage and representation of all stages of chondrogenesis is different from other malignant hyaline cartilage tumors. Sox-9, Beta-catenin, and INI-1 are immunohistochemnical studies against molecular events that aid in our understanding of the development of the cartilage and bone in this malignant, metastasizing tumor and separate it from tumors in the differential diagnosis. The proposed coupling effect between sox9 and beta-catenin in mesenchymal chondrosarcoma identify the process of benign endochondral ossification in this malignant neoplasm.
- Fanburg-Smith JC, Auerbach A, Marwaha JS, Wang Z, Santi M, Judkins AR, Rushing EJ. Immunoprofile of mesenchymal chondrosarcoma: aberrant desmin and EMA expression, retention of INI1, and negative estrogen receptor in 22 female-predominant central nervous system and musculoskeletal cases Annals Diagnostic Pathol 2009 [In Press].
- Fanburg-Smith JC, Auerbach A, Marwaha JS, Wang Z, Rushing EJ. Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and ß-catenin, Sox9, and osteocalcin immunostaining of 22 cases. Human Pathology 2009 [In Press].
- Fanburg JC, Rosenberg AE, Weaver DL, Leslie KO, Mann KG, Taatjes DJ, Tracy RP. Osteocalcin and osteonectin immunoreactivity in the diagnosis of osteosarcoma. Am J Clin Pathol. 1997;108(4):464-73.
- Fanburg-Smith JC, Bratthauer GL, Miettinen M. Osteocalcin and osteonectin immunoreactivity in extraskeletal osteosarcoma: a study of 28 cases. Hum Pathol. 1999;30 (1):32-8.
- Lichtenstein L., Bernstein D. Unusual benign and malignant chondroid tumors of bone: a survey of some mesenchymal cartilage tumors and malignant chondroblastic tumors, including a few multicentric ones, as well as many atypical benign chondroblastomas and chondromyxoid fibromas. Cancer 1959;12:1142-57 Cancer 1986 Jun 15;57(12):2444-53. Cancer 1996 May 1;77(9):1884-91. Cancer 2008 Jun;112(11):2424-31. Curr Treat Options Oncol. 2009 Apr;10(1-2):94-106.