Case 3 -

Dedifferentiated Gist (Gastrointestinal Stromal Tumor) with Osteoclast Giant Cells, (Very High Risk), Stomach, 18 cm., with Positive Serosal Extension; and Wild Type Kit & Pdgfra Genes in Both Elements John S. J. Brooks, Pennyslvania Hospital, Philadelphia, PA

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Clinical History An 88 year old male with end-stage renal disease, coronary artery disease, bladder cancer, diabetes and peptic ulcer disease, presented with nausea and vomiting and was found to have an intra-abdominal tumor. At exploratory laparotomy, the mass was attached to the stomach, transverse colon, and omentum. On sectioning, the mass was 18 x 10 x 10 cm., and was cystic, hemorrhagic, and necrotic; viable tumor was tan in color. A representative section is provided. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Low power with tumor in wall of stomach. Case 3 - Figure 2 Hemorrhagic tumor with osteoclast giant cells (OGC). Case 3 - Figure 3 Atypical mitoses, OGCs, and pleomorphic tumor cells. Case 3 - Figure 4 High power with tumor cells along with OGCs. Case 3 - Figure 5 CD34 stain was negative. Case 3 - Figure 6 Focal SMA (smoothmuscle actin) present. Case 3 - Figure 7 Negative DOG1 stain (and CD117 - not shown). Case 3 - Figure 8 Focal typical spindle cell GIST Case 3 - Figure 9 Diffuse CD34 positivity (CD117 & DOG1 also positive) Morphology: The sections show a neoplasm in the gastric wall with extensive hemorrhage, necrosis, and ulceration. Notable is the finding of numerous osteoclast-like giant cells throughout. In addition, there were intervening small mononuclear stromal cells, larger cells with hyperchromatic atypical nuclei, and atypical mitotic figures. Mitoses averaged 34/10 hpf. Differential Diagnoses: Osteoclast-Like Giant Cell Containing Lesions Soft Tissue Only (non-visceral) Nodular Fasciitis Giant cell tumor of tendon sheath (& PVNS) Aneurysmal bone cyst of soft tissue Giant cell tumor of soft tissue (GCT-ST) Plexiform fibrohistiocytic tumor (PFHT) Visceral location (intra-abdominal) possible Carcinoma with osteoclastic giant cells Melanoma with osteoclastic giant cells Undifferentiated pleomorphic sarcoma, giant cell type (prior MFH of bowel) Giant cell rich osteosarcoma Pleomorphic or dedifferentiated leiomyosarcoma Clear cell sarcoma of GI tract with osteoclast giant cells GIST with osteoclast giant cells Selected entities above will be discussed below (references under each entitiy). Giant Cell Tumor of Soft Tissue (GCT-ST). These occur in middle aged males and females about equally, predominately in the subcutaneous region (about 90%), on the extremities (about 80%), of 1.0-4.0 cm in size mainly, are reddish-brown or white-grey on cut surface. Morhologically, the tumors are often circumscribed but multinodular, with a mixture of small mononuclear stromal cells and osteoclast-like giant cells, exactly like giant cell tumor of bone. The nuclei of both cell types are similar in size, and no atypical or bizarre spindle or giant cells are present. Mitoses are present (nearly 10/10 hpf on average), as are hemorrhagic areas, occasional cystic regions, and metaplastic bone as a peripheral partial shell of bone or inside the tumor. CD68 is positive in the giant cells strongly, and usually focally in the stromal cells. Other stains are negative including S100, desmin, CD31; only a few cases have scattered SMA positive cells. The clinical course is practically always benign, although rare cases may metastasize even though they have similar features to those that do not. Oliveira AM, Dei Tos AP, Fletcher, CDM, Nascimento AG. Primary Giant Cell Tumor of Soft Tissues A Study of 22 Cases. Am J Surg Pathol 24(2): 248–256, 2000. O'Connell JX, Wehrli BM, Nielsen GP, Rosenberg AE. Giant cell tumors of soft tissue: a clinicopathologic study of 18 benign and malignant tumors. Am J Surg Pathol 2000; 24: 386. Folpe AL, Morris RJ, Weiss SW. Soft tissue giant cell tumor of low malignant potential: a proposal for reclassification of malig- nant giant cell tumor of soft parts. Mod Pathol 1999;12:894–902. Carcinoma with osteoclastic giant cells Various organs may exhibit carcinomas with osteoclastic giant cells, including the breast, pancreas, larynx, etc. In this author's experience, they may show three different patterns: 1) large areas resembling GCT of bone and just foci of invasive carcinoma; 2) admixed carcinoma cells and giant cells; and 3) sarcomatoid carcinoma with giant cells. This phenomenon was first recognized by Rosai in 1968. Rosai J. Carcinoma of the pancreas simulating giant cell tumor of bone. Cancer 22: 333-334, 1968. Factor S, Biempica L, Ratner I, et al. Carcinoma of the breast with multinucleated reactive stromal giant cells. Virchows Arch A 374: 1-12, 1977. Alguail-Garcia A, Alonso A, Pettigrew NM. Sarcomatoid carcinoma (so-called pseudosarcoma) of the larynx simulating malignant giant cell tumor of soft parts. Am J Clin Pathol 82:340-343, 1984. Melanoma with osteoclastic giant cells As the great mimicker, melanoma can seemingly exhibit any morphology and simulate almost any other tumor. There are even melanomas with osteosarcomatous differentiation. However, these odd variants do contain definitive S100 positive melanoma. Goel G, Rao S, Khurana N. Malignant melanoma with osteoclast-like giant cells: A report of two cases. J Cancer Res Ther. 7(3):336-8, 2011. Daroca PJ, Reed R, Martin P. Metastatic amelanotic melanoma simulating giant-cell tumor of bone. Hum Pathol 1990;21:978-80. Giant cell rich osteosarcoma This variant can occur in bone or soft tissue, and can be diagnosed when malignant osteoid is identified in the tumor. In most cases, the osteosarcoma is very apparent and the osteoclastic giant cells are sprinkled throughout a malignant appearing tumor. Bertoni F, Bacchini P, Staals EL. Giant cell-rich osteosarcoma. Orthopedics. 26(2):179-81, 2003. Won KY, Lee CH, Kim YW, Park YK. Primary giant-cell-rich osteosarcoma of the urinary bladder: usefulness of osteocalcin and osteonectin immunohistochemical staining and literature review. Pathology. 43(2):161-4, 2011. Leiomyosarcoma (LMS) with Giant Cells (including dedifferentiated) LMS is another tumr which may occasionally contain osteoclastic giant cells, either throughout a single tumor, or as a different appearing area representing dedifferentiation (resembling giant cell type of undifferentiated pleomorphic sarcoma (UPS/MFH). Such tumors have been identified in the uterus and soft tissue. A true smooth muscle morphologic component must be identified and confirmed with immunohistochemical markers such as SMA and/or desmin. Chen KTK: Leiomyosarcoma with osteoclast-like giant cells. Am J Surg Pathol 19:487-488, 1995. Mentzel T, Calonje E, Fletcher CDM: Leiomyosarcoma with prominent osteoclast-like giant cells: Analysis of eight cases closely mimicking the so- called giant cell variant of malignant fibrous histiocytoma. Am J Surg Pathol 18:258-265, 1994. Matthews T, Fisher C. Leiomyosarcoma of soft tissue and pulmonary metastasis both with osteoclast-like giant cells. J Clin Pathol 47: 370-371, 1994. Gibbons CL, Sun SG, Vlychou M, Kliskey K, Lau YS, Sabokbar A, Athanasou NA. Osteoclast-like cells in soft tissue leiomyosarcomas. Virchows Arch. 456(3): 317-23, 2010. Undifferentiated pleomorphic sarcoma, giant cell type (prior MFH of bowel) This would clearly be a diagnosis of exclusion, as it is in any location. A careful examination of the gross specimen for any possible liposarcomatous areas, and review of the histology to identify any smooth muscle type morphology should be performed. This presenter has seen mesenteric dedifferentiated liposarcoma simulate primary UPS/MFH; in such cases the well differentiated component can even involve the submucosa in a very subtle manner as to be overlooked. Shibuya H, Azumi N, Onda Y, Abe F. Multiple primary malignant fibrous histiocytoma of the stomach and small intestine. Acta Pathol Jpn 35:157- 164, 1985. Wright JR, Kyriakos M, DeSchryver-Kecskemeti K. Malignant Fibrous Histiocytoma of the Stomach. Arch Pathol Lab Med ll2: 251-258, l988. Agaimy A, Gaumann A, Schroeder J, Dietmaier W, Hartmann A, Hofstaedter F, W√ºnsch PH, Mentzel T. Primary and metastatic high-grade pleomorphic sarcoma/malignant fibrous histiocytoma of the gastrointestinal tract: an approach to the differential diagnosis in a series of five cases with emphasis on myofibroblastic differentiation. Virchows Arch. 451(5): 949-57, 2007. Clear cell sarcoma of GI tract with osteoclast giant cells These tumors, originally reported by Zambrano et al. (2003), occurred in young individuals aged 13-37, were located in the small intestine (5) and stomach (1). The tumors are generally large (>10 cm), ulcerate the mucosa, occasionally polypoid, and may be adherent to other structures. Microscopically, tumor nests are noted, with round or spindle cells containing clear or eosinophilic cytoplasm, central nuclei with inapparent or inconspicuous nucleoli, high mitoses, and limited necrosis. Osteoclast giant cells are often diffusely throughout, but may be sparse. Immunohistochemically, the tumors are diffusely S100 positive, but negative for HMB45, Mart-1, CD117, CD34, SMA, MSA, desmin, myogenin, and keratins AE1/3 and Cam5.2. Giant cells are positive for KP1 and CD68. Cytogenetics on the original case showed t(12;22)(q13;q12) translocation, which is similar to that in clear cell sarcoma of soft tissue (>90% of cases). Kosemehmetoglu and Folpe have found fusions EWS-CREB1 (3), EWS-ATF1 (2), and EWS-unknown partner (1). Antonescu et al. found 3 cases harbored EWSR1-CREB1 gene fusions (which probably would correspond to the translocation t(2;22)(q32.3;q12), but this same gene fusion has been observed in a small number of typical soft tissue clear cell sarcomas. This is a highly aggressive tumor with potential for nodal and visceral metastasis, and death from disease in nearly 100% of cases, often in less than 3 years. Because of the very aggressive clinical course and disparate morphology, it is regarded as likely different from the soft tissue tumor. Zambrano E, Reyes-Mugica M, Franchi A, Rosai J. An osteoclast-rich tumor of gastrointestinal tract with features resembling clear cell sarcoma of soft parts: reports of 6 cases of a GIST simulator. Int J Surg Pathol 11: 75–81, 2003. K. Kosemehmetoglu and A. L. Folpe, "Clear cell sarcoma of tendons and aponeuroses, and osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: a review and update," Journal of Clinical Pathology, vol. 63, no. 5, pp. 416–423, 2010. C. R. Antonescu, K. Nafa, N. H. Segal, P. Dal Cin, and M. Ladanyi, "EWS-CREB1: a recurrent variant fusion in clear cell sarcoma—association with gastrointestinal location and absence of melanocytic differentiation," Clinical Cancer Research, vol. 12, no. 18, pp. 5356–5362, 2006.) Final Diagnosis: Diagnostic Interpretation: Dedifferentiated Gist (Gastrointestinal Stromal Tumor) with Osteoclast Giant Cells, (Very High Risk), Stomach, 18 cm., with Positive Serosal Extension; and Wild Type Kit & Pdgfra Genes in Both Elements. Case Discussion: What's going on in various neoplasms with osteoclastic giant cells? The neoplastic cells, regardless of type, are likely to be shown to be capable of producing substances like those produced by giant cell tumors (GCT) of bone: substances that attract specific histiocyte-like cells and generate the giant cells in-situ. Osteoclasts in bone are formed from marrow derived precursors expressing a monocyte/macrophage phenotype. These precursors, which have the receptor activator for nfkB (RANK), differentiate into multinucleated cells in the presence of RANK lignad and M-CSF. In GCT and aneurysmal bone cyst, the antigenic phenotype of the giant cells is known (CD51+, CD14-, CD68+, cathepsin K+, TRAP+). Giant cells are formed in GCT by CD14+ mononuclear cells (macrophage precursors) under the proper conditions as above. Other CD14- mononuclear stromal cells produce osteoclastogenic factors (RANKL, osteoprotegerin, and M-CSF). Interestingly, the mononuclear stromal cells in a number of giant cell rich lesions including GCT-ST, giant cell granuloma of jaw, and chondroblastoma, all express RANKL. Lau YS, Sabokbar A, Gibbons CL, Giele H, Athanasou N. Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue. Hum Pathol 2005; 36:945-54. Maggiani F, Forsyth R, Hogendoorn PC, Krenacs T, Athanasou NA. The immunophenotype of osteoclasts and macrophage polykaryons. J Clin Pathol. 64(8) :701-5, 2011. Quinn JM, Elliott J, Gillespie MT, Martin TJ. A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. Endocrinology 1998; 139:4424-7. Won KY, Kalil RK, Kim YW, Park YK. RANK signalling in bone lesions with osteoclast-like giant cells. Pathology 2011; 43:318-21. Case Discussion: Back to the Case: Immunohistochemistry: The neoplasm was positive for fascin and CD68 (positive osteoclast giant cells and small stromal cells; negative atypical spindle cells). Negative stains included Cam5.2, CK-low, CK-high, desmin, SMA, CD34, CD31, S100, LCA, CD20, CD117, and DOG1. These stains exclude many of the above entities. Other findings: Careful re-examination of the glass slides was performed and on two slides, there was a small area (0.3-0.4 cm) of spindle cells with eosinophilic cytoplasm and elongated nuclei, resembling low risk GIST. The nuclei were bland and the mitotic rate was 0/50 hpf. These areas were positive for all GIST markers including CD34, CD117, and DOG1, and there was SMA positivity and very rare positive AE1/3 cells. Desmin and calponin were negative. About 95% of all GISTs are KIT CD117 positive, despite the fact that only 85% have mutations in either the KIT or PDGFRA genes. About 70% of GISTs are CD34 positive. Molecular Analysis: (Courtesy of Chris Corless, Knight Diagnostic Laboratories, Oregon Health & Science University): For both typical and giant cell areas, there was no detectable mutation in either the KIT or PDGFRA genes of the type seen in ~85% GISTs. However, this does not exclude a diagnosis of GIST, as 10-15% of these tumors are wild-type for these two kinase genes. Review of the Literature/Treatment Options: GIST with osteoclast giant cells There are now at least two patterns of this phenomenon: 1) a recognizable spindled GIST with scattered osteoclastic giant cells (Koçer et al., Leung et al.); and 2) the current case in which the giant cells occurred as part of a undifferentiated pleomorphic sarcoma (UPS-MFH)-like tumor next to a differentiated GIST. Insabato L, Vizio DD, Ciancia G, Pettinato G, Tornillo L, Terracciano L. Malignant gastrointestinal leiomyosarcoma and gastrointestinal stromal tumor with prominent osteoclast-like giant cells. Arch Pathol Lab Med 128:440–443, 2004. Leung KM, Wong S, Chow TC, Lee KC. A malignant gastrointestinal tumor with osteoclast-like giant cells. Arch Pathol Lab Med 126: 972–974, 2002. Terada T, Endo K, Maeta H, Horie S, Ohta T. Epithelioid leiomyosarcoma with osteoclast-like giant cells in the rectum. Arch Pathol Lab Med 124: 438–440, 2000. Koçer NE, Kayaselçuk F, Calişkan K, Ulusan S. Synchronous GIST with osteoclast-like giant cells and a well-differentiated neuroendocrine tumor in Ampula Vateri: coexistence of two extremely rare entities. Pathol Res Pract. 203(9): 667-70, 2007. Dedifferentiation in GIST: In 2007, Antonescu et al. reported in an abstract on dedifferentiation in GIST, with 4 cases having an abrupt transition from a classic KIT (CD117) positive spindle cell GIST to an anaplastic KIT negative tumor. Tumor giant cells, high mitotic rate, and necrosis were noted, with the loss of CD34 as well; cytokeratin AE1/3 (3/4) and desmin (1/4) were positive, unlike the vast majority of GIST. Curiously, all were in the stomach, as is the current case. Three of the four had no prior exposure to imatinib. Molecular analysis showed a wild type genotype in both components, as did the current case. One case had an exon 11 KIT mutation in both components. FISH showed gene copy abnormalities in ¾ cases in the dedifferentiated areas: loss of 1 KIT copy (1) and small KIT amplification (2 cases). Liegl et al. in 2009 also refer to the same abstract, stating "rare GISTs showing dedifferentiation, defined as an abrupt transition between a conventional GIST and a KIT-negative anaplastic high-grade sarcoma, have been reported to occur." In 2004, there were two anaplastic GIST cases that had minute foci of classic spindled CD34+/CD117+ GIST next to the anaplastic areas that were CD34- /CD117- (Debiec-Rychter et al.), suggesting to the authors that a "KIT non- mutant GIST had 'dedifferentiated' or progressed into a highly anaplastic neoplasm". This appears to be the first instance that the phrase "dedifferentiated" was applied to GIST. The combined IHC (negative c-Kit/DOG1) along with the wild-type molecular analysis raises the possibility of epigenetic regulation of these genes in the dedifferentiated tumor component. Tumors that are simply pleomorphic/anaplastic with intact KIT expression (Verma et al) are not considered dedifferentiated. Liegl B, Hornick JL, Lazar AJ. Contemporary pathology of gastrointestinal stromal tumors. Hematology/Oncology Clinics N Amer. 23: 49-68, 2009. Antonescu CR, Hornick JL, Nielsen GP et al. Dedifferentiation in gastrointestinal stromal tumor (GIST) to an anaplastic KIT-negative phenotype —a diagnostic pitfall. Mod Pathol 20 (suppl 2):11A, abstract, 2007. Verma P, Corless C, Medeiros F et al. Pleomorphic gastrointestinal stromal tumors: diagnostic and therapeutic implications. Mod Pathol 18(suppl 1):121A, abstract, 2005. Debiec-Rychter M, Wasag B, Stul M, De Wever I, Van Oosterom A, Hagemeijer A, Sciot R. Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. J Pathol 202: 430-438, 2004. Lessons: 1. Go back and look at the gross specimen for any different areas (not helpful in this case). 2. Look carefully at all sections taken. 3. Osteoclast giant cells can be seen in almost any location, and in a variety of carcinomas, melanoma, soft tissue and bone tumors, and some sarcomas. They are there because they are formed in-situ after the tumor recruits the specific mononuclear precursor CD14+ cells. 4. Dedifferentiated GIST exists, but is a very rare event, and frequently lacks KIT or PDGFRA mutations. Additional References: Other GIST Variants & Review Suster S, Sorace D , Moran CA. Gastrointestinal stromal tumors with prominent myxoid matrix. Clinicopathologic, imunohistochemical and ultrastructural study of nine cases of a distinctive morphologic variant of myogenic stromal tumor. Am J Surg Pathol 1995; 19: 59-70. Suster S, Fletcher CDM. Gastrointestinal stromal tumors with prominent signet-ring cell features. Mod Pathol 1996; 9: 609-613. Liegl B, Hornick JL, Antonescu C et al. Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression. Am J Surg Pathol 33(2):218–226, 2009. Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch 456: 111-127, 2010. Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130: 1466-78, 2006.