Gastrointestinal stromal tumor
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1 Gastrointestinal stromal tumor 영남의대병리학교실 최준혁
2 Classification of gastrointestinal mesenchymal tumor Gastrointestinal stromal tumor(gist) Smooth muscle tumors : leiomyoma, leiomyosarcoma Neurogenic tumors : schwannoma, neurofibroma, granular cell tumor, ganglioneuroma, MPNST Vascular tumors : hemangioma, lymphangioma, glomus tumor, angiosarcoma, Kaposi sarcoma Lipomatous tumors : lipoma, liposarcoma
3 Historical overview : Gastrointestinal mesenchymal tumors 1941 Golden,et al Smooth muscle tumor (leiomyoma, leiomyosarcoma) 1983 Mazur,et al Gastric stromal tumor - lack of smooth muscle differentiation 1984 Herrera,et al Plexosarcoma(or GANT) - autonomic nerve differentiation 1998 Hirota,et al Gastrointestinal stromal tumor(gist) - interstitial cells of Cajal phenotype differentiation - c-kit gene mutation 1998 Kindblom,et al Gastrointestinal pacemaker tumor
4 Interstitial cells of Cajal (ICC) Origin Multipotential mesenchymal stem cells Function Control of gut motility Site Between autonomic nerve and muscle wall of GIT Morphology Fusiform, stellate Proto-oncogene c-kit gene expression Immunostain c-kit(cd117) protein
5 Interstitial cell of Cajal, small intestine
6 c-kit(cd117) gene Location Chromosome 4q Proto-oncogene encoding c-kit(cd117), a transmembrane tyrosine-kinase receptor Function c-kit + stem cell factor(scf) development of interstitial cell of Cajal (ICC) Mutation Proliferation of ICC, GIST
7 Gastrointestinal stromal tumor(gist) Definition Neoplasm showing differentiation toward ( or being derived from) the phenotype of interstitial cells of Cajal (ICC) C-kit(CD117) Diagnostic immunohistochemical marker Anatomic sites 50-60% stomach 20-30% small bowel 10% large bowel 5% esophagus 5 % mesentery, omentum, retroperitoneum
8 Gross features of GIST 3 gross types 1. polypoid submucosal growth 2. exophytic subserosal lesion 3. dumbbell growth Smooth or bosselated outer surface Gray to pink in color with rubbery consistency Hemorrhage, necrosis, cystic degeneration
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10 Microscopic features of GIST Spindle cell(70%) spindle, elongated nuclei paler eosinophilic cytoplasm sheets, fascicles, storiform, palisading Epithelioid cell(20%) round or polygonal cells abundant eosinophilic or clear cytoplasm Mixed(10%)
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16 Skenoid fiber in GIST % of cases Hyaline or fibrillary eosinophilic structures, seemly composed of nodular tangles of collagen fiber No histogenetic significance
17 Skenoid fiber
18 Cytologic and growth patterns of GIST Cytologic types Growth patterns Spindle cell Fascicular Epithelioid Storiform Plasmacytoid cell Palisading Signet ring cell Diffuse, sheet-like Granular cell Organoid(nested) Multinucleated Myxoid Alveolar (Semin Diag Pathol 13: ,1996)
19 Immunophenotypes of GIST Immunostain Positivity c-kit(cd117) % CD % SMA 30-40% Desmin 1-2% S-100 protein 5%
20 CD 117
21 Parameters used in evaluation of GIST malignancy reported in literatures Site Size Mitosis Histologic type Cytologic atypia Necrosis Amin Kindblom Panizo Trupiano Miettinen Fletcher Amin, et al: Am J Clin Pathol 100:428-32,1993. Kindblom, et al : Am J Clin Pathol 152: ,1998. Panizo, et al: Int J Surg Pathol 8:133-44, 2000 Trupiano, et al : AJSP 26:705-14, Miettinen, et al : Hum Pathol 33:478-83, Fletcher, et al : Sarcoma 2:133-41,1998.
22 Criteria of GIST malignancy by Miettinen Probably benign Uncertain or Probably malignant LMP Stomach 5 cm 5-10 cm >10 cm <5/50HPF <5/50HPF >5/50HPF Intestine 2 cm 2-5 cm >5 cm <5/50HPF <5/50HPF >5/50HPF (Hum Pathol 33:478-83,2002)
23 Criteria of GIST malignancy by Fletcher Benign Borderline Malignant Mitosis/30HPF Histologic type spindle cells, no atypia epithelioid cell spindle cells, mild pleorphism/hyperchromasia spindle cells, no atypia epithelioid cell spindle cells, no atypia spindle cells, frank pleomorphism/hyperchromasia epithelioid cell (Sarcoma 2 :133-41,1998)
24 Pathology report form of GIST in Fletcher s Institute Dx: Stomach, antrum, wedge resection : Gastrointestinal stromal sarcoma with 1) Cell type : spindle 2) Tumor size : 7 cm 3) Mitosis : 11/30 HPF 4) Necrosis : present 5) No vascular invasion 6) c-kit(cd117) : diffuse cytoplasmic strong positive 7) Clear resection margin
25 Histologic grading is not correlated strongly with metastatic risk or survival At least 10% of GIST (<5 cm and <5/50HPF) in more than 500 GISTs reviewed by Dr. Fletcher metastasis Any GIST can not be definitely regarded as benign. Distinction between benign and malignant appears to be a practically impossible at current time.
26 Diagnosis of Gastrointestinal Stromal Tumors: A Consensus Approach Fletcher CDM, Miettinen M, Weiss S, et al (Hum Pathol 33:459-65,2002) develop a scheme based on risk assessment rather than try to define strict criteria to separate benign and malignant
27 Proposed Approach for Defining Risk of Aggressive Behavior in GIST Risk Size(cm) Mitotic count(/50hpf) Very low <2 <5 Low 2-5 <5 Intermediate < <5 High >5 >5 >10 any mitoses Any size >10 (Hum Pathol 33:459-65,2002)
28 Approximate risk of metastasis/death Risk Metastasis/death Very low <5% Low 5-20% Intermediate 20-50% High >50% (Fletcher CDM, letter communication, 2002)
29 Diagnostic term recommended by Fletcher Risk Size(cm) Mitotic count(/50hpf) Pathology diagnosis Very low <2 cm <5 Gastrointestinal stromal tumor Low 2-5 <5 Gastrointestinal stromal sarcoma Intermediate < Gastrointestinal stromal sarcoma 5-10 <5 High >5 >5 Gastrointestinal stromal sarcoma >10 any mitoses Any size >10 (Fletcher CDM, letter communication, 2002)
30 Suggested pathology report form of GIST Dx: Stomach, antrum, wedge resection : Gastrointestinal stromal sarcoma with 1) Tumor size : 7 cm 2) Mitosis : 9/50 HPF 3) cell type : spindle 4) necrosis : present 5) no vascular invasion 6) c-kit(cd117) : diffuse cytoplasmic strong positive 7) Clear resection margin Note : According to risk assessment (Hum Pathol, 33:459-65, 2002), this tumor is considered as high risk
31 Frozen section of GIST Is the lesion stromal tumor? Frozen diagnosis Stromal tumor; determination of specific type and whether it is malignant must await permanent sections (AFIP, Fascicle 18,1996)
32 Procedure for pathologic examination 1. Measure greatest diameter 2. Note location, color, necrosis, hemorrhage on cross section 3. Check if tumor appears to obliterate mucosal-submucosal interface 4. Sample 1) area where most closely approaches the mucosa, including ulcers 2) areas of different consistency and color 3) both intramural and extramural component of large tumor 4) about one block per centimeter of maximum diameter 5. Micro. examination 1) count mitoses in contiguous fields in the highest mitotic activity area 6. Immunostain 1) routine : CD117, CD34, SMA, desmin, S-100 protein (AFIP, Fascicle 18,1996)
33 Pathology report of c-kit(cd117) negative GIST Dx: Spindle cell(or epithelioid) stromal neoplasm, most consistent with gastrointestinal stromal tumor(or gastrointestinal stromal sarcoma) (Hum Pathol 33:459-65, 2002)
34 Gastrointestinal autonomic nerve tumor(gant) Definition : Stromal tumor showing autonomic nerve differentiation ultrastructurally Site GI tract : small intestine Mesentery, retropritoneum, pelvis Microscopic features Similar to GIST Immunostain CD117, CD34, S-100 protein, NSE, PGP 9.5 Synaptophysin, chromogranin
35 GANT, mesentery(77/f) (Courtesy of Dr. Fletcher)
36 GANT(AJSP 17: , 1993)
37 EM study for diagnosis of GANT is not required now Exact same KIT mutation and same biological behavior as other GISTs No longer worth diagnosing
38 No longer talk about divergent differentiation in GIST Differentiation Neural No meaning at all GANT no longer exists as separate entity Myoid SMA (+) Nothing Present focally in most GIST Desmin (+) Extremely rare(< 2% of cases)
39 Leiomyoma in GIT Esophagus : most common Well circumscribed, non-encapsulated Mature smooth muscle cells with eosinophilic cytoplasm Low cellular No tumor necrosis Immunostain : SMA, desmin
40 Leiomyoma, esophagus
41 Leiomyosarcoma in GIT Large bowel Spindle, cigar-shaped nuclei Epithelioid cells Large size : >5 cm Immunostain : SMA, desmin
42 Leiomyosarcoma
43 Epithelioid leiomyosarcoma, stomach(17/f) (Courtesy of Dr. Fletcher)
44 Epithelioid leiomyosarcoma vs Carcinoma Epithelioid leiomyosa. Carcinoma Cytokeratin + + EMA + Desmin + Caldesmon +
45 Criteria of leiomyosarcoma in GIT Ranchod Evans Cunningham <5 cm and <5/10HPF Watanabe Leiomyoma Leiomyosarcoma Ranchod, et al. Cancer 39:255-62,1977. Evans. Cancer 56: , Cunningham, et al. AJSP 17:588-94,1993. Watanabe, et al : WHO, 2 nd ed, /10HPF 1/10 HPF 10/10 HPF 10/50HPF
46 No any really meaningful criteria until now between leiomyoma vs leiomyosarcoma in GIT smooth muscle tumor Esophagus Large bowel most are benign submucosal small lesions are benign others malignant
47 Schwannoma in GIT Schwannoma in GIT Schwannoma in soft tissue Capsule - + Nuclear palisading - + Vascular hyalin. - + Verocay body - + Xanthoma cells -/+ + Lymphoid cuff + - Antoni A and B - + S-100 protein + +
48 Schwannoma, stomach
49 Soft tissue tumors histologically resembling GIST Intra-abdominal fibromatosis Solitary fibrous tumor Inflammatory myofibroblastic tumor Follicular dendritic cell tumor True histiocytic lymphoma
50 Intra-abdominal fibromatosis Pelvic, mesenteric, retroperitoneum Circumscribed or infiltrative, firm, homogenous Long fascicles of bland-looking spindle cells Collagenous or myxoid stroma Infiltrative margin Immunostain : Positive : CD117(focal weak), SMA, desmin Negative : CD34, S-100 protein
51 Intra-abdominal fibromatosis
52 Solitary fibrous tumor(sft) Pleura, intraabdomen, pelvis, retroperitoneum, peritoneum Well circumscribed Alternating hypercellular and hypocellular area Bland-looking short spindle or oval cells Haphazard, storiform or fascicular pattern of spindle cells Intimate intertwining of thin or thick collagen fibrils with spindle cells Hemangiopericytoma-like vascular pattern Immunostain : CD34, CD99, bcl-2 Malignant SFT: > 4/10 HPF, hypercellularity, pleomorphism
53 Solitary fibrous tumor, retroperitoneum
54 Solitary fibrous tumor
55 Inflammatory myofibroblastic tumor Abdominal cavity, gastrointestinal 10-25% local recur, 5% metastasis ALK(anaplastic lymphoma kinase) gene rearrangements Myofibroblastic proliferation with atypical nuclei 3 patterns : hypocelluar fibrous, cellular, myxoid/vascular Inflammatory cells, plasma cell, lymphocytes Immunostain : Vimentin(100%), SMA(78%), desmin(50%), ALK(36%), CD34(18%), EMA(16%)
56 IMT, mesentery (49/M) (Courtesy of Dr. Fletcher)
57 IMT, retroperitoneum (46/M)
58 IMT, retroperitoneum (46/M)
59 Follicular dendritic cell tumor Gastrointestinal tract, intra-abdominal Tumor cells are spindle, oval or polygonal shape Eosinophilic cytoplasm, poorly defined cell border Syncytial appearance Whorls, fascicles, storiform pattern, diffuse sheets Diffusely small lymphocytes Immunostain : CD21, CD35
60 FDRCT, small intestine (33/F) (Courtesy of Dr. Fletcher)
61 FDRCT
62 True histiocytic lymphoma Lymphoma showing true histiocytic differentiation : 0.5% of NHL Gastrointestinal tract, skin, soft tissue Spindle, round, irregular or grooved nuclei Abundant eosinophilic cytoplasm Diffuse, non-cohesive, sarcomatoid appearance Immunostain : CD68, lysozyme, CD4, CD11c, CD14,
63 True histiocytic lymphoma, mesentery (58/M) (Courtesy of Dr. Fletcher)
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