Gastrointestinal stromal tumours ppt


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Its a comprehensive histopathological presentation on GISTs..

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  • The major histologic patterns of GIST are spindle cell and epithelioid. GIST with a spindle cell morphology often will appear syncytial while clear cell borders are common in epithelioid GIST.
    Gastric GIST are often of spindle cell morphology, with the epithelioid GIST often historically misclassified as myoblastomas.
    GIST of the small intestine are primarily of spindle cell morphology. A salient feature of small intestine GIST, especially those of lower risk, is the presence of aggregates of collagen fibers known as skeinoid fibers. In contrast, epithelioid GIST of the small intestine are generally of high risk.
    Spindle cell morphologies dominate GIST at other sites.
  • GIST are often defined as KIT-positive mesenchymal tumors of the GI tract.
    Over 90% of reported cases (but not all GIST) express KIT.
    KIT is a type III transmembrane receptor tyrosine kinase, the protein product of the KIT proto-oncogene. KIT is the single most common tumor marker for GIST.
    CD34 is a mesenchymal and hematopoietic precursor cell marker that is positive in many tumors of mesenchymal origin. It is expressed in 60% to 70% of GIST, making it a modestly sensitive and specific diagnostic GIST marker.
    Vimentin and smooth-muscle actin are variably expressed by GIST.
    Desmin is rarely present in GIST. In contrast, true smooth-muscle tumors often express high levels of desmin and smooth-muscle actin.
    S-100 is used to distinguish tumors of neural crest origin, such as schwannomas and melanomas, and it is particularly useful for differentiating GIST with neural phenotype (formerly GANT) from primary schwannomas.
  • Gastrointestinal stromal tumours ppt

    1. 1. Gastrointestinal Stromal Tumours Dr Priyageet Kaur
    2. 2. Introduction • Gastrointestinal stromal tumors (GISTs) constitute a majority of mesenchymal neoplasms of the gastrointestinal (GI) tract and abdomen. • Pathologic activation of KIT signal transduction appears to be a central event in GIST pathogenesis
    3. 3. How did the concept of GIST evolve? • Mazur and Clark introduced the term stromal tumour in 1983 after they failed to find ultrastructural evidence of smooth muscle or nerve sheath differentiation • Tumours with unequivocal smooth muscle derivation are most commonly seen in esophagus and rectum • The lack of unequivocal smooth muscle derivation + presence of positivity for markers not indicative of smooth muscle origingave rise to concept of GIST
    4. 4. • Formerly regarded as leiomyomas and leiomyosarcomas based on morphology • Subsequent IHC & ultrastructural study showed that true e/o smooth muscle differentiation was infrequent in gastric and small intestinal stromal tumours- Desmin expression was unusual • Thus GIST was introduced
    5. 5. Incidence and distribution • GISTs represent about 1% of all GI malignancies • Malignant GISTs are rare with an incidence of about 5 million of population • Adults --- 50-60 years (mc age group)
    6. 6. • Incidence of GISTs (location-wise) - 5% esophageal - 50-70% stomach - 25-40% small intestine 10-20% duodenum 27-37% jejunum 27-53% ileum - <10% colorectal----------– 50% colonic; 50% rectal - Rare omentum, peritoneum, retroperitoneum
    7. 7. Nature and differentiation • Originally arised from interstitial cell of Cajal (ICC) • KIT-positive & CD34 positive fibroblast-like cells • Pacemaker cells of the gut--- Regulate GI motility • Location- – Auerbach’s plexus of stomach, SI & colon – Intercalated between intramural neurons and smooth muscle cells – Generate electrical slow waves • Loss of ICC function has been implicated in diabetic gastroenteropathy, gastroenteric arrhythmia, and Hirschsprung’s disease
    8. 8. Clinical features -Gastrointestinal bleeding or vague ulcer-like pain are the most common symptoms of GIST. -Anemia due to chronic bleeding -Those GISTs that do not cause ulceration can grow into a large size with little symptoms. -palpable abdominal masses -intestinal perforation. -disseminated intra-abdominal tumor.
    9. 9. Macroscopic features • Usually present as single intramural tumours - Ulceration seen more in endophytic tumours often with a central crater - Ulceration can occur in entirely benign tumours and does not necessarily suggest malignancy
    10. 10. Polypoid mass with a large central scar
    11. 11. • Extramural component -may be attached to the stomach by a thin isthmus • Both endophytic & exophytic components can also be present- dumbbell shape
    12. 12. GIST in the mesentery of a 50 y/o female who presented with an abdominal mass. The resected loop of small intestine measured 70 cm in length and contained a 30 x 20 x 13 cm fleshy tumor with hemorrhagic surface.
    13. 13. GIST in the stomach
    14. 14. Cut surface • Characteristically grey in colour (without the typical whorling pattern typical of leiomyomas) • Granular or rubbery • Circumscribed but not encapsulated • Coursing bvs may be seen • Malignant GISTs tend to be whiter in color- increased cellularity & are more likely to show areas of necrosis, hghe & myxoid degeneration.
    15. 15. An ulcerated GIST originating in the muscle layer
    16. 16. Microscopic features • Location: 1. submucosal 2. intramuscular– muscularis propria Often the muscularis appears hypertrophic with muscle bundles present within the tumour & forming muscular septa that may divide the tumour into lobules. 3. subserosal—predominantly in exophytic tumours
    17. 17. Spindle shaped • About 70% of gastric GISTs and majority of the rest of the bowel are spindle- celled tumours. • Oval uniform blunt-ended nuclei with abundant amphophilic or eosinophilic slightly fibrillary cytoplasm • Pattern: cellular sheets or fascicles with whorled storiform or palisaded patterns
    18. 18. GIST: Major Morphologic Patterns Spindle Cell (70%) Epithelioid (9%) urtesy of Dr. C. Corless. Other-> mixed 21%
    19. 19. Spindle cell GIST with short fascicles & whorls Spindle cell GIST with longer fascicles in bundles
    20. 20. • Hyalinisation & myxoid degeneration, hemorrhage & even necrosis may all occur in varying proportions in otherwise benign tumours • Mitotic activity is low & usually behave in a benign fashion
    21. 21. • Features s/o smooth muscle differentiation such as perinuclear vacuoles may be present but should not invite a diagnosis of leiomyoma in the absence of IHC evidence Spindle cell GIST showing characteristic cytoplasmic vacuoles indenting the nuclear poles
    22. 22. Spindle cell GIST with prominent nuclear palisading
    23. 23. Epithelioid GISTs • Most occur in the fundus of the stomach • These are the commonest GISTs prominent in the antrum • Rounded cells with abundant prominent cleared cytoplasm & well defined cell borders • The tumour cells are arranged in sheets or packets , rather than fascicles; & tend to be oriented in a perivascular pattern
    24. 24. Epithelioid GIST with more pleomorphic nuclei & deeply acidophilic cytoplasm Epithelioid GIST with round cells, clear cytoplasm & well defined cell borders
    25. 25. Epithelioid GIST with pleomorphic nuclei & clear vacuolated cytoplasm Epithelioid GIST with rhabdoid features
    26. 26. • Hyalinisation & myxoid change are common • Cellular pleomorphism is characteristic -large bizarre nuclei are often present this per se does not indicate malignancy • Malignant epithelioid GISTs tend to have smaller cells with less vacuolated cytoplasm • They have more monotonous nuclei- cells appear clustered with an alveolar pattern
    27. 27. GIST with abundant myxoid matrix separating the individual tumour cells
    28. 28. GIST with numerous multinucleated giant cells
    29. 29. • Criteria for malignancy is based on proliferative indices, tumour size & infiltrative pattern
    30. 30. Genetics-KIT Gene and Protein and Their Alterations in GIST • KIT gene, mapped to 4q12, encodes a 145 - 160kDa protein, a transmembrane tyrosine kinase receptor (RTK) for stem cell factor (SCF, previously also called Steel factor). • KIT displays extensive homology with other members of RTK type III family, such as platelet- derived growth factor receptors (PDGFR), colony-stimulating factor-1 receptor (CSF1R) and FMS-related tyrosine kinase 3 (FLT3).
    31. 31. • Activation of KIT leads to downstream phosphorylation of substrate proteins and subsequently activates networks of signal transduction pathways which regulate important cell functions including proliferation, apoptosis, chemotaxis and adhesion. • KIT expression is critical for the development and maintenance of mast cells, hematopoietic stem cells, melanocytes, gametocytes, and ICCs in the GI tract.
    32. 32. • Structurally similar, constitutional, inheritable germline mutations have been found in patients with familial GISTs. • In GISTs, the majority of KIT mutations have been identified in the juxtamembrane domain, exon 11. • In addition, mutations in the extracellular (exon 9) and tyrosine kinase domains (exons 13, 14 and 17) have also been reported.
    33. 33. • Type of KIT mutation may have an impact of Imatinib treatment. • GISTs with KIT mutations affecting extracellular (exon 9) and tyrosine kinase domains (exons 13 & 14) may not respond to tyrosine kinase inhibitors equally well as do tumors with mutated KIT juxtamembrane domain (exon 11)
    34. 34. Alternative receptor tyrosine kinase mutations in PDGFRA Approximately 35% of GISTs negative for KIT mutations were recently shown to have activating mutations in the PDGFRA gene encoding the platelet derived growth factor alpha leading to similar signaling consequences as KIT mutations did. Notably, tyrosine kinase inhibitor Imanitib also inhibits PDGFR kinase.
    35. 35. Behaviour –general
    36. 36. • Malignant GISTs recur locally and spread mainly to adjacent organs, omentum or mesentery, retroperitoneum & liver • Less commonly 0-15% to LN or rarely bone • Distinction between benign & malignant cannot be made with certainty: 1. poorly differentiated tumours do not always behave in a malignant fashion 2. very small GISTs in some locations have been recorded to metastasize 3. even the blandest looking tumours can recur esp wen large even after 20-30 years
    37. 37. Gross appearance of liver metastasis from GIST
    38. 38. Esophagus • GISTs account for 25% of esophageal stromal tumours • Lower third or GEJ • Pred in males • Spindled or epithelioid • Majority are aggressive
    39. 39. Stomach • Gastric GISTs are more frequent in males • Young patients esp females have a better outcome • Epithelioid GISTs – 11% of gastric GISTs, of which 73- 81% behave in a benign fashion • Large tumours in the fundus or cardiac area and posterior wall are more likely to be aggressive
    40. 40. Duodenum • Mc in the second part • 35-50% are malignant • Cellular, have more than 2 mitoses per hpf • Greater than 45mm in diameter Jejunum and ileum • Worse outcomes than gastric GISTs
    41. 41. Extragastrointestinal GISTs
    42. 42. Immunohistochemistry • ~95% of reported cases of GIST are positive for KIT (CD117) • Other markers often positive in GIST – CD34 (mesenchymal/hematopoietic precursor cell marker) • Positive in 60%-70% – Smooth-muscle actin • Focal-Positive in 25%- 40% – S-100 • Positive in 10% • GIST rarely express desmin. Different KIT staining patterns in GIST Courtesy of Dr. C. Corless. Miettinen and Lasota. Virchows Arch. 2001;438:1.
    43. 43. GIST with strong and diffuse cytoplasmic staining of CD117 (c-kit)
    44. 44. • The most convincing pattern of CD117 positivity is one featuring a cell membrane component in addition to a cytoplasmic one • The presence of CD117 immunoreactivity in a tumor does not necessarily indicate that a mutation of the gene is present. Conversely, a CD117 mutation can exist in the absence of the immunohistochemically detectable marker.
    45. 45. A. Spindle cell GIST with strong and diffuse cytoplasmic staining of CD117 (c-kit) (×400); B. Spindle cell GIST with strong and diffuse membrane staining of CD34 (×400)
    46. 46. Epithelioid cell GIST with strong cytoplasmic staining of CD117 (×100)
    47. 47. Epithelioid cell GIST with patchy and heterogeneous staining of CD34 (×400)
    48. 48. Epithelioid cell GIST with punctate staining of h- Caldesmon (×100)
    49. 49. Epithelioid cell GIST with patchy mambrane staining of h-Caldesmon (×400)
    50. 50. Treatment • The primary treatment of GIST consists of surgical excision of the tumour with a good margin of normal tissue • Wide resection of LN areas is not indicated because of the extreme rarity of LN metastasis. • Gene product targeted therapy • Imatinib (Glivec), a 2-phenylaminopyrimidine derivative, a selective inhibitor of c-abl, c-kit & PDGFR tyrosine kinases.
    51. 51. Prognostic indicators • Mitotic activity & tumour size • Site • Proliferation markers ( Ki-67) • Pattern of differentiation • Loss of p16 regulator, loss of CD44 expression & overexpression of HSPsunfavourable factors • Presence and type of KIT mutation • Presence of PDGFR mutation • Other molecular genetic features
    52. 52. Differential diagnosis • Intramural leiomyoma 1. Most common in the esophagus 2. Composed of well differentiated smooth muscle cells, and usually much less cellular than GIST; focal atypia may occur. 3. Smooth muscle actin and desmin-positive 4. CD117 and CD34- negative
    53. 53. • Leiomyoma of muscularis mucosae 1. Usually endoscopically diagnosed as an incidental diminutive polyp in colon or rectum of older adults. 2. Composed of well- differentiated smooth muscle cells merging with muscularis mucosae and usually covered by intact mucosa. 3. Focal atypia may occur, but behavior is benign.
    54. 54. • Retroperitoneal & peri-intestinal leiomyoma 1. Occurs nearly exclusively in adult women, histologically similar to uterine leiomyoma. 2. Can form a large retroperitoneal tumor or smaller nodule attached to external aspect of intestines, usually colon or rectum. 3. Positive for actins, desmin and estrogen and progesterone receptors
    55. 55. • Leiomyosarco ma 1. Rare in stomach and intestines (at most 5 - 10% of GISTs), but retroperitoneum is a common site. 2. Usually occurs in older adults, with a significant female predominance in retroperitoneal tumors
    56. 56. • Histologically usually composed of well- differentiated smooth muscle cells, but may be focally pleomorphic. • Immunohistochemically typically positive for smooth muscle actins and desmin.
    57. 57. • Inflammatory myofibroblastic tumour 1. gastric or intestinal mass simulating a GIST. 2. More often omental or mesenteric. 3. Spindled or slightly epithelioid cells with amphophilic cytoplasm and cytoplasmic processes. 4. Has ALKgene expression and rearrangements.
    58. 58. • Schwannomas 1. Usually a relatively small (<5 cm), yellow circumscribed submucosal tumor, most commonly in the stomach and secondly in the colon. 2. Slender, often bundled S100- protein positive spindle cells. 3. GFAP-positivity is typical; this is almost never seen in GISTs
    59. 59. • Inflammatory fibrous polyp 1. Spindle cell lesion, mc seen in the small intestine of adults as an ulcerated intraluminal polyp. 2. oval or slender spindle cells in highly vascular granulation tissue-like stroma 3. Some examples are CD34-positive, but all are KIT-negative. 4. Smooth muscle actin positivity is possible; negative for desmin
    60. 60. • Glomus tumour 1. Conceptually identical with glomus tumor of peripheral soft tissue. 2. Occurs almost exclusively in the stomach in the GI- tract, mostly in the antrum. 3. Round tumor cells arranged around prominent, often dilated vessels.
    61. 61. • Immunohistoche mically positive for smooth muscle actin and negative for desmin. • Variably CD34- positive,but is KIT-negative
    62. 62. • Fibromatosis/mesenteri c desmoid 1. Can be extraintestinal or have GIST-like gastric or intestinal wall involvement. Grossly very firm and white. 2. Histologically composed of fibroblasts and myofibroblasts in collagenous, often focally myxoid background. 3. CD34-negative; can be focally smooth muscle actin and desmin positive
    63. 63. • Solitary fibrous tumour 1. May present on the peritoneal surfaces, pelvis or occasionally in the liver. 2. Collagenous spindle cell tumor, often with a focal hemangiopericytoma-like pattern. 3. Nearly always CD34- positive and negative for smooth muscle actin and desmin
    64. 64. • Spindle cell carcinoma • Follicular dendritic cell sarcoma • PEComas • Mesothelioma • Dedifferentiated liposarcoma
    65. 65. Thank you!