Page 1 ALK FUSION-POSITIVE MESENCHYMAL TUMORS Jason L. Hornick, MD, PhD March 13, 2016 Department of Pathology Brigham and Women’s Hospital Harvard Medical School Boston, MA, USA Companion Meeting of the International Society of Bone and Soft Tissue Pathology The Evolving Concept of Mesenchymal Tumors ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Jason Hornick declares he has no conflicts of interest to disclose. Anaplastic Lymphoma Kinase CD30 Tumor types with ALK rearrangements Hematolymphoid ALK+ anaplastic large-cell lymphoma ALK+ diffuse large B-cell lymphoma Systemic histiocytosis Epithelial Lung adenocarcinoma Renal cell carcinoma Other carcinomas (very rare) Melanocytic Spitz tumor Mesenchymal Inflammatory myofibroblastic tumor Epithelioid fibrous histiocytoma
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ALK FUSION-POSITIVE MESENCHYMAL TUMORSALK FUSION-POSITIVE MESENCHYMAL TUMORS Jason L. Hornick, MD, PhD March 13, 2016 Department of Pathology Brigham and Women’s Hospital Harvard
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ALK FUSION-POSITIVE MESENCHYMAL TUMORS
Jason L. Hornick, MD, PhDMarch 13, 2016
Department of PathologyBrigham and Women’s Hospital
Harvard Medical SchoolBoston, MA, USA
Companion Meeting of the International Society of Bone and Soft Tissue Pathology
The Evolving Concept of Mesenchymal TumorsACCME/DisclosuresThe USCAP requires that anyone in a position to influence or control the content of CME disclose
any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their
spouse/partner have, or have had, within the past 12 months, which relates to the content of
this educational activity and creates a conflict of interest.
Dr. Jason Hornick declares he has no conflicts of interest to disclose.
Anaplastic Lymphoma Kinase
CD30
Tumor types with ALK rearrangementsHematolymphoid
ALK+ anaplastic large-cell lymphomaALK+ diffuse large B-cell lymphomaSystemic histiocytosis
• Reparative/post-inflammatory condition?• Similar lesions other sites• Distinctive clinical features:
– Predilection for children– Subset with systemic symptoms
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20 cases (19 lung)– Immunohistochemical and ultrastructural
features of fibroblasts and myofibroblasts
1 patient 2 recurrences10 pts with follow-up, ANED
38 casesIntra-abdominal, retroperitonealChildren and adolescents27 cases with follow-up
–10 (37%) local recurrence–3 (11%) metastasis–5 (19%) died from disease
84 extrapulmonary casesSignificant clinical/histologic overlap with “inflammatory fibrosarcoma”Mostly children, young adults75% abdomen, pelvis or retroperitoneum53 cases with follow-up
–13 (25%) local recurrence–No metastases
Inflammatory Myofibroblastic Tumor
• Predilection for children/adolescents• Wide age range• Most common sites:
– Abdominopelvic region, retroperitoneum, lung
• Most present with mass• Subset with constitutional symptoms• Wide size range (mean, 5-6 cm)• Subset in abdomen multiple discrete
masses
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Inflammatory Myofibroblastic Tumor: Histologic Features
• Fascicles of uniform, elongated spindle cells with vesicular nuclei
• At most mild nuclear atypia• Prominent inflammatory infiltrate:
– Primarily plasma cells and lymphocytes
• Occasionally myxoid stroma• Sometimes hypocellular/fibrous• Subset contain “ganglion-like” cells
• Local recurrence:<2% lung25% extrapulmonary (intra-abdominal++)
• Metastasis:1-3%Lung, brain, liver, bone
Inflammatory Myofibroblastic Tumor: Prognosis
• In general, poor correlation between histology and behavior
• May occasionally recur with higher-grade histology:– Increased cellularity or nuclear atypia, high
mitotic rate–Histiocytoid or round cell cytology
• Referred to as “round cell transformation”• May also be seen de novo – distinctive
aggressive variant
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Inflammatory Myofibroblastic Tumor
Abdomen Primary
Inflammatory Myofibroblastic Tumor
Recurrence (3 yrs)Abdomen
Inflammatory Myofibroblastic Tumor ALK in IMT
• ALK rearrangement in 60% of IMT<10% in adults >50 yrs
• Heterogeneous fusion partners• Strong correlation between detection
of ALK expression by IHC and ALKrearrangement (new highly sensitive antibodies better)
• ALK negative in other myofibroblastic and smooth muscle tumors, GIST
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ALK
Inflammatory Myofibroblastic TumorFISH
Courtesy of Paola Dal Cin
Selected for local recurrence or metastasisIncluded 6 metastatic tumorsNone of the metastatic tumors were positive for ALKALK favorable prognostic indicator?
Predilection for young male adultsEpithelioid morphology, myxoid stroma, prominent neutrophilsNuclear membrane pattern of ALK stainingRANBP2-ALK fusionAggressive sarcoma with rapid recurrences
• Clinical benefit for patients with advanced EML4-ALK+ lung adenocarcinomas
• Efficacy in ALK+ IMT promising
Multifocal Recurrent EIMS Treated with ALK Inhibitor Crizotinib
Butrynski et al. N Engl J Med 2010
3 months
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3 of 7 patients with ALK-rearranged IMT partial response4 of 7 patients with stable disease
Same patient with EIMS from the NEJM case report
1 patient with IMT who progressed on another TKI had a partial response
ALK-Negative Inflammatory Myofibroblastic Tumors?
• Until recently, molecular pathogenesis unknown
• Recent reports identified fusions involving receptor tyrosine kinase genes other than ALK
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Lovly et al. Cancer Discovery 2014
Lovly et al. Cancer Discovery 2014
8-year-old boy with IMT harboring TFG-ROS1 fusion
Antonescu et al. Am J Surg Pathol 2015
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Courtesy of Paola Dal Cin
Inflammatory Myofibroblastic Tumor
ALKROS1
Lung AdenocarcinomaCD74-ROS1
ROS1
Inflammatory Myofibroblastic TumorTFG-ROS1
ROS1
ALK-CLTCInflammatory Myofibroblastic Tumor
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Epithelioid Fibrous Histiocytoma• Also known as “epithelioid cell histiocytoma”• Traditionally considered morphologic variant
of cutaneous benign fibrous histiocytoma (dermatofibroma)
• Flesh-colored nodule on extremities of young to middle-aged adults
• Exophytic, well-circumscribed, sometimes with epidermal collarette
• Uniform bland epithelioid cells with vesicular nuclei, small nucleoli, and moderate amounts of eosinophilic or amphophilic cytoplasm; some binucleate cells