the pathology of rare cancer -...
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The Pathology of Rare Cancer
Angelo Paolo Dei Tos M.D.Departments of Pathology & Oncology, Treviso, ITALY
University of Padua School of Medicine
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Rare Cancers
• Incidence: 6 cases/100.000• RareCare
• Sarcoma: 5 cases/100.000
• Single histotype much rarer• DSRCT: < 1 case/1.000.000
• Diagnosis and treatment = problematic worldwide
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Case History
• 23 year old female
• Mass in the abdominal wall
• Core biopsy
• Low-grade Sarcoma
• 2nd opinion: myositis ossificans
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Case History
• 23 year old female
• Mass in the abdominal wall
• Core biopsy
• Low grade Sarcoma
• 2nd opinion: myositis ossificans
• Frozen section: low grade sarcoma
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Case History
• 37 year male
• Mass in the orbit
• Biopsy
• Leiomyosarcoma
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Nodular Fasciitis
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Case History
• 41 year old female
• Mass in right thigh
• Core biopsy
• Reactive mesenchymal proliferation
• Recurrence at 6 months
• 2nd opinion: CIC-rearranged high-grade round cell sarcoma
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Source of Errors in Pathology of Rare Cancers
• Insufficient exposure to significant number of cases• 5-6 cases/100.000
• Low impact of educational efforts
• Lack of reinforcement
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Diagnostic Errors in Pathology of Rare Cancers
• Clinical trials• 7-10%
• Second opinion• 15-35%
• Rare Cancer Networks• 5-40%
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What about Italy?
• Informal survey on Rete Tumori Rari
• Approx 500 cases
• Evaluation of major and minor discordances
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• Major discordances: • benign lesions misdiagnosed as malignant• malignant lesions misdiagnosed as benign• non mesenchymal lesions misdiagnosed as sarcoma
• carcinoma; melanoma; NHL• other changes in histotype impacting treatment choices
• Minor discordances:• changes in histotype non impacting treatment
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Results
• Diagnosis confirmed 197/365 (54%)
• Major discordances 131/365 (36%)
• Minor discordances 17/365 (5%)
• No diagnosis at origin 20/365 (5%)
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Errors in Pathology of Rare Cancers
• Avoid “blame and shame” attitude
• Risk management
• Transparent management of second opinion• Best strategy to minimize medical litigation
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Ann Oncol 2012;23:2442
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Source of Errors in Pathology of Sarcomas/Rare Cancers
• Diagnosis intrinsically difficult
• Common criteria of malignancy not always applicable
• Several mimics
• Benign lesions mimicking malignancies and vice versa
• Complex integration of morphology, immunophenotypeand genotype
• Failure of ancillary techniques
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Diagnosis intrinsically difficult
• Common criteria of malignancy not always applicable
• Low grade fibromyxoid sarcoma
• Mantle cell limphoma
• Endocrine tumors
• Adrenal tumors
• Parathyroid
• Subependimal giant cell astrocytoma
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Complex integration of morphology, immunophenotype and genotype
• Combination of morphologic and molecular expertise
• Main risk: good molecular analysis on the wrong tumors
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Failure of Ancillary Techniques
• Immunohistochemistry• IHC false positivity/negativity• Misinterpretation of immunolocalization
•Molecular pathology/genetics• Contamination: the t(X;18) saga• GIST “wild type”• EWS FISH “split apart” approach
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Continuous Evolution of Tumor Classification
• Significant conceptual shifts
• Better understanding of tumor biology/genetics
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EMACK
CD99
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EWSR1
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Source of Errors
• Lack of multiprofessional collaboration
• Imaging
• Clinical presentation• Anatomic location
• Duration
• History of trauma
• Association with genetic syndromes
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More issues
• Incorrect identification of the specific histotype• Round cell sarcoma, NHL, SNC tumors, germ cell tumors, NUT
+ carcinoma etc.• Therapy associated histotypes
• MPNST vs LMS vs SS
• Target therapy associated histotypes• GIST, DFSP, Chordoma, PEComa…
• Risk assessment in GIST
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How can we define expertise?
• Those characteristics, skills and knowledge of a person (that is, expert), which distinguish experts from novices and less experienced people.
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How can we define expertise?
• The Expert is the individual who knows more and more of less and less
• At the end he knows everything about nothing
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How can we promote expertise?
• Proper specific training
• Continuous access to cases
• Technical platforms• IHC• Molecular genetics• VEQ
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Referral to expert rare cancer pathologists is crucialfor appropriateness
Networks are the best tool for proper referralMultidisciplinarity is the best environment for rare
cancer patient healthcare
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Solutions
• Referral to centers of Excellence• Bone, pediatric cancers…
• Enforce Clinical Networks• Reduction of social costs• Broadening of knowledge
• Diagnostic second opinion
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>100 oncology units
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R
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Histotype-driven therapy
• GIST; imatimib/sunitinib/regorafenib
• DFSP and PVNS: imatinib
• IMT: crizotinib
• WD/DDLPS: anti MDM2/CDk4
• Angiosarcoma: taxanes/gemcitabine
• Malignant PEComa: mTor inhibitors
• ASPS: sunitinib/cediranib
• SFT: sunitinib
• Leiomyosarcoma: gemcitabine/dacarbazine/trabectedin/pazopanib
• Myxoid liposarcoma: trabectedin/eribulin
• GCT/ABC: denosumab
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Conclusions
• Accurate diagnosis of rare cancers is a challenge
• Integration of morphology, immunohistochemistry, and molecular genetics
• Multidisciplinary approach
• Rare Cancer Networks may represent the most effective solution
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