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
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Case History
• 23 year old female
• Mass in the abdominal wall
• Core biopsy
• Low-grade Sarcoma
• 2nd opinion: myositis ossificans
Rare adult solid ca
ncers
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Rare adult solid ca
ncers
Rare adult solid ca
ncers
Case History
• 37 year male
• Mass in the orbit
• Biopsy
• Leiomyosarcoma
Rare adult solid ca
ncers
Nodular Fasciitis
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Diagnostic Errors in Pathology of Rare Cancers
• Clinical trials• 7-10%
• Second opinion• 15-35%
• Rare Cancer Networks• 5-40%
Rare adult solid ca
ncers
What about Italy?
• Informal survey on Rete Tumori Rari
• Approx 500 cases
• Evaluation of major and minor discordances
Rare adult solid ca
ncers
• 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
Rare adult solid ca
ncers
Results
• Diagnosis confirmed 197/365 (54%)
• Major discordances 131/365 (36%)
• Minor discordances 17/365 (5%)
• No diagnosis at origin 20/365 (5%)
Rare adult solid ca
ncers
Errors in Pathology of Rare Cancers
• Avoid “blame and shame” attitude
• Risk management
• Transparent management of second opinion• Best strategy to minimize medical litigation
Rare adult solid ca
ncers
Ann Oncol 2012;23:2442
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Complex integration of morphology, immunophenotype and genotype
• Combination of morphologic and molecular expertise
• Main risk: good molecular analysis on the wrong tumors
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Continuous Evolution of Tumor Classification
• Significant conceptual shifts
• Better understanding of tumor biology/genetics
Rare adult solid ca
ncers
Rare adult solid ca
ncers
EMACK
CD99
Rare adult solid ca
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EWSR1
Rare adult solid ca
ncers
Rare adult solid ca
ncers
Rare adult solid ca
ncers
Source of Errors
• Lack of multiprofessional collaboration
• Imaging
• Clinical presentation• Anatomic location
• Duration
• History of trauma
• Association with genetic syndromes
Rare adult solid ca
ncers
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
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.
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
How can we promote expertise?
• Proper specific training
• Continuous access to cases
• Technical platforms• IHC• Molecular genetics• VEQ
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Solutions
• Referral to centers of Excellence• Bone, pediatric cancers…
• Enforce Clinical Networks• Reduction of social costs• Broadening of knowledge
• Diagnostic second opinion
Rare adult solid ca
ncers
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>100 oncology units
Rare adult solid ca
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Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
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
Rare adult solid ca
ncers
Rare adult solid ca
ncers