The Pathology of Rare Cancers  and its Pitfalls Angelo Paolo Dei Tos M.D. Departments of Pathology & Oncology Treviso, ITA...
Rare Cancers <ul><li>Incidence: 6 cases/100.000 </li></ul><ul><ul><li>RareCare </li></ul></ul><ul><li>Sarcoma: 5 cases/100...
Source of Errors in Pathology of Rare Cancers <ul><li>Insufficient exposure to significant number of cases </li></ul><ul><...
Diagnostic Errors in Pathology of Sarcomas <ul><li>Clinical trials </li></ul><ul><ul><li>7-10% </li></ul></ul><ul><li>Seco...
What about Italy? <ul><li>Informal survey on Rete Tumori Rari </li></ul><ul><li>490 cases </li></ul><ul><li>Evaluation of ...
<ul><li>Major discordances:  </li></ul><ul><ul><li>benign lesions misdiagnosed as malignant </li></ul></ul><ul><ul><li>mal...
Results <ul><li>Diagnosis confirmed 197/365  (54%) </li></ul><ul><li>Major discordances 131/365  (36%) </li></ul><ul><li>M...
Results Major   discordancies <ul><li>25 malignant lesions misdiagnosed as benign </li></ul><ul><li>6 cases benign lesions...
Errors in Pathology of Rare Cancers <ul><li>Avoid  “ blame and shame ”  attitude </li></ul><ul><li>Risk management </li></...
Source of Errors in Pathology of Sarcomas/Rare Cancers <ul><li>Diagnosis intrinsically difficult </li></ul><ul><ul><li>Com...
Diagnosis intrinsically difficult <ul><ul><li>Common criteria of malignancy not always applicable </li></ul></ul><ul><ul><...
<ul><li>Young adults </li></ul><ul><li>Fast growing lump </li></ul><ul><li>Upper arm </li></ul><ul><li>Grossly variegated ...
 
Diagnosis intrinsically difficult <ul><li>Common criteria of malignancy not always applicable </li></ul><ul><ul><li>Low gr...
LGFMS
Multiplex RT-PCR 1: 4 FUS F primers and 2 R primers CREB3L2/L1 exon 5 2: 4 FUS F primers and 2 R primers CREB3L2/L1 exon 6...
Benign lesions commonly mistaken for sarcomas <ul><li>Nodular fasciitis and variants </li></ul><ul><li>Myositis ossificans...
Cellular Schwannoma <ul><li>Woodruff, 1981 </li></ul><ul><li>Mistaken  for sarcoma in 30% of cases </li></ul><ul><li>Retro...
S-100
Sarcomas commonly mistaken for benign STT lesions <ul><li>Epithelioid sarcoma </li></ul><ul><li>Low grade fibromyxoid sarc...
Epithelioid Sarcoma Franz Enzinger   Cancer 1970; 26: 1029-1041
Cytokeratin
Complex integration of morphology, immunophenotype and genotype <ul><li>Combination of morphologic and molecular expertise...
Failure of ancillary techniques <ul><li>Immunohistochemistry </li></ul><ul><ul><li>IHC false positivity/negativity </li></...
EWSR1 in sarcomas <ul><li>AFH t(12;22)(q13;q12) EWSR1-ATF1 </li></ul><ul><ul><ul><ul><ul><li>t(2;22)(q34;q12) EWSR1-CREB1 ...
Continuous evolution of tumor classification <ul><li>Significant conceptual shifts </li></ul><ul><li>Better understanding ...
 
 
EMA CK CD99
EWSR1
 
 
Source of Errors <ul><li>Lack of multiprofessional collaboration </li></ul><ul><li>Imaging </li></ul><ul><li>Clinical pres...
 
 
 
More subtle potential issues <ul><li>Incorrect identification of the specific histotype </li></ul><ul><ul><li>Round cell s...
How can we define expertise? <ul><li>Those characteristics, skills and knowledge of a person (that is, expert), which dist...
How can we promote expertise? <ul><li>Proper specific training </li></ul><ul><li>Continuous access to cases </li></ul><ul>...
Few Golden Rules <ul><li>Always check clinical presentation </li></ul><ul><li>Start from H&E morphology </li></ul><ul><li>...
 
MDM2
Retroperitoneal WDLPS Normal tissue
 
Tumor type  Cytogenetic changes Gene rearrang t Ewing’s sarcoma/PNET t(11;22)(q24;q12) FLI-1-EWS t(21;22)(q22;q12) ERG-EWS...
Impact of Molecular Genetics/Pathology <ul><li>Diagnostic confirmation </li></ul><ul><ul><li>Challenging cases, rare locat...
<ul><li>ETV6-NTRK3 / t(12;15) in:  </li></ul><ul><ul><li>Infantile FS  </li></ul></ul><ul><ul><li>AML </li></ul></ul><ul><...
Few Golden Rules <ul><li>Always check clinical presentation </li></ul><ul><li>Start from H&E morphology </li></ul><ul><li>...
CD99 EWSR1 rearrangement
Few Golden Rules <ul><li>Always check clinical presentation </li></ul><ul><li>Start from H&E morphology </li></ul><ul><li>...
                                           >100 oncology units
Solutions <ul><li>Referral to centers of Excellence </li></ul><ul><ul><li>Bone, pediatric cancers… </li></ul></ul><ul><li>...
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Rare Solid Cancers: An Introduction - Slide 11 - A.P. Dei Tos - The pathology of rare cancers and its pitfalls

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  • In 2000 Bejarano et al: t(7;16) in a case of HSCTGR Mezzelani et al: ring chromosome derived from chr 7 and 16 in a lung met (HSCTGR) In 2003 Reid et al: t(7;16)(q34;p11) in both LGMS and HSCTGR Storlazzi et al: FUS-BBF2H7 (CREB3L2) In 2004 Panagopoulos et al: t(7;16) is specific In 2005 Mertens et al: t (11;16)(p11;p11) with FUS-CREB3L1 Guillou 2007: Specificity 45/52 sarcomas: absence of FUS-CREB3L2 7/52 sarcomas: FUS-CREB3L2 (4 SEF, 1MFS, 1MPNST, 1 perineurioma ) Hypothesis: SEF belong to the same spectrum
  • Rare Solid Cancers: An Introduction - Slide 11 - A.P. Dei Tos - The pathology of rare cancers and its pitfalls

    1. 1. The Pathology of Rare Cancers and its Pitfalls Angelo Paolo Dei Tos M.D. Departments of Pathology & Oncology Treviso, ITALY [email_address]
    2. 2. Rare Cancers <ul><li>Incidence: 6 cases/100.000 </li></ul><ul><ul><li>RareCare </li></ul></ul><ul><li>Sarcoma: 5 cases/100.000 </li></ul><ul><li>Single histotype much rarer </li></ul><ul><ul><li>DSRCT: < 1 case/1.000.000 </li></ul></ul><ul><li>Diagnosis and treatment = problematic worldwide </li></ul>
    3. 3. Source of Errors in Pathology of Rare Cancers <ul><li>Insufficient exposure to significant number of cases </li></ul><ul><ul><ul><li>5-6 cases/100.000 </li></ul></ul></ul><ul><li>Low impact of educational efforts </li></ul><ul><li>Lack of reinforcement </li></ul>
    4. 4. Diagnostic Errors in Pathology of Sarcomas <ul><li>Clinical trials </li></ul><ul><ul><li>7-10% </li></ul></ul><ul><li>Second opinion </li></ul><ul><ul><li>15-35% </li></ul></ul><ul><li>Rare Cancer Networks </li></ul><ul><ul><li>5-40% </li></ul></ul>
    5. 5. What about Italy? <ul><li>Informal survey on Rete Tumori Rari </li></ul><ul><li>490 cases </li></ul><ul><li>Evaluation of major and minor discordances </li></ul>
    6. 6. <ul><li>Major discordances: </li></ul><ul><ul><li>benign lesions misdiagnosed as malignant </li></ul></ul><ul><ul><li>malignant lesions misdiagnosed as benign </li></ul></ul><ul><ul><li>non mesenchymal lesions misdiagnosed as sarcoma </li></ul></ul><ul><ul><li>other changes in histotype impacting treatment choices </li></ul></ul><ul><li>Minor discordances: </li></ul><ul><ul><li>changes in histotype non impacting treatment </li></ul></ul>
    7. 7. Results <ul><li>Diagnosis confirmed 197/365 (54%) </li></ul><ul><li>Major discordances 131/365 (36%) </li></ul><ul><li>Minor discordances 17/365 (5%) </li></ul><ul><li>No diagnosis at origin 20/365 (5%) </li></ul>
    8. 8. Results Major discordancies <ul><li>25 malignant lesions misdiagnosed as benign </li></ul><ul><li>6 cases benign lesions misdiagnosed as malignant </li></ul><ul><li>29 cases: diagnosis of sarcoma rendered on non sarcomatous lesion </li></ul><ul><ul><li>mostly malignant melanomas and sarcomatoid carcinomas </li></ul></ul><ul><li>14 GI tract mesenchymal tumors were misdiagnosed as GIST </li></ul><ul><li>57 cases: a change in histotype was made that led to a change in therapeutic strategy </li></ul>
    9. 9. Errors in Pathology of Rare Cancers <ul><li>Avoid “ blame and shame ” attitude </li></ul><ul><li>Risk management </li></ul><ul><li>Transparent management of second opinion </li></ul><ul><ul><li>Best strategy to minimize medical litigation </li></ul></ul>
    10. 10. Source of Errors in Pathology of Sarcomas/Rare Cancers <ul><li>Diagnosis intrinsically difficult </li></ul><ul><ul><li>Common criteria of malignancy not always applicable </li></ul></ul><ul><ul><li>Several mimics </li></ul></ul><ul><ul><ul><li>Benign lesions mimicking malignancies and vice versa </li></ul></ul></ul><ul><ul><li>Complex integration of morphology, immunophenotype and genotype </li></ul></ul><ul><ul><li>Failure of ancillary techniques </li></ul></ul>
    11. 11. Diagnosis intrinsically difficult <ul><ul><li>Common criteria of malignancy not always applicable </li></ul></ul><ul><ul><ul><li>Necrosis </li></ul></ul></ul><ul><ul><ul><li>Pleomorphism </li></ul></ul></ul><ul><ul><ul><li>Mitotic Activity </li></ul></ul></ul>
    12. 12. <ul><li>Young adults </li></ul><ul><li>Fast growing lump </li></ul><ul><li>Upper arm </li></ul><ul><li>Grossly variegated and well circumbscribed </li></ul><ul><li>Hypercellular spindle cell neoplasm </li></ul><ul><li>High mitotic activity </li></ul>
    13. 14. Diagnosis intrinsically difficult <ul><li>Common criteria of malignancy not always applicable </li></ul><ul><ul><li>Low grade fibromyxoid sarcoma </li></ul></ul><ul><ul><li>Mantle cell limphoma </li></ul></ul><ul><ul><li>Endocrine tumors </li></ul></ul><ul><ul><ul><li>Adrenal tumors </li></ul></ul></ul><ul><ul><ul><li>Parathyroid </li></ul></ul></ul><ul><ul><li>Subependimal giant cell astrocytoma </li></ul></ul>
    14. 15. LGFMS
    15. 16. Multiplex RT-PCR 1: 4 FUS F primers and 2 R primers CREB3L2/L1 exon 5 2: 4 FUS F primers and 2 R primers CREB3L2/L1 exon 6 3: 1 beta actin F and 1 beta actin R primers FUS exon 6-CREB3L2 exon 5 FUS exon 6-CREB3L1 exon 6 Case A Case B Case B Case B Case A Case A NC NC NC 1 2 3
    16. 17. Benign lesions commonly mistaken for sarcomas <ul><li>Nodular fasciitis and variants </li></ul><ul><li>Myositis ossificans </li></ul><ul><li>Cellular schwannoma </li></ul><ul><li>Cellular FH </li></ul><ul><li>Atypical FH </li></ul><ul><li>AFX </li></ul><ul><li>Myxoid spindle cell lipoma </li></ul><ul><li>Epithelioid angiomatous nodule </li></ul><ul><li>Pseudosarcomatous myofibroblastic lesion of urinary bladder </li></ul><ul><li>Vascular lesions </li></ul>
    17. 18. Cellular Schwannoma <ul><li>Woodruff, 1981 </li></ul><ul><li>Mistaken for sarcoma in 30% of cases </li></ul><ul><li>Retroperitoneum/mediastinum </li></ul><ul><li>Capsulated </li></ul><ul><li>Predominantly Antoni A </li></ul><ul><li>Currently the most common cause of GIST misdiagnosis </li></ul>
    18. 19. S-100
    19. 20. Sarcomas commonly mistaken for benign STT lesions <ul><li>Epithelioid sarcoma </li></ul><ul><li>Low grade fibromyxoid sarcoma </li></ul><ul><li>Low grade myofibroblastic sarcoma </li></ul><ul><li>GIST </li></ul><ul><li>“ Low-grade ” angiosarcoma </li></ul>
    20. 21. Epithelioid Sarcoma Franz Enzinger Cancer 1970; 26: 1029-1041
    21. 22. Cytokeratin
    22. 23. Complex integration of morphology, immunophenotype and genotype <ul><li>Combination of morphologic and molecular expertise </li></ul><ul><li>Main risk: good molecular analysis on the wrong tumors </li></ul>
    23. 24. Failure of ancillary techniques <ul><li>Immunohistochemistry </li></ul><ul><ul><li>IHC false positivity/negativity </li></ul></ul><ul><ul><li>Misinterpretation of immunolocalization </li></ul></ul><ul><li>Molecular pathology/genetics </li></ul><ul><ul><li>Contamination: the t(X;18) saga </li></ul></ul><ul><ul><li>GIST “ wild type ” </li></ul></ul><ul><ul><li>EWS FISH “ split apart ” approach </li></ul></ul>
    24. 25. EWSR1 in sarcomas <ul><li>AFH t(12;22)(q13;q12) EWSR1-ATF1 </li></ul><ul><ul><ul><ul><ul><li>t(2;22)(q34;q12) EWSR1-CREB1 </li></ul></ul></ul></ul></ul><ul><li>CCS t(12;22)(q13;q12) EWSR1-ATF1 </li></ul><ul><ul><li>t(2;22)(q34;q12) EWSR1-CREB1 </li></ul></ul><ul><li>DSRCT t(12;22)(q22;q12) EWSR1-WT1 </li></ul><ul><li>EMCHS t(9;22)(q22:q12) EWSR1-NR4A3 </li></ul><ul><li>MLPS t(121;22)(q13;q12) EWSR1-DDIT3 </li></ul><ul><li>MET (6;22)(p21;q12) EWSR1-POU5F1 </li></ul>
    25. 26. Continuous evolution of tumor classification <ul><li>Significant conceptual shifts </li></ul><ul><li>Better understanding of tumor biology/genetics </li></ul>
    26. 29. EMA CK CD99
    27. 30. EWSR1
    28. 33. Source of Errors <ul><li>Lack of multiprofessional collaboration </li></ul><ul><li>Imaging </li></ul><ul><li>Clinical presentation </li></ul><ul><ul><li>Anatomic location </li></ul></ul><ul><ul><li>Duration </li></ul></ul><ul><ul><li>History of trauma </li></ul></ul><ul><li>Association with genetic syndromes </li></ul>
    29. 37. More subtle potential issues <ul><li>Incorrect identification of the specific histotype </li></ul><ul><ul><li>Round cell sarcoma, NHL, SNC tumors </li></ul></ul><ul><ul><li>Therapy associated histotypes </li></ul></ul><ul><ul><ul><li>MPNST vs LMS vs SS </li></ul></ul></ul><ul><ul><li>Target therapy associated histotypes </li></ul></ul><ul><ul><ul><li>GIST, DFSP, Chordoma, PEComa … </li></ul></ul></ul><ul><li>Myogenic differentiation </li></ul><ul><li>Risk assessment in GIST </li></ul>
    30. 38. How can we define expertise? <ul><li>Those characteristics, skills and knowledge of a person (that is, expert), which distinguish experts from novices and less experienced people. </li></ul>
    31. 39. How can we promote expertise? <ul><li>Proper specific training </li></ul><ul><li>Continuous access to cases </li></ul><ul><li>Technical platforms </li></ul><ul><ul><li>IHC </li></ul></ul><ul><ul><li>Molecular genetics </li></ul></ul><ul><li>VEQ </li></ul>
    32. 40. Few Golden Rules <ul><li>Always check clinical presentation </li></ul><ul><li>Start from H&E morphology </li></ul><ul><li>Create differential diagnosis </li></ul><ul><li>Integrate immunophenotypic panel </li></ul><ul><li>When necessary integrate genetics </li></ul><ul><li>Multiprofessional approach </li></ul>
    33. 42. MDM2
    34. 43. Retroperitoneal WDLPS Normal tissue
    35. 45. Tumor type Cytogenetic changes Gene rearrang t Ewing’s sarcoma/PNET t(11;22)(q24;q12) FLI-1-EWS t(21;22)(q22;q12) ERG-EWS t(7;22)(p22;q12) ETV1-EWS t(17;22)(q12;q12) EIAF-EWS t(2;22)(q33;q12) FEV-EWS Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FKHR t(1;13)(p36;q14) PAX7-FKHR Myxoid/round cell liposarcoma t(12:16)(q13;q11) CHOP-TLS t(12;22)(q13;q11-12) CHOP-EWS DSRCT t(11;22)(p13;q12) WT1-EWS Synovial sarcoma t(X;18)(p11.2;q11.2) SSX1-SYT SSX2-SYT Clear cell sarcoma t(12;22)(q13;q12) ATF-1-EWS Extraskeletal myxoid CHS t(9;22)(q22;q12) TEC-EWS DFSP/GCF t(17;22)(q22;q13) PDGFB-COL1A1 Infantile fibrosarcoma t(12;15)(p13;q25) ETV6-NTRK3 Alveolar soft part sarcoma t(X;17)(p11;q25) ASPL-TFE3 Low grade fibromyxoid sarcoma t(7;16)(q33;p11) FUS-BBF2H7
    36. 46. Impact of Molecular Genetics/Pathology <ul><li>Diagnostic confirmation </li></ul><ul><ul><li>Challenging cases, rare locations … </li></ul></ul><ul><li>Prognostic stratification </li></ul><ul><li>Prediction of Response </li></ul><ul><li>Only in context with morphology </li></ul><ul><ul><li>Same genetic aberrations in unrelated entitites </li></ul></ul>
    37. 47. <ul><li>ETV6-NTRK3 / t(12;15) in: </li></ul><ul><ul><li>Infantile FS </li></ul></ul><ul><ul><li>AML </li></ul></ul><ul><ul><li>Secretory breast carcinoma </li></ul></ul><ul><li>ALK fusions in: </li></ul><ul><ul><li>Inflammatory myofibroblastic tumor </li></ul></ul><ul><ul><li>Anaplastic large cell lymphoma </li></ul></ul><ul><li>FUS-ERG / t(16;21) in: </li></ul><ul><ul><li>Ewing ’ s sarcoma </li></ul></ul><ul><ul><li>AML </li></ul></ul><ul><li>ASPL-TFE3 / t(X;17) in: </li></ul><ul><ul><li>ASPS </li></ul></ul><ul><ul><li>subset of pediatric renal carcinomas </li></ul></ul><ul><li>EWS-ATF1/ t(12;22) and EWS-CREB1 a t(2:22) in: </li></ul><ul><ul><li>CCS and AFH </li></ul></ul>
    38. 48. Few Golden Rules <ul><li>Always check clinical presentation </li></ul><ul><li>Start from H&E morphology </li></ul><ul><li>Generate differential diagnosis </li></ul><ul><li>Integrate immunophenotypic panel </li></ul><ul><li>When necessary integrate genetics </li></ul><ul><li>Remember that diseases may be ignorant </li></ul>
    39. 49. CD99 EWSR1 rearrangement
    40. 50. Few Golden Rules <ul><li>Always check clinical presentation </li></ul><ul><li>Start from H&E morphology </li></ul><ul><li>Generate differential diagnosis </li></ul><ul><li>Integrate immunophenotypic panel </li></ul><ul><li>When necessary integrate genetics </li></ul><ul><li>Remember that diseases may be ignorant </li></ul><ul><li>Asking for second opinion is not a crime </li></ul>
    41. 51.                                            >100 oncology units
    42. 52. Solutions <ul><li>Referral to centers of Excellence </li></ul><ul><ul><li>Bone, pediatric cancers… </li></ul></ul><ul><li>Enforce Clinical Networks </li></ul><ul><ul><li>Reduction of social costs </li></ul></ul><ul><ul><li>Broadening of knowledge </li></ul></ul><ul><li>Diagnostic second opinion </li></ul>
    43. 53. [email_address]

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