PROBLEMS OF PROGNOSTICATION IN SOFT TISSUE TUMOURS Christopher D.M. Fletcher Brigham and Women s Hospital and Harvard Medical School Boston, MA
Dr. Fletcher has no conflict of interest or disclosures to make.
PROGNOSTIC PROBLEMS Soft tissue sarcomas Soft tissue tumours with biologic continuum Tumours which rarely metastasise Benign tumours which exceptionally metastasise
VARIABLE BEHAVIOUR OF SOFT TISSUE SARCOMAS Usually metastasise, usually < 2 years Usually metastasise, maybe up to 20 years + 50% metastasise, usually < 5 years 20-30% metastasise, some predictable Rarely metastasise, unpredictable Some tumour-type specific Some types spread across spectrum
SOFT TISSUE SARCOMAS CLINICAL PROGNOSTIC FACTORS Stage Tumour size Depth Anatomic site Status of margins Disease-free interval Treatment response
SOFT TISSUE SARCOMAS PATHOLOGIC PROGNOSTIC FACTORS Diagnosis/histotype Histologic grade Tumour size Status of margins Vascular invasion Proliferative indices Molecular genetics
SOFT TISSUE SARCOMA PURPORTED REASONS FOR GRADING Prognostication Staging / planning management Avoids pathologists disagreement Copes with unclassified sarcomas Provides supposed objectivity
SOFT TISSUE SARCOMAS GENUINE REASONS FOR GRADING Prognostication Staging / planning management Clinical trials Comparisons of outcome data
SOFT TISSUE SARCOMAS HISTOLOGIC GRADING Histologic grade (however derived) is the single best prognostic indicator in some tumour types. Major staging systems (e.g. AJCC) use grade as a key parameter Modern oncologic practice attaches great importance to histologic grade Emphasis on grade, at least in part, paralleled the pre-eminence of MFH
POTENTIAL GRADES 1. Low Surgery alone 2. Low-to-intermediate 3. Intermediate Don t know 4. Intermediate-to-high 5. High Add chemo
SOFT TISSUE SARCOMAS POTENTIAL HISTOLOGIC COMPONENTS OF GRADE Cellularity Pleomorphism / anaplasia Necrosis Mitotic activity Character of margin Vascular invasion
SOFT TISSUE SARCOMAS PROBLEMS IN ASSESSING NECROSIS Macroscopic vs. microscopic Present vs. absent (EORTC) 15% (NCI) vs. 50% (French) Tumor necrosis vs. ischaemia/ infarction Treatment effect(s)
SOFT TISSUE TUMOURS MORPHOLOGY / OUTCOME MISMATCH Atypical fibroxanthoma Pleomorphic hyalinising angiectatic tumour Infantile fibrosarcoma Low-grade fibromyxoid sarcoma Rare benign lesions which metastasise Presumably relates to genetic hits / progression
SOFT TISSUE SARCOMAS Grading is heavily dependent upon the ability to accurately diagnose malignancy
SOFT TISSUE SARCOMAS KEY ELEMENTS IN CURRENTLY ACCEPTED GRADING SCHEMES Histotype / differentiation Mitoses Necrosis French (FNCLCC) & NCI systems best known and best validated French system is more discriminatory
Guillou et al. J Clin Oncol 1997; 15:350-362
Guillou et al. J Clin Oncol 1997; 15:350-362
HISTOLOGIC GRADING OF SOFT TISSUE SARCOMAS WHEN DOES IT WORK? In tumours which show a morphologic spectrum that correlates with outcome In the context of an accurate histologic diagnosis e.g. leiomyosarcoma, myxofibrosarcoma
TUMOUR TYPES IN WHICH FNCLCC SYSTEM DOES NOT WORK MPNST (?) Angiosarcoma Epithelioid sarcoma Clear cell sarcoma Extraskeletal myxoid chondrosarcoma Alveolar soft part sarcoma
SOFT TISSUE SARCOMAS TYPE-SPECIFIC GRADING PROBLEMS No differentiated tissue equivalent - synovial sarcoma - clear cell sarcoma - epithelioid sarcoma Usually low mitotic rate - high grade myxoid liposarcoma - alveolar soft part sarcoma - clear cell sarcoma Usually high mitotic rate - infantile fibrosarcoma (pseudosarcomatous lesions)
SOFT TISSUE SARCOMAS INTRINSIC PROBLEMS IN GRADING Determination of mitotic activity Determination of necrosis Sampling / regional variability Influence of histologic type Effect(s) of pre-op therapy Grade change in recurrence
In attempting to correlate structural grade and clinical course in the neurogenic sarcomas, it must be recognized that. histology may vary widely in different regions, that two adjacent tumor nodules may show two extremes of cellularity and that the structure of the recurrent tumors may be quite different from the primary growth. Stewart FW & Copeland MM, Am J Cancer 1931; 15: 1235-1320
Tumors of the soft tissues, Atlas of Tumor Pathology, 3 rd Series, RL Kempson et al, eds. Washington DC: AFIP 2001
SOFT TISSUE TUMOURS GRADING TRUISMS Grading on needle biopsies or FNA is often unreliable/may be misleading Grading on an incisional biopsy may be an underestimate Grading a pre-treated lesion most often is meaningless Provision of a grade without a diagnosis is often absurd
HISTOLOGIC GRADING OF SOFT TISSUE SARCOMAS PROBLEMS WITH MOST STUDIES To obtain statistically useful case numbers, histotypes are lumped together Only rare studies stratify by tumour type Any statistical analysis of large mixed series underestimates the importance of prognostic factors relevant in rare histotypes
HISTOLOGIC GRADING OF SOFT TISSUE SARCOMAS No reason to believe or expect that prognostic parameters would be same in all tumour types Grade - Myxofibrosarcoma Cellularity - Myxoid liposarcoma Size - Myxoid chondrosarcoma Location - Dedifferentiated liposarcoma Genotype - Alveolar rhabdomyosarcoma Clinical stage - Embryonal rhabdomyosarcoma Patient age - Alveolar soft part sarcoma
PROGNOSTICATION IN SOFT TISSUE SARCOMAS BROAD ISSUES Influence of histologic type very dependent on reproducibility Grading schemes don t work for some tumour types Type-specific influence of site (eg embryonal rhabdo, leiomyosarc) Prognostic factors change with time Specimen type (problem of needle bx) Use of preoperative therapy
LEIOMYOSARCOMA* INFLUENCE OF SITE ON PROGNOSIS Overall mortality SKIN 0 SUBCUT 20-30% INTRAMUSC ~ 50% RETROPERIT ~ 100% LARGE VESSEL 80-100% *Taking all grades together
DISEASE-SPECIFIC SURVIVAL FOR SOFT TISSUE SARCOMAS* 2 yrs 5 yrs 10yrs Day 0 88% 76% 67% Disease-free at 2 yrs 97% 90% 82% Disease-free at 5 yrs 99% 96% 92% *Localised / completely resected - J Clin Oncol 2002; 20:4344-4352
PROGNOSTICATION IN SOFT TISSUE SARCOMAS INFLUENCE OF TIME At resectable locations, tumour size and histologic grade predict disease-free interval for first 3 years At resectable locations, status of margins is more important for patients disease free > 3 years At hard to resect locations, prognostic factors (size, grade, margins) remain unchanged over time
Kattan et al. J Clin Oncol 2002; 20:791-796
MANAGEMENT OF SOFT TISSUE SARCOMAS A MODERN ONCOLOGIC PARADIGM Needle biopsy Grade and (maybe) diagnosis Neoadjuvant XRT or chemo Excision of undiagnosable altered / dead tissue Who knows what has been treated? How can one reliably predict behaviour?
Never mind grading how good are we at recognising a malignant lesion?
NON-VISCERAL SMOOTH MUSCLE TUMOURS CRITERIA FOR MALIGNANCY (1) RETROPERITONEUM Either more than minimal atypia or coagulative necrosis or > 10 mitoses / 50 HPF (females) (Insufficient data in males) DEEP SOFT TISSUE (LIMBS / TRUNK) Either more than minimal atypia or coagulative necrosis or > 1 mitosis / 50 HPF
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NON-VISCERAL SMOOTH MUSCLE TUMOURS CRITERIA FOR MALIGNANCY (2) SKIN If typically infiltrative growth pattern and confined to dermis, designate as atypical intradermal smooth muscle neoplasm SUBCUTIS Any mitotic activity - almost always accompanied by nuclear pleomorphism / atypia
NON-VISCERAL SMOOTH MUSCLE TUMOURS CRITERIA FOR MALIGNANCY (3) VULVA Three or more of the following: -> 5 cm - infiltrative margins - > 5 mitoses / 10 HPF - moderate or severe atypia SCROTUM Any mitotic activity
NON-VISCERAL SMOOTH MUSCLE TUMOURS CRITERIA FOR MALIGNANCY (4) Criteria ( rules ) continue to shift with time as more data are gathered Many studies plagued by inadequate follow-up data Individual cases with aberrant behaviour may have significant impact Need for pathologists to be aware of site-specific differences
MEASURES OF PROLIFERATIVE ACTIVITY Mitotic activity Ki-67 / MIB-1 PCNA DNA polymerase α Cyclins / CDKs S-phase fraction (FCM) AgNORs BrdU / Thymidine labelling The cloak of objectivity.
SOFT TISSUE SARCOMAS FUSION GENES / BREAKPOINTS CLAIMED TO BE OF PROGNOSTIC VALUE Ewing s / PNET Synovial sarcoma Alveolar rhabdo EWSR1-FLI-1 fusion types SYT-SSX-1 vs. SYT-SSX-2 PAX3-FOXO1A vs. PAX7-FOXO1A Problems of reproducibility/large scale confirmation
PUTATIVE PROGNOSTIC RELEVANCE OF FUSION GENES IN EWING S / PNET Breakpoint location in FLI1 gene more important than translocation partner % Cases Med survival Type I EWS exon 7/FLI1 exon 6 60-65 > 100 months Type II EWS exon 7/FLI1 exon 5 20-35 Approx 2 yrs Now firmly disproved in large EORTC trial (J Clin Oncol 2010; 28: 1982-1988)
GENE EXPRESSION FOR PROGNOSIS - THE WAY FORWARD? (1) Large study by French Sarcoma Group 183 1º non-translocation-type sarcomas - validated in independent cohort of 127 cases Genomic profiling 3 groups - simple amplification type (DDLPS) (16%) - few alterations, whole arm / chromosome (23%) - high level of complexity (UPS/LMS) (61%) Genomic complexity histologic grade
GENE EXPRESSION FOR PROGNOSIS - THE WAY FORWARD? (2) Then selected genes reflecting (1) greatest CGH imbalance, (2) grade 3 vs 2, (3) chromosome instability final 67 gene set (CINSARC) 1) CINSARC better than FNCLCC grade 2) CINSARC also works in GIST, breast Ca, DLBCL Chibon et al, Nat Med 2010; 16:781-788 Needs independent validation
SOFT TISSUE TUMOURS WITH MORPHOLOGIC / BIOLOGIC CONTINUUM Smooth muscle tumours GIST Solitary fibrous tumour Ossifying fibromyxoid tumour
PROPOSED GUIDELINES FOR DEFINING RISK OF AGGRESSIVE BEHAVIOUR IN GISTs (NCI 2002) Size Mitotic Count Very low risk < 2 cm < 5 per 50 HPF Low risk 2-5 cm 5 per 50 HPF Intermediate risk 5 cm 5-10 cm > 5 cm 6-10 per 50 HPF 5 per 50 HPF > 5 per 50 HPF High risk > 10 cm > Any size Any mitotic rate > 10 per 50 HPF
GASTROINTESTINAL STROMAL TUMOURS PROGNOSTICATION (2002) Unpublished clinical data from large trials of Gleevec Approx. 10% of 1 tumours < 5 cm Approx. 10% of tumours < 5 mitoses / 50 HPF Approx. 15% of primaries were excised 5-10 yrs (or more) earlier
GASTROINTESTINAL STROMAL TUMOURS MUTATIONAL ANALYSIS Approx. 75-80% have KIT mutations and 5-7% have PDGFRA mutations, irrespective of type/size % of cases Gleevec response KIT exon 11 60-65 80-85% KIT exon 9 10-15 45-50% KIT exon 13 < 5% Too few data KIT exon 17 < 5% Too few data PDGFRA ~ 6% Variable (exons 12/18) Tumors with PDGFRA mutations seem more indolent Tumours lacking either KIT or PDGFRA mutations still show 40-45% response but progress sooner Gleevec response, predicted by mutation type, correlates with survival (resistance due to 2 o mutations)
SOFT TISSUE TUMOURS WITH MORPHOLOGIC / BIOLOGIC CONTINUUM Sharp dichotomy is not possible (at present) Usual parameters are size and mitotic rate - but cut-offs not well defined To date, most objective parameters have provided no real improvement Morphologically benign lesions in these categories rarely metastasise May use risk assessment as alternative
SOFT TISSUE TUMOURS WHICH RARELY METASTASISE, GENERALLY IN THE ABSENCE OF MORPHOLOGIC CLUES Inflammatory myofibroblastic tumour Plexiform fibrohistiocytic tumour So-called angiomatoid MFH Retiform HE / Dabska tumour Others which we more readily accept as sarcoma (e.g. infantile fibrosarcoma)
BENIGN SOFT TISSUE TUMOURS WHICH EXCEPTIONALLY METASTASISE Cutaneous fibrous histiocytoma Diffuse-type giant cell tumour (Smooth muscle tumours) (GIST) Impact of/on pathologists perception
NOTABLE FEATURES OF METASTASISING CUTANEOUS FH Frequently preceded by repeated local recurrence Predilection to spread to lymph nodes and lung Metastases may be very delayed and may be indolent Metastases usually closely resemble the primary lesion Similar findings in diffuse-type GCT
CUTANEOUS FH / DERMATOFIBROMA CONSIDERATIONS History of local trauma Spontaneous regression Persistent growth Potential for recurrence Rarely reported metastasis Clonality
METASTASING BENIGN TUMOURS POTENTIAL RESPONSES Disbelieve Ignore Regard all histologically similar lesions as sarcomas Acknowledge unpredictability Work towards identification of reliable predictors -? genetic continuum
To accept an orthodoxy is always to inherit unresolved contradictions. George Orwell, 1948
World Health Organization Classification of Tumours of Soft Tissue BENIGN CATEGORY Most benign soft tissue tumours do not recur locally. Those that do recur do so in a non-destructive fashion and are almost always readily cured by complete local excision. Exceedingly rarely (almost certainly <1/50,000 cases, and probably even less than that), a morphologically benign lesion may give rise to distant metastases. This is entirely unpredictable on the basis of conventional histological examination and, to date, has been best documented in cutaneous benign fibrous histiocytoma.
PROGNOSTICATION IN SOFT TISSUE TUMOURS STEPS FORWARD (1) Acknowledgement of uncertainty Acknowledgement of biologic continuum Uncovering of molecular genetic steps
Autonomous local growth Local infiltration / invasion + angiogenesis Independent nodal growth Vascular invasion Independent growth in lung (or elsewhere) Local expansion and spread to other sites
PROGNOSTICATION IN SOFT TISSUE TUMOURS STEPS FORWARD (2) Larger multicentre collaborative studies Development of more objective approaches (where possible) Histotype-specific grading schemes (where possible) Increasing use of risk assessment
A man should never be ashamed to own that he has been wrong, which is but saying, in other words, that he is wiser today than he was yesterday. Jonathan Swift, 1711