2014%11%13' BRENDAN C. DICKSON! BA, BSc, MD, MSc, FCAP, FRCPC! " Staff Pathologist! DISCLOSURE! Pathology and Laboratory Medicine" Mount Sinai Hospital" " Assistant Professor! Laboratory Medicine and Pathobiology" I"have"no"actual,"or"poten0al,"conflict"of"interest" University of Toronto" in"rela0on"to"this"presenta0on"to"disclose" RETROPERITONEUM: spindle cell lesions" OUTLINE! DEFINITIONS! Goal% Retroperitoneum! •Offer"approach"to"‘common’"retroperitoneal"so;" • Space between the 0ssue"tumours"(and"their"mimics)" parietal peritoneum and the posterior Defini+ons% abdominal wall" Pa+ents%(x3)% " •Case'presenta0on' •Diagnosis'–'audience'par0cipa0on' •Discussion'of'differen0al'diagnosis' Summary% ' "retroperitoneum,'n."'OED"Online.'2014.'Oxford'University'Press:'web.'(accessed'November'1,'2014).' Bourgery'MJ.'Traité"complet"de"l'anatomie"de"l'homme"comprenant"la"médecine"operatoire.'1831%1854.'C.'Delaunay:'Paris.'' ' (hRp://link.library.utoronto.ca/anatomia/applica0on/index.cfm)' ' DEFINITIONS (2)! DEFINITIONS (3)! Boundaries! Contents" • Adrenal glands" • Anterior: peritoneum" • Colon (ascending and • Posterior: abdominal descending; rectum)" wall" • Connective tissue" • Duodenum" • Lateral: quadratus • Esophagus" lumborum" • Kidneys and ureters" • Superior: 12th rib and • Lymph nodes " vertebra" • Nerve branches" • Pancreas" • Inferior: sacrum and • Vessels (e.g., aorta and iliac crest " inferior vena cava)" " Van'Roggen'JF,'Hogendoorn'PC.'Sarcoma.'2000;4(1%2):17%26.' Quain'J.'The"muscles"of"the"human"body.'1836.'London':'Taylor'and'Walton.'' Van'Roggen'JF,'Hogendoorn'PC.'Sarcoma.'2000;4(1%2):17%26.' (hRp://link.library.utoronto.ca/anatomia/applica0on/index.cfm)' Maclise'J.'Surgical"anatomy.'1856.'London:'J.'Churchill.'(hRp://link.library.utoronto.ca/anatomia/applica0on/index.cfm)' 1' 2014%11%13' RETROPERITONEUM CASE 1! Spindle cell lesions" • 54'M.'Presented'to'family'physician'with' symptoms'of'early'sa0ety' Mesenchymal' • Past'medical'history'significant'for' Mesenchymal' (malignant)' (benign)' hypertension'and'DM'type'II' • On'examina0on'the'pa0ent'was'obese,'with' Epithelial' abdominal'“fullness”' Haematolymphoid' Metastasis% CASE 1 (2)! • MRI'revealed'a'large'mass'in0mately' associated'with'the'right'kidney' • Pa0ent'referred'to'community'urologist,'with' resec0on'of'puta0ve'renal'cell'carcinoma' 2' 2014%11%13' CASE 1 (3)! Differen+al%diagnosis% a)Sarcomatoid'renal'cell'carcinoma' b)Dedifferen0ated'liposarcoma' c)Nerve'sheath'tumour'(e.g.,'neurofibroma,' MPNST)' d)Retroperitoneal'fibrosis'(Ormond’s'disease)' e)I'do'not'know'–'need'immunohistochemistry' CASE 1 (4) Immunohistochemistry" Screening Panel (spindle cell neoplasms) ! • Desmin" • Smooth muscle actin" • S100" • CD34" • Keratin (AE1/AE3) / epithelial membrane antigen" Desmin! 3' 2014%11%13' Smooth muscle actin! S100! CD34! Keratin (AE1/AE3)! CASE 1 (6) CASE 1 (5)! Immunohistochemistry" Diagnosis% Screening Panel! Confirmatory Panel! a)Sarcomatoid'renal'cell'carcinoma' • Desmin" • PAX8" • Smooth muscle actin" • MDM2 / CDK4 / p16" b)Dedifferen0ated'liposarcoma' • S100" • Neurofilament / CD56 / c)Nerve'sheath'tumour'(e.g.,'neurofibroma,' • CD34" PGP9.5" MPNST)' • Keratin (AE1/AE3) / • IgG / IgG4" epithelial membrane d) Retroperitoneal'fibrosis'(Ormond’s'disease)' antigen" e)I' s0ll"do'not'know' 4' 2014%11%13' MDM2! MDM2 – fluorescence in situ hybridization ! CASE 1 (7)! Diagnosis% a)Sarcomatoid'renal'cell'carcinoma' b) Dedifferen0ated'liposarcoma' c)Nerve'sheath'tumour'(e.g.,'neurofibroma,' MPNST)' d) Retroperitoneal'fibrosis'(Ormond’s'disease)' e)I' s0ll"do'not'know' Sarcomatoid RCC (inset: PAX8)! Neurofibroma! Malignant peripheral nerve sheath tumour (inset: S100)! 5' 2014%11%13' LIPOSARCOMA! World Health Organization (2013)! Well differentiated liposarcoma (atypical lipomatous tumour *)" Dedifferentiated liposarcoma " Myxoid / round cell liposarcoma " Pleomorphic liposarcoma " Retroperitoneal fibrosis! Fletcher CDM et al. WHO Classification of Tumours of Soft Tissue and Bone. 2013;1-242. LIPOSARCOMA! LIPOSARCOMA (2)" World Health Organization (2013)! DIFFERENTIATION% Well differentiated liposarcoma (atypical lipomatous tumour *)" Well=differen+ated% Dedifferen+ated% Dedifferentiated liposarcoma " LowJgrade" High%grade* Myxoid / round cell liposarcoma " Pleomorphic liposarcoma " Fletcher CDM et al. WHO Classification of Tumours of Soft Tissue and Bone. 2013;1-242. Adipocytic ‘lipoma-like’ subtype! Sclerosing subtype! 6' 2014%11%13' Inflammatory subtype! Dedifferentiated liposarcoma! Small cell morphology! Large cell morphology! ! Dedifferentiated liposarcoma with meningothelial-like whorls! WD- and DD- liposarcomas with prominent myxoid stroma! ! ! Fanburg-Smith JC, Miettinen M. Histopathology. 1998;33(5):414-24.! Sioletic S, Dal Cin P, Fletcher CD, Hornick JL. Histopathology. 2013;62(2):287-93.! ! 7' 2014%11%13' “Homologous" lipoblastic differentiation (pleomorphic liposarcoma-like)! Myxofibrosarcoma-like pattern! ! ! Mariño-Enríquez A, Fletcher CD, Dal Cin P, Hornick JL.Am J Surg Pathol. 2010;34(8):1122-31.! Huang HY, Brennan MF, Singer S, Antonescu CR. Mod Pathol. 2005;18(7):976-84.! LIPOSARCOMA (3)! LIPOSARCOMA (4)! Defini+on% Histology% • Well%differen0ated'and/or'dedifferen0ated'' • Malignant'neoplasm'with'adipocy0c' • Plethora'of'histomorphologies' deriva0on' Immunohistochemistry% • Rou0ne'stains'typically'non%diagnos0c'(+/%'CD34,'+/% Epidemiology% desmin,'+/%'SMA,'+/%'S100,'+/%'EMA)' • MDM2'and'CDK4'helpful,'par0cularly'with'dedifferen0a0on' • Most'common'sarcoma'of'retroperitoneum' • Molecular% 90%'of'dedifferen0ated'cases'arise'de"novo,' • Characterized'by'MDM2'amplifica0on' with'10%'occurring'on'recurrence'' LIPOSARCOMA (6) LIPOSARCOMA (5)! Histotype (WD vs DD)" Prognosis% Disease'Specific'Survival' Local'Recurrence' n=30' • Clinical' – Completeness'of'resec0on' n=74' • Pathologic' n=74' %'Recurrence' – Histotype'(well'differen0ated'vs'dedifferen0ated)' %'Survival' – FNCLCC'grade' n=30' p=0.01' p<0.01' Follow'Up'Time' Follow'Up'Time' (Months)' (Months)' Cannell AJ, Burtenshaw SM, Blackstein ME et al.. CTOS meeting. 2014. Mussi C, Collini P, Miceli R et al. Cancer. 2008;113(7):1657-65. Singer S, Antonescu CR, Riedel E et al.. Ann Surg. 2003;238(3):358-70. Cannell AJ, Burtenshaw SM, Blackstein ME et al.. CTOS meeting. 2014. 8' 2014%11%13' LIPOSARCOMA (7) CASE 2! FNCLCC Grade (1, 2, 3)! Disease'Specific'Survival' Local'Recurrence' • 64'F.'Presented'to'family'physician'with' n=31' abdominal'pain' n=68' • Past'medical'history'is'significant'for' n=5' th n=68' leiomyomata.'Hysterectomy'aoer'4 'child' %'Survival' %'Recurrence' n=5' • On'examina0on'palpable'LUQ'mass' n=31' p=0.03' p=0.01' Follow'Up'Time' Follow'Up'Time' (Months)' (Months)' Cannell AJ, Burtenshaw SM, Blackstein ME et al.. CTOS meeting. 2014. CASE 2 (2)! • MRI'reveals'a'large'mass'abupng'the'IVC,' stomach'and'head'of'pancreas'' • Biopsy'performed' 9' 2014%11%13' CASE 2 (4) CASE 2 (3)! Immunohistochemistry" Differen+al%Diagnosis% Screening Panel (spindle cell neoplasms) ! a)Gastrointes0nal'stromal'tumour' • Desmin" • Smooth muscle actin" b)Angiomyolipoma'(fat%poor)' • S100" c)Leiomyosarcoma' • CD34" d) ‘Benign’'metastasizing'uterine'leiomyoma'' • Keratin (AE1/AE3) / epithelial membrane e)I'do'not'know'–'need'immunohistochemistry' antigen" Desmin! Smooth muscle actin! 10' 2014%11%13' S100! CD34! CASE 2 (5)! Diagnosis% a)Gastrointes0nal'stromal'tumour' b)Angiomyolipoma'(fat%poor)' c)Leiomyosarcoma' d)‘Benign’'metastasizing'uterine'leiomyoma'' e)I' s0ll'do'not'know' Keratin (AE1/AE3)! CASE 2 (6) Immunohistochemistry" Screening Panel! Confirmatory Panel! • Desmin" • CD117/ DOG1" • Smooth muscle actin" • HMB45 / MART1" • S100" • H-caldesmon" • CD34" • ER/ PgR" • Keratin (AE1/AE3) / epithelial membrane antigen" H-caldesmon! 11' 2014%11%13' CASE 2 (7)! Diagnosis% a)Gastrointes0nal'stromal'tumour' b)Angiomyolipoma'(fat%poor)' c)Leiomyosarcoma' d)‘Benign’'metastasizing'uterine'leiomyoma'' e)I' s0ll'do'not'know' Estrogen receptor! Gastrointestinal stromal tumour (inset: CD117)! Angiomyolipoma (inset: MiTF)! ‘Benign’ metastasizing leiomyoma (inset: ER)! 12' 2014%11%13' LEIOMYOSARCOMA! Defini+on% •Malignant'neoplasm'showing'‘pure’'smooth' muscle'differen0a0on' Epidemiology% •Second'most'common'sarcoma'arising'in' retroperitoneum' •Predominant'sarcoma'arising'from'large'blood' vessels'(esp.'IVC)' •F'>M' LEIOMYOSARCOMA (2)! LEIOMYOSARCOMA (3)! Histology! Leiomyoma! Leiomyosarcoma! • No ‘significant’ atypia" • At least focal atypia" • Intersecting fascicles of spindle-epithelioid cells" • At most, very low mitotic • Mitotic activity" activity*" • May see necrosis" • Eosinophilic cytoplasm" – M (< 1 per 50 HPFs)" • May have perinuclear vacuole" – F (≤ 5 per 50 if ER / PR positive)" • Cigar-shaped nucleus with • May see degenerative hyperchromasia" changes but not necrosis" • Mitotic activity (1 or more per 50 HPFs)*" " • +/- Necrosis" ' Fletcher CDM et al. WHO Classification of Tumours of Soft Tissue and Bone. 2013;1-242. LEIOMYOSARCOMA (4)! LEIOMYOSARCOMA (5)! Immunohistochemistry! Prognosis! • (+) smooth muscle actin, desmin, H-caldesmon" • Retroperitoneal cases frequently fatal:" • (+/- focal) keratin, CD34, CD117, S100" May"have"loss"of"desmin,"SMA,"HJcaldesmon"with" – Attain large size prior to detection" dedifferen0a0on" – Intimate with vital organs and vessels, making it difficult to attain clear margins" Molecular Analysis! – Grade important for predicting risk of • Complex genetic aberrations (MED12, other metastasis" mutations)" • Not diagnostically relevant" Gladdy RA, Qin LX, Moraco N et al.. Ann Surg Oncol. 2013;20(6):1851-7. 13' 2014%11%13'