Classification and diagnostic approach to fnac of mediastinal
- 1. DR. INDIRA SHASTRY.K KASTURBA MEDICAL COLLEGE MANIPAL UNIVERSITY, MANIPAL. Classification and diagnostic approach to FNAC of mediastinal tumours
- 2. Mediastinum
- 4. • CT : locating small lesion in thoracic inlet, hilum and middle mediastinum , via supraclavicular, suprasternal and parasternal approach. But continues real time monitoring is not possible without radiation exposure. • USG : • via percutaneous route ; it provides both spatial orientation as well as real time monitoring with out exposure to radiation • Via bronchoscopy / endoscopy via oesophagus. Approach to mediastinum
- 5. • Epithelial tumors • Thymoma • Thymic carcinoma • Germ cell tumors • Pure GCT’s : GCT’s with only one histological type • Mixed GCT : GCT with more than one histological type • GCT’s with somatic type malignancy • GCT’s with associated malignancy WHO Classification of thymic tumors and mediastinal tumors
- 6. • Mediastinal lymphomas and haematopoietic neoplasms: • B-cell lymphoma • T-cell lymphoma • Hodgkin’s lymphoma • Histiocytic and dendritic cell tumors • Myeloid sarcoma and extra-medullary acute myeloid leukaemia • Mesenchymal tumors of mediastinum: • Thymolipoma • Lipoma of mediastinum • Liposarcoma of mediastimum • Solitary fibrous tumors • Synovial sarcomas
- 7. • Vascular neoplasms • Rhabdomyosrcoma • Leiomyomatous tumors • Peripheral nerve sheeth tumors • Ectopic tumors of mediastinum • Ectopic tumors of thymus • Ectopic tumors of thyroid • Ectopic tumors of parathyroid • Metastasis to thymus and to anterior mediastinum
- 8. To simplify Benign Maliganat Thymoma Benign teratoma Neurilemmnoma Neurofibroma Paraganglioma Thymic carcinoama Lymphoma Seminoma Embryona carcinoma Yolk sac tumor Choriocarcinoma Immature teratoma Neuroblastoma Metastatic tumors
- 9. • Located in superior and / or anterior mediastinum. • Can occur in all age groups but MC seen in in adults and peaks in 6 th decade. • 10-80 % have symptoms of MG • Histological classification of thymoma is confusing. According to updated WHO, thymoma has been classified in to 3 catagories – • Thymoma with spindle bland looking neoplastic cells ( type A ) • Thymoma with round to polygonal neoplastic cells ( type B ) • Mixed thymoma ( type AB ) Thymoma
- 10. • Thymoma : • Type A ( spindle cell; medullary) • Type AB ( mixed ) • Type B1 ( lymphocyte rich; lymphocyte predominantly cortical; organoid ) • Type B2 ( cortical ) • Type B3 ( epithelial ; atypical; squamoid ; well differentiated squamous cell carcinoma) • Micronodualr thymoma • Metaplastic thymoma • microscopic thymoma • Scerosing lipoma • lipofibroadenoma WHO classification
- 11. • Dual population of epithelial cells and lymphocytes in varying proportions. • Cytological appearance depends on relative population of • Epithelial V/S lymphoid cells • Medullary V/S cortical component Key diagnostic features of thymoma on FNAC
- 12. • Cohesive sheets – cytologically bland and mitotically inactive spindle cells , with sprinkling of small lymphoid cells ; pseudo glandular spaces some times seen. • Elongated ovoid nuclei, delicate nuclear membrane, fine chromatin , inconspicuous nucleoli and ill defined cell borders. • Cyto-architecture : arranged in short fascicles and whorls with focal storiform architecture. Thymoma with predominance of medullary component : type A/ spindle cell/ medullary thymoma
- 13. • Small no of extremely elongated “ fibroblast like “ spindle cells may be seen. • Hassall corpuscles are absent. • IHC: • Ck (+) , CD 20 (+) – epithelial cells . • Background lymphoid cells TDT negative. • Thymic medullary cells CD 57 (+) neoplastic cells CD5(-) CK 3 CD 20
- 14. • Type B3 thymoma ( well differentiated thymic carcinoma ) : CD 20 – ve, koilocyte like cortical epithelial cells. • Metastatic spindle cell carcinoma : loosely dispersed single / dys-cohesive clusters of more pleomorphic tumor cells. , • Spindle cell malignant melanoma : prominet nucleoli ; more cellular dispersion ; melanin pigment +/- • Basaloid ( CD 20 – ve / CD 5 + ve)/ sarcomatoid type spindle cell carcinoma • Soft tissue tumors ( solitary fibrous tumors and synovial sarcoma ) – IHC • Spindle cell carcinoid • Benign mesothelial cell clusters Differential diagnosis
- 15. • Small lymphoid cells mimicking lymphoid lesion. • Small no of loosely cohesive and bland looking large polygonal cells containing round to ovoid nuclei, fine chromatin, inconspicuous small nucleoli, ill-defined cell borders among sea of small lymphoid cells • Solitary small nucleoli may be seen specially in B2 type; • In general these cells are 4 times the size of a small lymphocyte. Thymoma with predominance of cortical component
- 16. • Some times abortive hassall corpuscles seen – B2 type • Plasma cells not seen, lympho-glandular bodies not apparent – R/O lymph node ( reactive ) • IHC : epithelial cells – Ck positive , CD 57 focally positive, background lymphoid cells are TdT, CD1a and CD99 positive
- 17. Differential diagnosis : • Reactive lymphoid hyperplasia : polymorphous population of lymphoid cells along with tingible body macrophages, and lympho-glandular bodies. • Cytological distinction between thymus and thymoma are difficult. • Follicular lymphoma : CK and TdT negative • Precursor T lymphoblastic lymphoma: CK negative. • Lympho-epithelioma like thymic carcinoma : EBV associated, more nuclear pleomorphism, no dendritic cytokeratin staining pattern.
- 18. • Well differentiated thymic carcinoma –muller- hermelink classification ( WHO-B3) is different entity , than thymic carcinoma. • Thymic carcinoma is rare- mainly adults. • Cytomorohological features of thymic carcinoma are highly variable and virtually indistinguishable from non- small cell carcinoma of non thymic origin. Thymic carcinoma
- 19. • Abundant malignant cells with varying degree of cohesiveness. Coagulative tumor necrosis +/- • Nuclear pleomorphism , prominent nucleoli, coarse chromatin, • IHC : CK , CD-5, CD-117, positive and CD-57 negative.
- 20. • Squamous cell carcinoma – 90% in asia. • Basaloid carcinoma • Mucoepidermoid carcinoma • Lymphoepithelioma like carcinoma • Sarcomatoid carcinoma • Clear cell carcinoma • Adenocarcinoma • Papillary adenocarcinoma • Well – differentiated neuroendocrine neoplasm ( typical and atypical ) • Poorly differentiated neuroendocrine carcinomas ( large cell and small cell ) • Undifferentiated carcinoma • Combined thymic epithelial tumors ; including neuroendocrine tumors WHO classification
- 21. • Metastatic carcinoma : CD-5 neg • Thymoma with predominant medullary component : bland looking, mitotically inactive spindle cells. • Thymoma with predominant cortical component : bland looking polygonal cells with TdT positivity. • Seminoma . • Primary mediastinal large B cell lymphoma. Differential diagnosis :
- 22. • Often occur in anterior mediastinum : 2-4 % of thymic carcinoma. • May be associated with Cushing's syndrome, 25 % associated with MEN I. • Further divided in to: • Well differentiated neuroendocrine carcinoma( typical and atypical ) • Poorly differentiated neuroendocrine carcinoma ( large cell and small cell type ) Thymic neuroendocrine tumors
- 23. • Monotonous population. • Dispersed and in loosely cohesive pattern. • “Plasmacytoid “ tumor cells, ecentrically placed nuclei. • Finely stippled chromatin and granular eosinophilic cytoplasm • Pseudo inclusions + • “ comet like phenomenon “ – tumor cell nucleoli dragging cytoplasm behind.
- 24. • Seminoma • Embryonal carcinoma • Yolk sac tumors • Choriocarcinoma • Teratoma ; mature • Teratoma; immature Germ cell tumors
- 25. • K/as primary mediastinal seminoma / germinoma. • 8% of all extra gondal germ cell tumors and 2nd MC mediastinal germ cell tumor. • Males ; > 50% occur in 30-40 yr age. • Distinction between primary and secondary tumors are based entirly on clinical background rather cytological bacground. Seminoma
- 26. • Smears : abundunt cellularity. • Dispersed or in loosly cohesive clusters. • Necrotic cellular debris, lymphoid cells, and histioid cells in “ tigroid “ background. • Large round ovoid nuclei, vesicular chromatin, prominent solitary eosinophilic nucleoli and fragile cytoplasm. • Mitosis and apoptosis is common. • IHC: CD-117, PLAP pos. CK – focally / weakly pos.
- 27. • Thymic carcinoma : CK , CD-117 and CD-5 pos • metastatic non-small cell carcinoma – CK pos and CD-117 neg • Primary mediastinal large B cell lymphoma: B cell markers pos and CD-117 neg • Anaplastic large cell lymphoma : CD-30 pos and T cell markers pos • Metastatic malignant melanoma ; S-100, HMB 45 pos . Differential Diagnosis
- 28. • MC mediastinal germ cell tumor ( 50-70 % ) • Mature teratoma : adult type tissue • Immature teratoma: immature embryonal type of tissue; exclusively affects males, • Mostly benign; • Mixture of somatic tissue ; ectoderm, endoderm, mesoderm. • Immature teratoma : biphasic cell pattern ; loose aggregates of small round cells in fibrillary matrix represents neuronal component. • Malignant transformation can occur : MC is SCC or adenocarcinoma. Teratoma
- 29. • Admixture of epithelial and mesenchymal elements • Bland looking epithelial ( squamus / coulmnar ) cells with neural component : small round cells. • DD: from bronchogenic cyst : cystic change in mature teratoma can immitate. • Granulomatous response can be mistaken for tuberrculosis. • Squamous flakes and epithelium can be mistaken for SCC. • R/O mixed germ cell tumor with teratomatous component
- 30. • Rare type of non seminomatous germ cell tumor in young males. • Often associated with teratoma ( teratocarcinoma ), Choriocarcinoma, or seminoma. • Cytologically embryonal carcinoma is indistinguishable from poorly differentiated carcinoma of non germ cell origin. • Mitotically active tumor with malignant cells arranged in poorly cohesive 3 D clusters , with syncitial growth pattern. Embryonal carcinoma
- 31. • Nuclear overlapping, vesicular chromatin with prominent nucleoli, with small to moderate amount of cytoplasm and ill defined cell borders. • IHC : CK, CD- 30 pos, EMA, vimentin, CD-117 and CD_5 neg. • Differential diagnosis: • Thymic carcinoma. • Metastatic non-small cell carcinoma. • Yolk sac tumor.
- 32. • Rare mediastinal tumor can occur both in paediatric ( female predilection ) as well as in adults ( male predilection ). • Commonly associated with elevated AFP levels. • Coagulative tumor necrosis is abundant • Schiller- Duval bodies/ Glomeruloid bodies – diagnostic are seldom seen. • Identification of eosinophilic “ basal –lamina like “ substances and intra-cytoplasmic hyaline globules ( PAS + & diastase resistant), give clue to diagnosis. Yolk sac tumor / endodermal sinus tumor
- 33. • Small clusters and sheets of pleomorphic tumor cells • +/- microglandular and papillary pattern. • Round to ovid nuclei, small nucleoli, scanty some times vacuolated cytoplasm, varying degree of pleomorphism. • IHC : CK +, AFP variably +, CD- 30, CD-117, & CD-5 neg. • DD: • Embryonal carcinoma. • Thymic carcinoma • Metastatic non-small cell carcinoma.
- 34. • Pure medastinal choriocarcinoma is extremely rare – virtualy non existent in children. • Highly aggresive tumor. • Elevated S.β HCG level. • Mixture of syncytiotrophoblasts and cystotrophoblasts against haemorrhagic background. • Syncytiotrophoblastic giant cells with eosinophilic cytoplasm , pleomorphic nuclei, prominent nucleoli, • Cytotrophoblasts are medium sized cells with vaculated basophilic cytoplasm. Choriocarcinoma
- 35. • Primary mediastinal large B cell lymphoma • Precursor T lymphoblastic lymphoma/leukemia • Anaplastic large T cell lymphoma , mature T cell lymphoma. • MAT lyphoma. • Hodgkin’s lymphoma. • Histiocytic and dendritic cell tumors • Myeloid sarcoma and extra-medullary acute myeloid leukaemia Lymphomas
- 36. • Affects young adults of 30-40 yrs • Slight female predilection, MC present with superior venacaval syndrome. Generalised lymphadenopathy and HSP is rare. • Monotonous population of dispersed large lymphoid cells • Mitotocally active large “ centroblast “ like cells ; • lymphoglandular bodies + • IHC : B cell markers + , CD-23 + , CD-10 and CD- 15 negative Primary mediastinal large B cell lymphoma
- 37. Monomorphic population ; centroblast like cells with round nuceli and several small basophilic nucleoli.
- 38. • DD: • seminoma ( CD-117 + , CD-20 - ) , • poorly differentiated small cell carcinoma ( CK +, CD 5 + if thymic origin, CD 20 neg ), • Hodgkin’s lymphoma ( CD-30 and CD-15 pos ) • Anaplastic large cell lymphoma ( CD-30 , T cell markers pos , EMA sometimes +, CD-20 neg ) • Metastatic malignant melanoma ( S100 and HNB 45 pos )
- 39. • Children and in young adults. • Heterogenous population of atypical lymphoid cells and polymorphs. • Atypical lymphoid cells of various morphology : “ hallmark cells” , “ plasmacytoid cells “, “ hand mirror cells “, multinucleated cells with “ wreath like” arrangement of nucleus, multilobulated nucleus cells, and non descript small round cells. • DD: poorly differentiated non small cell carcinoma, primary mediastinal large B cell lymphoma, hodgkin’s lymphoma, metastatic malignant melanoma. Anaplastic large cell lymphoma
- 40. Hallmark cell with embryo like nucleus Doughnut cell Hand mirror Multinucleated Multilobated
- 41. • Childhood and in adolescence . • Male predominance • Typically involves thymus and mediastinal lymphnode; associated pleural and pericardial effusion, superior mediastinal syndrome and tracheal compression. • Cytology : “ sea of small lymphoid cells “ • Monotonus population of mitotically active small lymphoid cells • “ No atypical lymphoid cells “ • lymphoglandular bodies + Precursor T lymphoblastic lymphoma
- 42. • DD: • Cortical type of thymoma : B1 and B2 :a diagnostic pitfall, demonstration of monoclonality proves malignancy . • Reactive lymphoid hyperplasia : TDT neg • Low grade non-Hodgkin’s lymphoma • Neuroblastoma • Rhabdomyosarcoma • Small cell carcinoma TdT
- 43. • From post-germinal centre activated B cells. • Female predilection ; late adults / in 30‘s • MC : nodular sclerosis type • Cytology : heterogenous population of lymphoid cells with “ Reed- Sternberg” like cells associated with lymphocytes plasma cells, eosinophils and histeocytes in background. • IHC : CD-30 and CD-15 positive • DD : primary large B cell lymphoma , anaplastic large cell lymphoma Hodgkin’s lymphoma
- 44. • Commonest neurogenic tumor in mediastinum. • Common in posterior mediastinum : develop from peripheral nerve, sympathetic and parasympathetic ganglion , neural tube embryonic remnants. • Neurofibroma : small loosely cohesive groups of spindle cells in disorderly arrangement , non specific. • Focal pleomorphism of nucleus can be seen. • Features of Neurilemmnoma are rather specific : • Spindle cells associated with fibrillary matrix • Mitotically inactive oval nuclei, sometimes “ fish –hook “ nuclei, with fine chromatin; occ pseudo-nuclear inclusions. • Rarely Verocay body formation seen Neurilemmnoma ( schwannoma ) & neurofibroma
- 46. • Tumor of infancy 1-10 yrs • Occur in posterior mediastinum • Cytology : loose aggregates of small round cells with various amount of fibrillary matrix, in loosly cohesive clusters or in isolation. • Bland looking with indiscriminant small nucleoli, some nuclear moulding + • Vague rosette formation may be seen ( HW ) Neuroblastoma
- 48. • Ganglioneuroma • Granular cell tumor • MPNST • Ganglioneuroblastoma • Paraganglioma • Pigmented neuroectodermal tumor of infancy Other Neuronal tumors
- 49. • Majority of mediastinal neoplasms. • MC from lung and are small cell type followed by breast, thyroid and prostate. Metastatic tumors SCC AdenocarcinomaSmall cell carcinoma
- 50. • Morphologic heterogeneity with in lesion. • Stromal sclerosis resulting in low cellularity. • Poor preservation due to extensive necrosis ; seminoma. • Sampling error due to cystic change: thymoma, thymic carcinoma, seminoma, mature teratoma – yield cyst fluid only. • Abundant lymphocytes obscuring diagnostic cells : cortical thymoma – reactive LN and other lymphoma, IHC is necessary for demonstrating clonal population. • Thymic carcinoma ( < 30yr ) is indistinguishable from metastatic carcinoma ( older ) on cyto-morphology. Diagnostic pitfalls
- 51. • Mediatinal germ cell tumors; non seminomatous can be mistaken for poorly differentiated non small cell carcinoma of lung – clinical and serological correlation required for diagnosis. • Stromal sclerosis is seen in some of lymphoid malignancy : primary mediastinal large B cell lymphoma and nodular sclerosis type of HL . • If mediastinal FNAC contain monotonus population of small round cells the list of DD: T- lymphoblastic lymphoma, low grade NHL, neuroblastoma, Ewing’s sarcoma/primitive neuroectodermal tumors, rhbdomyosarcoma, small cell carcinoma.
- 52. Diagnosis requires combination of clinical, radiological, biochemical, and cytomorphological information. • Age : In children : commonest thymic tumor is NHL. Thymoma is extremely rare in childhood. Adults : mets and benign mediastinal cyst of celomic origin or GI origin. In adults : thymoma represents commonest primary thymic tumor, followed by mediastinal lymphoma. Approach to mediadiastinal tumors Step 1 : clinical history
- 53. • located in which part of mediastinum • Extremely useful in diagnosis of tumors • Depending on predominant cell morphology diagnosis can be approached. Step 2 : radiological localisation Step 3 : cytomorphology
- 54. History and relevant information for diagnosis
- 56. Small cell rich lesion Monotonous small lymphoid cells Precursor T lymphoblastic lymphoma , extra nodal marginal B zone lymph Polymorphous lymphoid cells Reactive lymphnode / Hodgkin’s Admixed non lymphoid large tumor cells Thymoma with predominance of cortical component Non lymphoid small tumor cells Neuroblastoma, Ewing’s, PNET, rhabdo, small cell Ca
- 57. Large cell rich lesions Cohesive large tumor cells Thymic carcinoma, non seminomatous germ cell tumors Loosely cohesive large cells Thymic neurendocrine tumor, seminoma, some metastatic carcinoma Widely dispersed large tumor cells Diffuse large B cell lymphoma, anaplastic large cell lymphoma
- 59. Spindle cell rich lesions Reactive fibroblast &/ histiocytes Granulomatous lymphadenitis , chronic sclerosing mediastinitis, nodular sclerosis HL, deep fibromatosis Bland looking spindle cells Thymoma ( medullary), spindle cell thymic carcinoid, neurofibroma, neurilemmnoma. Malignant spindle cells Metastatic MM, diffuse large B cell lymphoma with sclerosis, sarcomas, spindle cell SCC.
- 62. Ancillary techniques for mediastinal tumors
- 63. • Establish primary pathologic diagnosis, or separating surgical from non-surgical cases. • Staging of primary lung cancer. • Detecting residual disease or recurrent tumor after therapy. • Rapid diagnosis of mediastinal neoplasm. • When definitive diagnosis not possible : guide clinician in planning subsequent management approach. conclusion
- 64. • WHO pathology and genetics – tumors of lung, pleura, thymus and heart. 2004. • Comprehensive cytopathology . M.Bibbo, 3rd ed. • Surgical pathology. Rosai and Ackerman’s. 10th ed. • Pranab dey. Diagnostic dilema: diagnostic algorthem in fine needle aspiration cytology of mediastinal tumors. Indian journal of pathology and microbiology. 2010. 53. 395-402. References :
Editor's Notes
- #11: Muller hermelink – well differentiated SCC ; B3 thymoma
- #14: IHC : CK 3 and aberrant expression of CD 20
- #15: SFT – CD 99, CD 34, bcl-2 positive and CK neg Synovial sarcoma - CK is weakly and focally positive , CD 20 neg and CD 5 pos Malignant melanoma : S100 , HMB-45 pos and CK neg Most of benign mesothelial clusters are calretinin positive ( ovoid nuclei nuclear folding +/-, fine chromatin, delicate nuclear membrane, moderate amount of amorphophilic cytoplasm and window bwn cells.
- #16: Small eosinophilic nucleoli are seen especially in B2 type of thymoma. Thymoma with cortical predominant architecture is very difficult to distinguish from reactive lymphnode. In type B1 or B2 thymoma tingible body macrophages are also seen.
- #17: Fig A &C are of B2 thymoma Fig F is B1 thymoma – cell block – CK 3 staining dendritic cell type.
- #19: No associated MG or hypogammaglobulinemia.
- #20: Cohesive sheets of malignant cells with areas of coagulative necrosis, and aberrant expression of CD 5 in cell block preparation.
- #26: 1 st MC mediastinal germ cell tumor is teratoma.
- #27: Tigroid Background is seen in glycogen-containing tumors: Ewing’s sarcoma, Seminoma, SCC , clear cell carcinoma , Primary large B cell lymphoma Fig shows loose aggregates of maononuclear cells with stipled nuclei and necrotic background. Higher power shows round to ovid cells with delicate nuclear membrane, prominent nucleoli, and fragile cytoplsm. CD117 positive and histopathology shows associated granulomatous inflammation
- #29: Mature teratoma shows : squamous epithelium, hair shaft, respiratory epithelium, chondromyxoid stroma which is better demonstrated with diff stick ( MGG ) stain- Metachromatic colour.
- #30: R/O mixed germ cell tumor with teratomatous component : especially when there is immature component.
- #31: Occur either as mixed or pure form. AFP levels are elevated in all cases.
- #32: Poorly cohesive clusters of pleomarphic cells, mot like those cells seen in poorly differentiated carcinoma H/P shows marked nuclear pleomorphism of nucleus with nuclear overlapping and crowding , vesicular nucleus, prominent nucleoli, illdefined basophillic cytoplasm.
- #33: S-D bodies are formedd due to invagination of tumor cells and capillaries in to cystic space.
- #34: Pleomorphic tumor cells associated with Ribbon like basal lamina like substance H/P shows Schiller duvel bodies and AFP positive in cytoplsm
- #35: Haematogenous spread , pt present with features of gynacomastia. Practically speaking – the ability of FNAC in separating various non semonomatous germ cell tumors, specially between embryonal carcinoma, yolk sac tumor, and choriocarcinoma are rather limited. There is often morphological overlap and its not uncommon to find mixture of various germ cell tumor components with in single lesion.
- #38: Nuclear membrane irregularities noted
- #40: Widely dispersed atypical lymphoid cells of various morphology “ hallmark cells “ – ecentric kidney shaped or embyo-like nuclei, with several rod like or angulated basophilic nucleoli and abundunt amorphophillic cytoplsm “ Doughnut “ cells – tumor cells with multilobated nuclei, and multinucleated giant cells with “ wreath –like “ arrangement.
- #42: No atypical lymphoid cells “
- #43: IHC : TdT pos
- #45: both neurilemmnoma and neurofibroma yeilds spindle cells.
- #49: rare
- #53: MG : myasthenia grevis , HSM : haepato-spleenomegaly. Taking the anatomic location of the lesion and age of the patient in to consideration, a narrow list of DD can be produced even before FNAC. clinical H/o of MG associated with thymoma . past H/o of malignancy . lymphadenopathy, HSM, others .