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FNA Cytopathology of the Mediastinum
The Hawaii Cytopath Conference –
Maui, HI
October, 2018
P.E. Wakely, Jr., M.D.
The Ohio State University
Wexner Medical Center
Columbus, OH
U.S.A.
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Notice of Faculty Disclosure
In accordance with ACCME guidelines, any individual in a position to
influence and/or control the content of this ASCP CME activity has
disclosed all relevant financial relationships within the past 12 months
with commercial interests that provide products and/or services related to
the content of this CME activity.
The individual below has responded that he has no relevant financial
relationship with commercial interest to disclose:
Paul E. Wakely, Jr., MD
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EUS guided FNA, Mediastinum
No. Sensitivity (%) Specificity(%)
Ann Thorac Surg
2004;77:1763.*69 61 98
Eur J Cancer
2004;40:55920 69 100
Thorax. 2002;5:98. 79 92 100
Am J Gastroenterol.
2004;99:628.103 98 100
Cancer Cytopathol
2006; 108:206.
155
mediastinal/
celiac nodes
92 100
* pts. with NSCLC without enlarged mediastinal lymph nodes by CT
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Mediastinal FNA
variety of tissue types
♦ epithelial
♦ mesenchymal
♦ lymphoid
♦ germ cell
♦ neural/neuroectodermal
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Approaches to Mediastinal Cytopathology
– your colleagues
• EBUS-guided FNA: pulmonologist/surgeon
• EUS-guided FNA: gastroenterologist
• percutaneous CT-guided FNA: radiologist
• transbronchial FNA (Wang): pulmonologist/
surgeon
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Anterior/AnteroSuperior Mediastinum
• thyroid
– hyperplasia/neoplasm
• parathyroid
– cyst/neoplasm
• thymic lesions
– thymoma
– thymic carcinoma
– thymic cysts
• lymphomas
– NHL
– Hodgkin lymphoma
• germ cell tumors
• paraganglioma
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Mediastinal Cysts
• often incidental; asymptomatic
• requires correlation with imaging
• congenital
– bronchogenic, esophageal, enteric, mesothelial,
thymic, parathyroid
• acquired
– thoracic duct, lymphangioma
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Mediastinal Cysts
• thymic (unilocular/multilocular)
– squames, ± lymphocytes, cholesterol crystals, debris
• mesothelial (pericardial)
– acellular, macrophages, ± mesothelial cells
• foregut [bronchogenic, esophageal, gastro-enteric]
– columnar cells (± ciliated), squames, mucoid material,
debris
* all cysts can be secondarily inflamed
* several neoplasms may undergo cystic change
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pericardial cyst
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bronchogenic cyst
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cholesterol crystals
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Thymoma
• most common 1o mediastinal neoplasm
• anterio-superior mediastinum; middle age
• cytopathology:
– mixture of epithelial cells & lymphocytes
– former in clusters or single cells
– epithelial cells: cytologically bland, rounded or
spindle, indistinct nucleoli, poorly defined
cytoplasm, blend with lymphocytes
– potentially mistaken for dendritic cells or
histiocytes
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thymoma
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thymoma
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pan-cytokeratin
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Thymoma, WHO type B1 CK AE1/AE3
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Thymoma, WHO type B1
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Thymoma, WHO type B1
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Thymoma, WHO type B2
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Thymoma, WHO type B3
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Thymoma, WHO Type B1Reactive Lymph Node
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Thymoma, WHO type A
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Thymoma, WHO Type A
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Thymoma, WHO type A
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Reasons for Difficulty in FNA Dx of Thymoma
• proper and adequate sampling is extremely important
– highly dependent on the technical skill of the interventional radiologist
• helpful histologic features that are not discernible on smears:
– organotypical differentiation
– lobule formation
– dilated perivascular spaces (or marked cystic transformation)
– capsular invasion
• difficult to distinguish epithelial cells without a cytokeratin stain
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FNA & Thymoma Classification
• no reliable correlation of FNA cytology of
thymoma with any of the specific histologic
subtypes as delineated by the WHO
classification
• it is not infrequent for there to be histopathologic transitions in thymoma (mixture of B1, AB, B2, and B3 subtypes) even within the same mass
Suster S, Moran CM. On the histologic heterogeneity of thymic epithelial neoplasms.
Impact of sampling in subtyping and classification of thymomas. AJCP 2000;114:760-6
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Cytologic Imitators of Thymoma
• Dendritic-lymphocytic aggregates
• Lymphoproliferative Neoplasm
• Spindle cell mesenchymal tumor
• Spindle cell NEC, i.e. Carcinoid
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dendritic cell
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Thymic Carcinoma
– Squamous Cell CA
– Adenocarcinoma
– Basaloid CA
– Clear Cell CA
– Mucoepidermoid CA
– Lymphoepithelioma-
Like CA
– Sarcomatoid CA
– CA with adenoid cystic
CA-like features
– Carcinoma with t(15;19)
*before you ascribe any of these carcinomas to the thymus
make sure they are not of lung origin
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Thymic Carcinoma
• Carcinoma
– Squamous Cell Carcinoma; Basaloid CA; Clear Cell
CA; Mucoepidermoid CA; Lymphoepithelioma-Like
CA; Sarcomatoid CA
• Neuroendocrine CA
– w-d neuroendocrine CA [Carcinoid Tumor]
– moderately-differentiated NEC [Atypical Carcinoid]
– p-d Small Cell NEC
– p-d Large Cell NEC
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w-d NEC, “Carcinoid Tumor”
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w-d NEC, “Carcinoid Tumor”
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case
• 71 y/o man with progressive vocal cord
paralysis
• imaging: 2.4 cm. enlarged anterior mediastinal
mass
• suspect malignancy
• no lab values; no relevant history
• EUS-guided FNA performed
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cell-block
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cell-block, PAS
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immunostain results
positive
• CK AE1/3 (diffuse)
• RCC (focal)
• chromogranin (focal)
• synaptophysin (focal)
• PAS
negative
• PAX-2, PAX-8
• calcitonin
• mammaglobin
• CD56
• S-100
• TTF-1/thyroglobin
• p63, cytokeratin 5/6
• PAS-D
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initial FNA Dx
Epithelial Lesion, Suspicious For
Parathyroid Tissue/Neoplasm
- unstained slides sent for additional testing
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PTH
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GATA3
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GATA3
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GATA3• GATA = family of transcription factors
• 2 subgroups
• GATA1,-2,-3 assoc. with CNS/hematopoietic
development
• GATA4,-5,-6 assoc. with endo -, mesoderm derived
organs
• GATA3
– + normal tissues: T-cells, breast, PTH glands, urothelium,
distal renal tubules
– negative normal tissues: lung, parotid, GI tract, thyroid,
prostate
– application: primarily for urothelial, breast neoplasms
Ordoñez NG. Value of GATA3 immunostaining in
tumor diagnosis: a review. Adv Anat Pathol 2013;20:3523.
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FINAL DIAGNOSIS
Mediastinal Parathyroid
Adenoma
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Hodgkin Lymphoma
• most common mediastinal lymphoma
• female predominance
• 2nd – 4th decade
• cytopathology:
– heterogenous lymphocyte background
– randomly dispersed R-S cells
• large cells [>20 µm] smooth, multilobated nuclei
• bi – or uninucleated nuclei
• enlarged, often misshapen nucleoli
– pale cytoplasm
– may undergo cystic change
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A B
C D
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suppurative HL
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suppurative HL
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Cytologic Mimickers of R-S Cells
• Immunoblasts
• Megakaryocytes
• Dendritic Cells
• Reactive Mesothelial Cells
• Malignant Melanoma
• Large Cell ML (ALCL)
• Large Cell Carcinoma
• Plasmablasts (Myeloma)
• Sarcomas With Epithelioid Features
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plasma cell myeloma
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peripheral T-cell lymphoma
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melanoma
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WHO Classification – B Cell NeoplasmsPrecursor B-cell neoplasm
Precursor B lymphoblastic leukaemia/lymphomaMature B-cell neoplasms
CLL/small lymphocytic lymphomaLymphoplasmacytic lymphomaSplenic marginal zone lymphoma
Extranodal marginal zone B-cell lymphoma(MALT)Nodal marginal zone lymphoma
Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphomaMediastinal(thymic) large B-cell lymphomaIntravascular large B-cell lymphomaPrimary effusion lymphoma
Burkitt lymphoma/leukaemia
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Primary Mediastinal (thymic) Large B-Cell
Lymphoma
• 2-3% of NHL
• young adults, 3rd-4th decade; F:M, 2:1
• anterosuperior mediastinal mass
– often >10 cm.; ± SVC syndrome
– absent distant nodal or b. marrow involvement
• cytopathology
– monotonous large lymphocytes
– visible nucleoli, variable cytoplasm
– fibrous tissue → hypocellularity, distortion
• IHC: pan B-cell Ag’s, MUM1/IRF4, CD23, PDL2, CD200
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large cell NHL
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Immunophenotyping is
mandatory for the definitive
cytopathologic diagnosis and
subtyping of most NHL.
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primary mediastinal large B-cell NHL
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Fibrotic Mediastinal Lesions
• Diffuse Large B-Cell Lymphoma
• Hodgkin Lymphoma
• Thymoma
• Solitary Fibrous Tumor
• Inflammatory Myofibroblastic Tumor
• Non-Neoplastic Lesions
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Hodgkin DLBL
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• “Our experience demonstrates
that FNA cytology of primary
mediastinal DLBL with
sclerosis can be challenging,
with a potential for a false-
negative diagnosis due to
limited cellularity secondary to
the sclerosis or a misdiagnosis
as a spindle cell neoplasm due
to distortion of these cells by
the fibrous matrix.”
Silverman JF et al. Diagn Cytopathol 1993; 9:209.
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Lymphoblastic Lymphoma
• 30-45% pediatric lymphomas
• adolescents and young adults
• 80% - anterior mediastinal mass; SMS
• cytopathology
– uniform population of blasts
– L1 and L2 morphology
– TBMs, mitoses variable
• 85% T-cell
• pitfall: cortical thymic lymphocytes
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15 y/o ♂
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Superior Mediastinal Syndrome
• SVC compression/obstruction
• tracheal compression/respiratory symptoms
• signs and symptoms
– cough/ hoarseness/ dyspnea/ wheezing/
cyanosis/orthopnea/ syncope
Definition
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lymphoblastic lymphoma
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Tdt
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Lymphoblastic Lymphoma - accuracy
Year/Author/Journal Spec(%) Sens(%) # cases
1995/ Wakely / Ped Pathol
Lab Med100 100 16
1993 / Tani / Diagn
Cytopathol100 100 18
1992 /Jacobs / Acta Cytol 100 100 16
1987 / Kardos / Cancer 100 100 6
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Germ Cell Tumors
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Mediastinal Teratoma
• adolescents/ young adults
• anterior mediastinum
• mature teratoma (common, 70%)
– squames, sebaceous cells
– hyaline cartilage, adipose tissue
– goblet cells, ciliated respiratory epithelium
• immature teratoma (1-2% of cases, mostly males)
– neuroectodermal tissue: malignant small rounded cell tumor
– malignant mesenchymal components
• pitfall: mixed germ cell tumor
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immature teratoma
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IT, cell-block
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Mediastinal Germinoma/Seminoma
• 2nd most frequent mediastinal GCT
• almost exclusive to men
• cytopathology:
– dimorphic population of large & small cells
– loose groups, single cells
– macronucleoli, cytoplasmic vacuoles, “tigroid”
background, bare nuclei, ± granulomas
• pitfall: mixed germ cell tumor
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seminoma
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seminoma
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seminoma
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Non-Seminomatous GCT
• Yolk Sac T./ Embryonal CA/ ChorioCA
• clinical features similar to dysgerminoma
• cytopathology:
– cells in loose or tightly aggregated clusters
– ± papillary or glandular pattern
– large cytologically malignant cells
– cytoplasmic vacuoles
– ± hyaline globules
• unable to reliably distinguish by FNA smears alone
• pitfall: Non-Small Cell Carcinoma
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embryonal CA
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yolk sac tumor
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yolk sac tumor – PAS stain
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IHC – Germ Cell Tumors(positive staining)
• Seminoma
CD 117 (c-kit)
CAM 5.2 (weak)
cytokeratin AE1/3
(weak)
OCT 3/4
• Non-Seminomatous
cytokeratin AE1/3
CD 30 (embryonal CA)
SOX2
PLAP
β HCG (chorioCA)
OCT 3/4
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Posterior Mediastinum
• schwannoma
• ganglioneuroma
• MPNST
• paraganglioma
• neuroblastoma
• ganglioneuroblastoma
• neurofibroma
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Schwannoma
• most common posterior mediastinal tumor
• 20-40 yrs.
• cytopathology:
– spindle cell in syncytial clusters & single forms
– smooth or “wavy / fish-hook” nuclei
– pale, thin cytoplasmic processes
– nuclear palisading but Verocay bodies rare
• pitfall: ganglioneuroma
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Ganglioneuroma
• posterior mediastinum
• adolescents - young adults; females
• solitary, smooth contoured paraspinal mass
• cytopathology:
– extremely hypocellular smears
– microfragments of spindle and ganglion cells
– ganglion cells: enlarged, abundant cytoplasm, single or dual round nuclei, single nucleolus
• pitfall: differentiating neuroblastoma, PNST
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ganglioneuroma
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ganglioneuroma
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ganglioneuroma
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ganglioneuroma
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ganglioneuroma
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Neuroblastoma and Variants
• posterior mediastinum
• ~15% of all Nbl.; 2/3 of neurogenic mediastinal tumors in children
• birth –8 years
• cytopathology:
– hypercellular smears
– malignant “small” “round” cells
– variable neuropil [H-W rosettes]
– ± ganglion cells
• pitfall: other malignant SRCT
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neuroblastoma
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neuroblastoma
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ganglioneuroblastoma
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ganglioneuroblastoma
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ganglioneuroblastoma