tarik m. elsheikh, md€¦ · • 45 year old woman, presented with nausea, dyspnea, emesis and...
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Effusion Cytology:Diagnostic Challenges
Tarik M. Elsheikh, MDProfessor and Medical Director,
Anatomic Pathology
Cleveland Clinic
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Outside Consult Case
• 45 year old woman, presented with nausea, dyspnea, emesis and productive cough
• Chest X-ray: left pleural effusion, LLL consolidation and atelectasis
• CT: Mediastinal lymphadenopathy
• Never smoker, no significant PMH
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Left pleural fluid
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Additional IHC•P63 -, WT1 -, D240 -•TTF1 –•Mammaglobin -•CEA +
Outside Dx: Atypical, Favor reactive mesothelial cells
CK5/6
Calretinin
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Pleural fluid-Outside Consult
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Moc 31 BerEp4 GCFP GATA3
PAX8• WT1 -, D240 -, calretinin +, CK5/6 +• P63 -, P40 -• Moc 31+, BerEp4+, CEA+, B72.3 -• Napsin A -, TTF1 -• ER/PR -• PAX8 +, WT1 -• Mamaglobin -, GATA3 +, GCFP +
Dx: Met adenocarcinoma, breast or mullerian origin
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CAP Inter-laboratory Comparison Program in Body Cavity Fluids
• Data bank of 10,396 lab responses, 1997-2001
• Assessed characteristics of specimens that performed well and performed poor
• Poor performers in hypocellular and hypercellular malignant specimens
Moriarty et al 2004
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CAP inter-laboratory Comparison Program 2
Hypocellular: Location errors
• Rare malignant cells, had diagnostic features but were overlooked.
• Adeno ca, squamous ca, small cell ca, melanoma and lymphoma
• This emphasizes importance of careful methodical screening
Moriarty et al 2004
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Carcinoid tumor in peritoneal fluid- false negative
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CAP inter-laboratory Comparison Program 3
Hypercellular: Interpretation errors
Cellularity not a factor
• Poor carcinoma performers– Single cells
– 3-D clusters
• Poor mesothelioma and lymphoma performers
Moriarty et al 2004
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Common Challenges in Fluids
• Atypical cells, suspicious but not diagnostic of malignancy
• Obviously malignant cells, but uncertain of classification or site of origin
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Outline
• Benign effusions
• Work up of malignant effusions– Cytomorphologic features
– Specific histologic types
• Immunohistochemistry
• Diagnostic challenges and potential pitfalls
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Benign Effusions
• 70-80% of all effusions• Mesothelial cells, histiocytes, inflammatory cells• Common etiologies:
– Infectious: viral, bacterial, TB, fungal, parasitic– Congestive heart failure– Pulmonary embolism– Myocardial infarction– Cirrhosis– Nephritic syndrome– Collagen vascular disease– Pancreatitits– Trauma
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Benign Effusions
– Variable cellularity, mostly single cells– Occasional small clusters, < 10-12 cells
• Exception: washings
– Windows
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• Bi-nucleation and multi-nucleation common
• Dense cytoplasm, clear outer rim (lacy skirt)
• Oval-round nuclei, pale chromatin
• Small nucleoli, may be prominent
Spectrum of change
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Atypia in Reactive Mesothelial Cells
• Nuclear hyperchromasia• High N/C ratio• Prominent nucleoli
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Malignant effusions
• Rarely present as an occult malignancy (7-14%)
• Most patients have established history of malignancy
• Poor prognostic sign
• Lung, breast, ovary, GI tract- most common
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Work-up of MalignantEffusions
• Morphology– Low power architectural pattern
– High power cytologic detail
– Specific histologic types
• Ancillary studies– IHC
– Flow cytometry
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General Features of Malignancy
• Second (foreign) population– Distinctly different from mesothelial cells
– Cohesive clusters, > 10-12 cells
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General Features of Malignancy 2
Malignant Nuclear Features– High N/C ratio– Nuclear hyperchromasia– Nuclear irregularity– Irregular distribution of chromatin– Macro nucleoli
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Architectural Patterns in Fluids
• Cell balls/cannonballs
• Papillary
• Acini
• Single cells (large or small)
• Linear/Indian file
• Signet ring
• Multinucleation
• Bizarre giant cells
• Clear cells
• Psammoma bodies
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Cannonballs
• Tightly cohesive spherical cell clusters with an almost perfectly round contour and community border
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• Uniform cells� suggest breast (more common)
• Pleomorphic cells � suggest ovary, lung
• Other sources include GI tract, mesothelial hyperplasia and mesothelioma
Breast
Mesothelial hyperplasia
Cannonballs
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Papillary
• 3-D clusters that are longer than wider
• Ascites � ovary, uterus
• Pleural effusions � lung, breast
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• Others: GU, pancreas, primary peritoneal, mesothelial hyperplasia, mesothelioma
• Thyroid PC is rarely associated with effusions
Primary peritoneal CA
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Acinar groups
• 3D groups with lumens
• Characteristic of adeno ca, but not specific
– Lung, colon, ovary, stomach, breast, etc.
– Mesothelial hyperplasia, mesothelioma
– Small round cell tumors
Breast
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• Better appreciated on cell blocks
Lung
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Indian/single files
• Breast
• Small cell ca
• Carcinoid tumor • pancreas
• gastric
• mesothelioma
Small cell
PD carcinoma
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Single small cells
• Lymphoma/leukemia
• Small cell carcinoma
• Carcinoid
• Breast
• Stomach
• Small round cell tumor
Lymphoma
Carcinoid
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Single large cells
• Squamous carcinoma
• Melanoma
• Poorly differentiated adenocarcinoma
• Renal, adrenal, hepatocellular ca, germ cell tumors
• Sarcoma
• Lymphoma
• Reactive mesothelial cells, mesothelioma
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Lung non-small cell CA
Ber-EP4+
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Plasmacytoma, pleural
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Bizarre giant cells
• Undifferentiated carcinoma– lung or pancreas
• Squamous ca• Melanoma• Mesothelioma • Sarcoma • R/O rheumatoid effusion, as it may show
bizarre or giant cells
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Lung
Pancreas
Mesothelioma
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Cytoplasmic Vacuoles
Vacuoles without indentation
• Non-specific, often degenerative– Benign: degenerative
– Malignant: nonspecific-ovary, lung, pancreas, etc.
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Signet Ring Cells
Vacuoles indent the nucleus
• Lobular breast carcinoma
• Gastric carcinoma
• Colon
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Diff DX: Degenerative Changes
• Degenerated mesothelial cells and histiocytes can have large vacuoles imparting a signet ring appearance
CEABenign
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Multinucleated cells
• Reactive mesothelial cells, mesothelioma• Giant cell carcinoma• Hepatocellular carcinoma• Melanoma• Sarcoma• Renal cell carcinoma• Anaplastic large cell lymphoma• Hodgkin disease• Germ cell tumors
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Esophagus Breast
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Clear cells
• Kidney
• Ovary/GYN
• Germ cell tumor
Endometrium
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• Clear cells in fluids may have an unexpectedly dense cytoplasm
Clear cell ca cervix, peritoneal fluid
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Psammoma bodies
• Psammoma bodies have no diagnostic significance
• Ovary
• Thyroid
• Mesothelioma
• Mesothelial hyperplasia
• EndosalpingiosisMesothelial hyperplasia
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Specific Histologic Types
• Cells tend to round up in fluids� a certain degree of uniformity among various cell types– Exaggerated in ThinPrep (personal experience)
• Mets in fluids, therefore, may not necessarily exactly resemble the primary tumor
• Familiar with variable presentations of specific histologic types
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Histologic Types in Effusions
• Adeno CA: most common cancer
• Less common: squamous ca, small cell ca, lymphoma, melanoma
• Children: hematopoietic and SBCT
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Adenocarcinoma
• Large clusters or isolated cells• Foreign population• Cannonballs: more common in breast cancer• Signet ring: stomach and breast
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Columnar cells•Mucinous tumors, colon, ovary,endometriosis
Colon
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• Gastric and colo-rectal cancers:– may lose tall columnar
configuration in fluids
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• A second population of benign mesothelial cells may be absent
• Tumor cells resemble histiocytes
Pitfalls- Adeno CA
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• 86 yo woman, peritoneal fluid
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• Dx: Adenocarcinoma– Tumor cells resemble histiocytes
• Follow-up: Signet ring CA of stomach
B72.3
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Potential Pitfalls
• Breast– Relatively common: predominance of intermediate
cells with bland features, hidden among mesothelial cells � potential false negative diagnosis
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• Tumor cells may resemble mesothelial cells
• Lobular CA, lung, ovary, melanoma
• IHC helpful in these situations
Lung
MOC31
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Mesothelioma
• High cellularity, large clusters 30-200 cells• Clusters have irregular knobby borders
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• Mesothelial appearance of cells
• Spectrum: benign � atypical� malignant (No second foreign population)
• Single cells may predominate
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• Pleural fluid, 66 yo man
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• Dx: Mesothelioma
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Challenges in DX of Mesothelioma
• Sparsely cellular specimens-account for most of false Neg. cases
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Variable atypia: Moderate � Severe
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• Severe atypia- difficult to distinguish MM from CA
Calretinin
Carcinoma vs. Mesothelioma
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• Subtle atypia- indistinguishable from benign reactive cells• Mesothelioma should be considered when numerous
clusters with > 15 cells, even if no significant atypia
Mesothelioma
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Mesothelioma RMC
Groups Large clusters, many
Knobby borders
Papillary clusters
Cell in cell and chains
Small clusters, fewflat sheets
Rare
Rare
Cells Large, more variableMultinucleation
Less variable
Rare
Cell borders Lacy skirts and blebs Less prominent
Nucleus -Severe irregularity
-Irregular chromatin distribution
-Macro nucleoli
-Mild
-Finely granular chromatin
-Small nucleoli
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Pitfalls- adeno
• Degenerated reactive mesothelial cells and histiocytes can mimic malignancy
• Do not issue a definitive DX � additional specimens
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Diagnosis of Mesothelioma2
• Adequate cellularity: Dx established in 2/3 cases• Uncertain cases � “Atypical mesothelial
proliferation, recommend biopsy”• Pleural Bx alone � 40-60% • Combined cytology and Bx � 80%
• P16 deletion (FISH)-homozygous deletion of 9p21 in malignant mesothelioma– 60% sensitivity, 100% specificity in fluids
• Definitive DX: histology to document invasion (AFIP fascicle 2006)
Monaco 2011
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Squamous cell CA
• < 1% of effusions contain squamous ca • Primary tumor is known in most cases• Most commonly from lung, larynx and GYN• Single cells or clusters, dense cytoplasm • Keratinization is rarely seen (10%)
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• Squamous Cells tend to round up in fluids and may form balls
• Maybe difficult to distinguish squamous from adeno ca
FNA lung Pleural fluid
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• Squamous CA frequently vacuolated
• Cytoplasmic vacuoles are nonspecific in malignancy
Vaginal
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• Cell block: adeno CA may resemble squamous CA
TTF1 P63
• IHC and Pap cytology are more reliable
Pleural fluid from a 73 yoman
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Small Cell Carcinoma
• Isolated cells, clusters and chains • Round or angular nuclei, molding• May show elongation and spindling
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• Nuclear molding + Indian file
• Differential diagnosis:• Small cell CA
• Lymphoma
• Breast, GI tract
• Pediatric tumors
“Vertebral Column”arrangement
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Melanoma
Diagnosis can be very subtle in effusions
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– Resemble mesothelial cells• isolated round cells• prominent nucleoli• clusters are uncommon
- May show single bizarre cells
– Rarely pigment or intra-nuclear inclusions– ICC for S100, HMB 45, Melan A
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Lymphoma
• Specific classification seldom needed– Most patients have Hx of lymphoma
– May subclassify based on size of cells and nuclear irregularity
– FCM and/or IHC essential for DX
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Nuclear knobs suggest lymphoma, if single cells
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• Karyorrhexis and apoptosis suggest lymphoma, when extensive
• Mesothelial cells are conspicuously absent
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CAP inter-laboratory Comparison Program
Lymphoma– Good performers with
• History of malignancy
• Monomorphic hypercellular population
Chronic inflammation (negative/reactive) – Performed well when polymorphic: lymphs, plasma
cells, neutrophils, reactive mesothelial cells
– Poor performer, if lymphocytes predominated � mistaken for lymphoma
Moriarty et al 2004
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CD 3
CD 20
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Immunohistochemistry
• PD malignancy� specific cell lineage
• Determine primary site– Differential cytokeratins and non-keratins
– Organ specific markers
• Adeno CA vs. reactive mesothelial cells or mesothelioma
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Practical IHC Panel
* CD15: good marker in tissue, BUTin fluids, also stains inflammatory cells� interpretation compromised
Adeno CA Mesothelial
Ber-EP4, MOC-31, B72.3
+ -
Calretinin,WT1, CK5/6, D2-40
- +
TTF-1, Napsin A (lung) + -
mCEA + -
Leu-M1 (CD 15)* + -
EMA** + +/-
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IHC- issues
• EMA + in most adenoca and mesotheliomas– Thick membrane + in mesothelioma– Diffuse cyto + in adeno ca• Neg in reactive mesothelial cells (+ in 4% of cases)
• Antibody dependent and Lab dependent
RMC
EMA
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EMA: Antibody Dependent
(Creaney 2008)
• Clone E 29 (Dako) has best S&S for mesothelioma
Saad 2005, Leong 2006, Creaney 2008
• Clone Mc5 is not reliable to differentiate MM from RMC
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Case Study: Pleural fluid from 52 yo man
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• Diff DX: Reactive mesothelial cells vs. Adenocarcinoma
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MOC 31
Ber Ep4
B72.3
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DX:
Reactive mesothelial cells
• Benign Follow-up
CK 5/6 Calretinin
WT1
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• Calretinin + � 10-30% adenoca
• D2-40 + � 15% serous ca
• MOC 31 + � 10% mesothelioma
• Ber-EP4 +� 0-30% mesothelioma
Ber-EP4Mesothelioma
Mesothelial
Epithelial
•Many neoplasms show overlapping immunoreactivity
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Squamous CA vs. Mesothelioma• Overlapping Reactivity in IHC
Mesothelioma Squamous CA
Calretinin + 100% + 30 %
D2-40 + > 90% + 50 %
CK 5/6 + > 90% + 100 %
WT1* (+) > 90% (-) 0 %
P63* (-) 0 % (+) 100 %
MOC31,CEA,B72.3 (-)[+ < 10%, focal] (+) 50-95 %
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IHC issues
• Calretinin is sensitive for mesothelioma, but not specific
• Epithelial markers are useful in distinguishing mesothelioma from carcinoma, but not squamous ca from adeno ca
• IHC panel should include positive and negative markers for each possible DX• Optimum 2 positive and 2 negative markers
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Summary
• Careful methodical screening to eliminate location errors
• Appreciation of low power architectural patterns in addition to high power cytologic details
• Awareness of diagnostic challenges and potential pitfalls
• IHC is a powerful tool, but need to be familiar with overlapping reactivity patterns
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Thank You!