malignant mesothelioma in effusions and fine needle aspirates

Malignant Mesothelioma in Effusions and Fine

Needle Aspirates

No relationship exists that represents a possible conflict of interest with respect to the content of this presentation

Armando C. Filie, M.D.National Cancer Institute

CYTOTELECONFERENCE 2007 - 2008 2


OBJECTIVES

Objectives

• Recognize the cytological features of malignant mesothelioma (mesothelioma) in effusion samples

• Recognize the cytological features of fine needle aspirates of mesothelioma

• Recognize the cytological features of major lesions in the differential diagnosis of mesothelioma

• Familiarize with current ancillary studies in the diagnosis of mesothelioma


BLANK SLIDEMesothelioma

• Malignant neoplasm of pleura, peritoneal cavity and pericardium• Incidence of 2,500 cases/year (pleural)• Clinical Findings• age and presentation: males, 6th-8th decade, unilateral• pathogenesis: asbestos exposure (latency of 20-50 years), ?simian vacuolating virus (SV40)• imaging findings: CT scan [pleural masse(s)], invasion by magnetic resonance imaging (MRI)

• Diagnosis: clinical history + imaging findings + cytology(?)/biopsy


Mesothelioma

• Prognosis and Treatment• poor prognosis• treatment: surgery (most effective), chemotherapy, radiotherapy (localized recurrences), combine therapy

• Histologic Types• epithelioid (epithelial): up to 17 subtypes (deciduoid, clear cell, small cell, signet ring)• sarcomatoid: 8 subtypes (fibrosarcomatous, lymphohistiocytoid, MFH-like)• biphasic (mixed)• desmoplastic


Mesothelioma

• Cytological Features in Effusions• sample preparation: smear, cytocentrifugation, thin layer, cell block (immunostains)• stains: Diff-Quik, Papanicolaou


Mesothelioma

• Cytological Features in Effusions• patterns: epithelioid (malignant epithelial), sarcomatous (sarcomatoid), anaplastic, biphasic• sarcomatoid mesothelioma differential diagnosis: spindle cell sarcomas• biphasic mesothelioma differential diagnosis: carcinomas (renal cell carcinoma)• anaplastic mesothelioma differential diagnosis: pleomorphic sarcomas

• epithelioid mesothelioma: most frequent pattern, associated with effusion more frequently than other patterns.


Mesothelioma in Effusions

Cytological Features of Epithelioid Mesothelioma• cellular sample• one cell population• clusters (scalloped border)• cell-in-cell formations• intercellular spaces (“windows”)• two-tone cytoplasm• surface blebs• variable N/C ratio• multinucleation• macronucleoli



Cytological Features of Epithelioid Mesothelioma



Differential Diagnosis

• Metastatic carcinoma: adenocarcinomas (lung, breast, gynecologic tract, gastrointestinal tract), may be the first manifestation of an occult primary• Hematologic neoplasms: B-cell lymphomas (diffuse large B-cell), T-cell lymphomas (anaplastic large cell), plasma cell neoplasms, primary effusion lymphoma (PEL)• Melanoma: may be the first manifestation of disease• Others: squamous cell carcinoma, mesothelial cell lesions



Cytological Features of Metastatic Adenocarcinoma• cellular sample• two cell population• clusters (smooth border)• cell-in-cell formations• high N/C ratio• multinucleation• macronucleoli• irregular nuclear contours• delicate/dense cytoplasm• vacuole(s) displacing the nucleus



Cytological Features of Metastatic Adenocarcinoma



Cytological Features of Metastatic Melanoma• cellular sample• two cell population (?)• aggregates • cell-in-cell formations• low N/C ratio• multinucleation• macronucleoli• intranuclear cytoplasmic inclusions• melanin pigment• vacuoles



Cytological Features of Metastatic Melanoma



Cytological Features of PEL• cellular sample• two cell population• variable N/C ratio• multinucleation• macronucleoli• dense basophilic cytoplasm



Cytological Features of PEL


Mesothelioma in Fine Needle Aspirates

• Image-guided fine needle aspiration (FNA) may be used for the initial diagnosis of mesothelioma• 4% needle tract seeding for core-needle biopsy with sensitivity of 86% (pleural)

• FNA of metastatic mesothelioma (rare): scalp, thyroid, cervical lymph node, axillary lymph node, subcutaneous nodules, breast, liver• metastasis may be the first indication of mesothelioma• inclusions of benign mesothelial cells in lymph nodes

• Mesothelial cell lesions of pleura: solitary fibrous tumor (most benign, rare malignant), nodular pleural plaque, adenomatoid tumor, simple mesothelial cyst, multicystic mesothelioma, well-differentiated papillary mesothelioma, localized malignant mesothelioma



Cytological Features of Mesothelioma in FNAs• cellular aspirate• clusters and flat sheets• papillary groups (core)• acinar/tubular groups• single cells• intercellular spaces• round/polygonal shape• spindle cells (sarcomatoid, biphasic)• small cytoplasmic vacuoles• multinucleation



Cytological Features of Mesothelioma in FNAs



Differential Diagnosis

• Epithelioid: carcinoma - lung (adenocarcinoma and bronchoalveolar carcinoma [BAC]), ovary and peritoneal serous carcinoma; mesothelial cell lesions; thymoma; epithelioid sarcomas, reactive mesothelial proliferations• Sarcomatoid: mesothelial cell lesions, desmoid tumor, schwannoma, spindle cell sarcomas• Biphasic: thymoma, synovial sarcoma, desmoplastic small round cell tumor, pleuropulmonary blastoma• Anaplastic: pleomorphic sarcomas



Cytological Features of Lung BAC in FNAs• monolayer sheets• papillae• single cells• round nuclei• nuclear grooves and pseudoinclusions• nuclear crowding/overlapping• pleomorphic cells• mucin (mucinous)



Cytological Features of Lung BAC in FNAs


Mesothelioma (Ancillary Studies)

• Histochemical stains: mucin (Alcian blue, mucicarmin)• Electron microscopy: long microvilli (meso), short (adeno)• FISH: detection of chromosomal alterations• Hyaluronic acid levels in effusion samples• Immunocytochemistry: most commonly used• may be applied to cytocentrifuged samples, smears, thin layer samples, cell blocks (preferred)• panel of mesothelial cell and adenocarcinoma markers: 2 meso and 2 adeno markers or 1/2 meso and 3 adeno markers• other markers: hematopoietic markers, melanoma markers, site “specific” markers (TTF-1, PSA, PAP, CDX-2, GCDFP-15, thyroglobulin)



Mesothelial cell (Mesothelioma) Markers• calretinin: neuron-specific calcium binding protein (neural tissues and a few other cell types like mesothelial cells)• cytokeratin 5/6: intermediate filament (mainly keratinized and non-keratinized squamous cell carcinoma)• Others: HBME-1, WT1,Mesothelin, Podoplanin

calretinin



Mesothelial cell (Mesothelioma) Markers

HBME-1 CK 5/6



Adenocarcinoma Markers• B72.3: antibody detects a tumor associated protein• Ber-EP4: antibody against epithelial adhesion molecule• CA19.9: antibody against Lewisa blood group antigen• Others: mCEA, CD15, MOC-31

B72.3



Adenocarcinoma Markers

B72.3 Ber-EP4 CA19.9



• Melanoma markers: HMB45, Mart-1, KBA62, S100• Hematopoietic markers: LCA, L26, CD38, HHV8• Others: TTF-1, PSA and PAP, GCDFP-15, thyroglobulin

HMB45 Mart-1



Hematopoietic and other markers

HHV8 TTF-1 CK 7



Molecular Tests• Gene expression (quantitative RT-PCR)• Proteomics: protein complement of the genome (serum - early cancer diagnosis), potential in cytopathology• Surface enhanced laser desorption/ionization time of flight (SELDI-TOF): protein profile in cytology samples (Fetsch et al, 2002)• Initial set: 5 renal cell carcinomas, 9 metastatic melanomas, 6 reactive effusions• Unknown set: 4 renal cell carcinomas, 8 metastatic melanomas, 3 reactive effusions



Molecular Tests•SELDI-TOF in FNAs and fluid samples of 8 MM, 4 RCC, 3 reactive effusions

0

1

2

3

4

5

6

7

8

9

RCC Reac Meso Met Mel

Tested

+Cases


Mesothelioma in Effusions and FNAs

SUMMARY

• Cytological features of mesothelioma in effusions and FNAs overlap with those seen in other benign and malignant lesions (adenocarcinoma)

• Some cytologic features of mesothelioma are not often present in cytology samples of lesions that should be considered in the differential diagnosis

• Ancillary studies are important in supporting the diagnosis of mesothelioma (immunocytochemistry, electron microscopy)

• Diagnosis of mesothelioma has prognostic, treatment and legal implications

malignant mesothelioma in effusions and fine needle aspirates

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