serous effusion - bosnianpathology.org effusion pf.pdf · female-ovary, uterus, breast, gi tract,...

16.06.2016

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Cytology of Serous Effusions

From basics to challenges

Pınar Fırat, MD, MIAC

Department of Pathology, İstanbul University,

İstanbul Faculty of Medicine, TURKEY

• Objectives – Basic principles in the evaluation of serous effusions

– Differential diagnosis between reactive mesothelial

proliferations, metastatic carcinomas, and malignant

mesotheliomas

– Role of immunohistochemistry for correct

interpretation

– Use of other ancillary tests when needed.

Cytology of Serous Effusions

From basics to challenges

Serous effusion

• Systemic / local disease

• Common

• Frequently reactive

• Any type of tumor may cause malignant

effusion

Serous effusion Transudates Exudates Chylous

CHF Infections Trauma

Cirrhosis Collagen vascular

disease

Malignancies

Nephrotic

syndrome

Embolism/

infarction

Malnutrition Uremia

Vena cava obst. Pancreatitis

Meigs` syndrome Hemorrhage, fistulas,

perforation

Malignancies

Plazma ultrafiltrate / hypercellular- rich in protein / lipid-rich

Clear, yellowish / blurred, bloody / white, milky

If stands, thick bottom layer

develops, rich in cells

At least 20-50 ml

for optimal assesment

Large amount is

suspicious for malignancy-

re-prep further slides

Increased viscosity

suggests mesothelioma

Gross appearence is

important

Cell

blocks

BENIGN EFFUSIONS

Predominant cell type Underlying disease

Lymphocyte CHF

Renal failure

Cirrhosis

Infections /TBC, viral

Collagen vascular diseases

Malignancy

Neutrophil Infections/ empyema, pneumonia

Embolism, infarction

GIS rupture

Collagen vascular diseases

Eosinophil Idiopathic

Air / repeated asp, pneumothorax

Infections/ parasitic, fungal

Hypersensitivity/ asthma, drugs

Embolism, infarction

Asbestosis

Malignancy

Courtesy of Koray Ceyhan

and Claire Michael

Rheumatoid Artritis Lupus Erythematosus

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Main question is….

• Is it malignant? A malignant effusion may be the manifestation

of a known malignancy

Determines the stage of the disease and the

appropriate therapy

Not always malignant in cancer patients!

Initial presentation of an unknown malignancy

Primary site ?

Sensitive!

Specific!

Clinical features of malignant effusions

Most common histologic type is

adenocarcinoma

In children hematopoetic and small round

cells tumors

Rhabdomyosarcoma Burkitt

Clinical features of malignant effusions

Most common primary sites are:

Pleural

Male- Lung, lymphoma/leukemia, GI tract

Female- Breast, lung, genital tract, lymphoma/leukemia, GI

tract

Peritoneal

Male- GI tract, lymphoma/leukemia, pancreas, lung

Female- Ovary, uterus, breast, GI tract, lymphoma/leukemia

Pericardial

Breast, lung, lymphoma/leukemia

Differential diagnosis in the land of mesothelial cells

Mesothelioma

Mesothelial

hyperplasia

Metastatic

carcinoma

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Mesothelial cells

Firat P. Benign Effusions in Serous effusions, Ed. Davidson B, Firat P, Michael C, Springer, New York, 2012

Mesothelial cells

Mesothelial cells Vacuolation in mesothelial cells

• Degeneration

• Vacuoles in cytoplasms

• Vacuoles overlap the nucleus w/o pushing or distorting it

• No mucin

• Same nuclear morphology in both vacuolated and non-vacuolated cells

• No malignant nuclear features

• Larger vacuoles in chronic effusions

Adenocarcinoma

Mesothelium

Macrophage

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Adenocarcinoma

BerEp4 mucicarmin

Firat P. Benign Effusions in Serous effusions, Ed. Davidson B, Firat P, Michael C, Springer, New York, 2012

Atypia in mesothelial cells

• Pulmonary infart, uremia, pancreatitis,

radiation, chemotherapy, cirrhosis, heart

failure …,


Mesothelioma

Mesothelial

hyperplasia

Metastatic

carcinoma

Pattern

Cellular features

IHC

Dual cell population

Metastatic carcinoma

Pattern /

Unless all the cells are neoplastic

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Not all the foreigners are tumor cells

Endometrial cells

Endosalpingiosis

Tuba epithelium

Megakaryocyts

Colonic mucosa

Hepatocytes

Lung parenchyma

Striated muscle

Skin

Cartilage

Megakaryocyte

Tight 3-D clusters Pattern /


Mesothelium

Carcinoma Mesothelium

Intracytoplasic mucin

Mucin in the background

Psammoma bodies • 3.7% (Parwani, et al. Cancer 2004)

• Most often in peritoneal effusions

~ 2/3 is malignant

~ 1/3 is benign

• Alarming if it is in pleura or pericardium

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Cellular features

Pitfalls…

Mesothelial cells may mimic malignant cells

Some carcinomas may look rather bland

Golden standart ...?

Accuracy in effusion cytology

Sensitivity Specificity

Metzgeroth, 2007 84 92

Grefte, 2008

78

73

Grefte JM, de Wilde PC, Salet-van de Pol MR, Tomassen M, Raaymakers-van Geloof WL,

Bulten J. Acta Cytol. 2008; 52(1):35-44.

Metzgeroth G, Kuhn C, Schultheis B, Hehlmann R, Hastka J. Cytopathology 2008; 19: 205-11

Accuracy in effusion cytology

Sensitivity Specificity

Metzgeroth, 2007 84 94 92 100

Grefte, 2008

78 96

73 91

Grefte JM, de Wilde PC, Salet-van de Pol MR, Tomassen M, Raaymakers-van Geloof WL,

Bulten J. Acta Cytol. 2008; 52(1):35-44.

Metzgeroth G, Kuhn C, Schultheis B, Hehlmann R, Hastka J. Cytopathology 2008; 19: 205-11

Immuno

stains

Mesothelial

cell

Lung

adeno

Ovarian

carcinoma

Breast

carcinoma

SqCC RCC

MOC-31 - + + + +/- -

Ber-EP4 - + + + +/- -

CEA - + - + +/- -

B72-3 - + + + - -

TTF-1 - + - - - -

p63 - - -/+ + -

Pax8 - + - - +

Claudin4 - + + + +/- +

Non- mesothelial markers Metastatic carcinoma

Pattern

– Any discrete cell population ?

– 3-D tight, crowded groups ?

Cellular features

– Nuclear ?

– Cytoplasmic ?

Cell block- IHC

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Serous effusion

• If it is malignant where is the primary?

ER TTF-1

• Cell balls

– Breast

– Lung

– Ovary

– Mesothelioma calretinin

PSA

81y, M

Followed-up with

prostate carcinoma

Mediastinal LAP,

Nodules in the lung,

Pleural effusion

• Papillary groups

– Ovary

– Lung

– GIS

– Mesothelioma...

Mesothelioma

Ovary Lung

• Vacuolization

– Ovary

– Pancreas

– Lung

– Renal cell

Pancreas

Ovary

Pancreas

Renal cell

• Giant cells

– Pancreas

– Lung

– Ovary

– Mesothelioma...

Mesothelioma

Ovary

Pancreas

Lung

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Breast

• Single cells

– GI tract

– Breast

– Lung

– Mesothelioma

– Lymphoma/ leukemia...

M.Myeloma

GIS Single small cells: • Lymphoma/leukemia

• Small cell carcinoma

• Breast

• Stomach

• Small round cell tmrs

Single large cells: • Squamous cell carcinoma

• Melanoma

• Poorly diff adenocarcinoma

• Germ cell tumors

Squamous Ca Lung adenoca DLBCL

• Indian files

– Breast

– Small cell

– GI tract

Breast Breast

Small cell Ca

Stomach

p63

Squamous cell carcinoma

Urothelial carcinoma

CD56 Syn

Small cell carcinoma

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Mesothelioma

Mesothelial

hyperplasia

Metastatic

carcinoma

IHC

Main

difficulty!

Cytology of malignant mesothelioma

• Absence of a discrete

cell population

• Morphologic continuum

between native

mesothelial cells and

malignant cells

“More and bigger cells in

more and bigger clusters”

Complex groups, three

dimentional aggregates

Cell-in cell arrangements

more common

DeMay

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• If sufficiently well

differentiated to be

easily recognized as

mesothelial, difficult

to call them malignant


calretinin

CK 5/6

WT-1

D2-40

Ber-Ep4 CEA TTF-1

2 mesothelial + 2 carcinoma related

markers

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Positive mesothelial markers

Marker

Differential Diagnosis

Useful Not useful

Calretinin Lung adenocarcinoma

Breast carcinoma

Renal cell carcinoma


Serous carcinoma (?)

Keratin 5/6 Lung adenocarcinoma



Serous carcinoma (limited)

Breast carcinoma (limited)

Podoplanin/D2-40 Lung adenocarcinoma Serous carcinoma


WT1 Lung adenocarcinoma



Serous carcinoma

Thrombomodulin Lung adenocarcinoma

Serous carcinoma



Mesothelin Renal cell carcinomas

Adenocarcinoma (limited)


(limited)

Serous carcinoma

Modified from Ordonez NG, Human Pathology 2013; 44: 1-19

Negative staining strongly

indicates against a

mesothelioma

Marker


Useful Not useful

MOC-31 Adenocarcinoma


Serous carcinoma

Breast carcinoma


Ber-EP4 Lung adenocarcinoma

Breast carcinoma

Serous carcinoma



CEA Lung adenocarcinoma

Breast carcinoma

Serous carcinoma


TAG-72 Lung adenocarcinoma

Breast carcinoma



BG-8 Lung adenocarcinoma

Breast carcinoma


Serous carcinoma


CD15 Renal cell carcinoma

Lung adenocarcinoma (limited)

Serous carcinoma


Positive carcinoma markers


Marker


Useful Not useful

MOC-31 Adenocarcinoma


Serous carcinoma

Breast carcinoma


Ber-EP4 Lung adenocarcinoma

Breast carcinoma

Serous carcinoma



CEA Lung adenocarcinoma

Breast carcinoma

Serous carcinoma


TAG-72 Lung adenocarcinoma

Breast carcinoma



BG-8 Lung adenocarcinoma

Breast carcinoma


Serous carcinoma


CD15 Renal cell carcinoma

Lung adenocarcinoma (limited)

Serous carcinoma


Positive carcinoma markers


New Marker :

• Claudin-4: Mesothelioma vs. Lung adenocarcinoma

Mesothelioma vs. Breast carcinoma

Mesothelioma vs. Serous carcinoma

Mesothelioma vs. Renal cell carcinoma

Mesothelioma vs. Squamous cell carcinoma

84 AdenoCa, 75 MM

Membranous staining

99% AdenoCa

0% MM

Marker

Organ

Positive Negative

TTF-1 Lung adenocarcinoma (75-85%) Mesothelioma


Napsin A Lung adenocarcinoma (80-90%)

Clear cell RCC (40%)

Papillary RCC (75%)

Mesothelioma


PAX 8 Renal cell carcinoma

Serous carcinoma (non-mucinous

ovarian)

Epithelial thymic tumors

Thyroid tumors

Mesothelioma

PAX 2 Renal cell carcinoma

Serous carcinoma

Mesothelioma

GCDFP-15 Breast carcinoma (70%) Mesothelioma

Mammaglobin Breast carcinoma (50-85%) Mesothelioma

CDX2 Gastrointestinal

Pancreatobiliary

Mesothelioma

P63 Squamous cell carcinoma (80-100%) Mesothelioma

Organ specific markers



Mesothelioma

Mesothelial

hyperplasia

Metastatic

carcinoma

?

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EMA Desmin

Expected immun pattern in malignant mesothelioma

Glut-1

p53

E-cadherin Sensitivity, specificity, and positive and negative

predictive values for detection of MM by FISH were

79%, 100%, 100%, and 72%,

Cyto+Bx (TMA)

Homozygote deletion

Effusion cytology – the role of morphology

Not to miss

Not to overcall

Where is the primary ?

Is it mesothelioma ?

IMMUNOCYTOCHEMISTRY

ANCILLARY TESTS

If in doubt

IMMUNOCYTOCHEMISTRY

ANCILLARY TESTS

“.....morphology is our first line of defense, and if

the case passes through this, we have already

lost the battle”

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“.....morphology is our first line of defense, and if

the case passes through this, we have already

lost the battle”

“.....immunocytochemistry adds great value to our

interpretation, and may be the only tool to save

the patient ”

NOT

always

serous effusion - bosnianpathology.org effusion pf.pdf · female-ovary, uterus, breast, gi tract,...

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