W4L5 - Malignant Metastatic Effusions Flashcards
Metastatic Effusion
When cancer grows in the pleural space (for example), it causes a malignant pleural effusion
This condition is a sign that the cancer has spread, or metastasized, to other areas of the body
Identifying Malignancy in Effusions
Two stage process:
1. To establish a malignancy (benign or malignant)
2. Determine the phenotype (mesothelioma vs metastatic malignancy)
Most malignant effusions need to be differentiated into two major categories:
1. Malignant mesothelioma
2. Metastatic adenocarcinoma
Low Power Clues for Metastatic Effusions
Evidence of 2 populations of cells Large cohesive aggregates and clumps of cells Papillary formations Acinar formations Proliferation spheres Solid cell clusters Non-cohesive cell clusters
Incidence of Serous Membrane Involvement in Pleural and Peritoneal Cavities - Female
Pleural: - breast - ovary - lung - haematolymphoid Peritoneal: - ovary - breast - GI tract - pancreatobiliary
Incidence of Serous Membrane Involvement in Pleural and Peritoneal Cavities - Males
Pleural: - lung - haematolymphoid - genitourinary - GI tract Peritoneal: - haematolymphoid - GI tract - genitourinary - pancreatobiliary
Incidence of Serous Membrane Involvement in Pleural and Peritoneal Cavities - Children
Pleural: Leukemia/lymphoma Small round cell tumours - neuroblastoma - nephroblastoma Peritoneal: Leukemia/lymphoma Small round cell tumours Others
Identification of Malignancy in Effusion
Diagnosis of malignant effusions incorporate large amounts of criteria, some subtle, including the familiarity of the type of specimen your reviewing, the type of preparation and the context in which the diagnosis is being made
- diagnosis of malignancy in effusion samples does not depend on any single morphologic criteria
- cytology does not depend on large cells, with high N/C ratio, hyperchromatic, irregular nuclei and macronucleoli
Metastatic Adenocarcinoma
These are by far the most common metastatic malignancy found in serous effusions
This differentiation is dependant upon certain morphologic features associated with adenocarcinoma, taking into consideration the sex of the patient, age and site of the effusion samples
The most common metastatic adenocarcinomas in serous effusions originate from neoplasms of breast, lung, haematolymphoid and ovary
Classically, the cells from these lesions show:
- cellular specimens
- smoothly contoured cohesive aggregates
- containing large cells with eccentric nucleoli and vacuolated cytoplasm
Metastatic Adenocarcinoma - Cell Clusters
Adenocarcinoma may present singly or in cell aggregates composed of a few cells to a large papillary fragment
These may be neatly circumscribed, non-vacuolated spheroids, some termed ‘proliferation spheres’
These proliferation spheres may be hollow or solid
In smears the hollow appearance results in an empty sphere
Mesothelioma cells may also form these spheres however with close investigation mesothelial differentiation can be determined
Metastatic Adenocarcinoma of the Breast
Metastatic breast carcinoma are mostly found in pleural effusions, occasionally in peritoneal and pericardial.
Patient will have a clinical history of treated breast carcinoma
An effusion 2º to the primary may not occur for decades after initial treatment of the 1º lesion
Due to the high incidence of breast carcinoma, the frequency with which it metastasises to serous membranes is important
Cytology of Metastatic Breast Carcinoma
Usually abundantly cellular
Aggregates may appear as rounded spheres
On CB preparation these spheres may be solid or hollow
The hollow appearance may suggest a cribriform growth pattern
Cytology of Metastatic Breast Carcinoma - Lobular Carcinoma
Typically present as numerous small, isolated malignant cells
These can be mistaken for macrophages or mesothelial cells
However, they appear monotonous throughout the smear
Uniform in appearance
Individual cells show irregular nuclear shape
Prominent nucleoli
These cells have a tendency to form small palisaded strips
Single cells may contain a large vacuole with a mucin target
IHC - Breast vs Other Adeno Carcinomas
Breast vs other - GCDFP-15 positivity indicates breast - Gata3 demonstrates high specificity for met breast ca ~90% - mammaglobin - expressed in 48%-72% of breast ca Breast vs Lung - TTF-1 positivity favours lung Breast vs ovarian serous - WT-1 positivity indicates ovarian, negativity favours breast Breast vs ovarian mucinous - CK20 positivity indicates ovarian - CA125 negativity favours breast Breast vs stomach - ER positivity favours breast - CK20 positivity favours stomach
Metastatic Adenocarcinoma of Lung
Approximately 40% of pleural fluid containing cancer cells are derived from primary carcinoma of lung
Cytology
- large, obviously malignant cells are present occurring singly or in papillary aggregates
- aggregates show glandular differentiation
- acinar arrangements
- eccentric, irregular nuclei
- prominent nucleoli
- abundant delicate vacuolated cytoplasm
- population of mesothelial cells in background
IHC for Metastatic Lung Ca
TTF-1: Positivity in 75% of cases (BAC is often negative for TTF-1) AE1/AE3: Positive CAM5.2 Positive CK7 usually positive CK20 usually negative EMA positive CEA positive Thyroglobulin negative
Metastatic Adenocarcinoma of Ovary
Ovarian carcinoma is frequently identified in ascites and to a lesser extent in pleural effusions
The first clinical manifestation of ovarian carcinoma is abdominal wall swelling possibly due to peritoneal effusion
Wide panel of IHC stains to confirm 1◦:
- CK7 positive in most cases
- CK20 focal positivity
- MUC5AC positivity diffuse in 90% cases
Cytology of Metastatic Adenocarcinoma of Ovary
Abundant cellular proliferation
Cells present in large, acinar or papillary aggregates
A background of single abnormal cells
Papillary clusters containing psammoma bodies
Cytoplasm can show hypervacuolisation
Mitotic figures are common in invasive ovarian carcinoma
Metastatic Adenocarcinoma of GIT
The cytological presentation of colonic and gastric adenocarcinoma in serous cavities are similar
Most of the lesions present as single cells, although some colonic lesions can present in small strips of palisaded cells
Cytology of single cells often show eccentric, irregular nuclei often with a ‘signet’ ring appearance
Large cytoplasmic vacuoles often distend the nucleus
Cytoplasmic vacuoles often contain abundant mucin
Metastatic Squamous Cell Carcinoma
Identification of keratinising SCC in effusion is relatively easy
Anucleated masses of keratinised flakes may be seen throughout the smear
Cells are round to oval with dense cytoplasm and well defined cell borders
Well differentiated SCC still demonstrates the bright orangeophilic dense cytoplasm
The cytoplasm on the MGG is a ‘sky’ blue compared to the normal mesothelial cells
Pyknotic nuclei may show a coarse granular pattern
Small Cell Anaplastic Carcinoma
Cytology similar to those seen in bronchial samples
Cells are small to medium in size with indistinct cytoplasm
Nuclei are hyperchromatic and nucleoli are absent
The chromatin pattern is coarsely granular and represents a ‘salt and pepper’ appearance.
Nuclear moulding is one of the most striking features resulting in a typical ‘pile of coins’
Metastatic Melanoma
Metastatic melanomas may occur as a 2º in serous effusions
Effusions in malignant melanoma may occur as the 1º evidence of metastatic disease making it difficult to identify the likely site of origin
A diagnosis of malignant melanoma must always be considered when a population of malignant cells are present in the absence of a known primary tumour
Cytology of Metastatic Melanoma
Vary in size from spindle cells to rounded malignant cells
A single cell presentation is common with occasional small clusters
Phagocytic cell in cell engulfment is typical
The cells may be mono or binucleated
Often demonstrate a large often eccentric nucleus
Coarsely granular chromatin pattern
Single or multiple macronucleoli
May demonstrate intranuclear invaginations/inclusions
Presence of melanin pigment is within cancer cells or mesothelials = metastatic melanoma
Lymphoma and Leukemia - Groups for Diagnosis
Malignant lymphomas can be separated into 4 groups for diagnosis:
- large cell lymphomas
- small cell lymphomas
- Hodgkin lymphoma
- miscellaneous lymphoproliferative and haematologic disorders
Hodgkins Lymphoma
Represents metastatic spread of disease
In cytology, see the classic and diagnostic Reed-Sternberg cells, or multinucleated ‘Pop corn’ cells
Reed sternberg cells represent binucleated cells with two nuclei forming mirror image of themselves
Background may contain scattered mononucleated cells similar to those described for a large cell lymphoma with numerous lymphocytes, scattered plasma cells.
Pitfalls include; atypical mesothelial cells (RS cell), other epithelial malignancy, malignant melanoma.
IP’s include; positive for CD15 and CD30
IHC Markers for Diagnosis of Carcinomas
EMA - epithelial membrane antigen (epithelial malignancy)
CEA - carcino-embryonic antigen (+ve in adenocarcinomas)
PAS+/-D
CK5/6 - +ve for MM, –ve for reactive mesothelial proliferations
Calretinin - +ve MM and reactive mesos (staining pattern different), -ve Adeno
BAP1
BerEP4 - : +ve in adenocarcinomas –ve mesotheliomas
TTF-1 - thyroid transcription factor for carcinomas of lung and thyroid
ER/PR - estrogen and progesterone receptors for carcinomas of breast and FGT origin
IHC Markers for DDx of MM and Adenocarcinomas
CEA and BerEP4 - MM -ve - AdCa +ve PAS+/-D - MM +ve for glycogen - AdCa +ve for mucin EMA (E29 clone) - MM +ve membrane - AdCa +ve cytoplasmic CK5/6 - MM + - AdCa +ve in breast, lung, ovary Calretinin - MM +ve - AdCa -ve BAP1 - MM loss of expression - AdCa no loss of expression TTF-1 - MM -ve - AdCa +ve for lung/thyroid
