Australian Society of Cytology

CEC Resources

Respiratory Cytopathology

Unusual Neoplasms and Metastatic Disease

Mark Stevens CFIAC
Principal Medical Scientist
Institute of Medical and Veterinary Science
Adelaide, Australia 5000

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Cytology has been shown to be useful not only in the diagnosis of primary neoplasms of the lung but also confirming the presence of metastatic disease. This lecture describes the cytological features of some unusual pulmonary neoplasms and summarises features typifying common metastatic neoplasms.

Adenoid Cystic carcinoma is a common bronchial gland tumour of the trachea but may involve the central bronchi usually as a metastases.

The tumour is rarely diagnosed by sputum, as the lesion is often covered by intact mucosa, but diagnostic cells can be seen in bronchial and FNA specimens. The tumour presents as three dimensional clusters of cells with round to oval hyperchromatic nuclei and small nucleoli. The cells have a high nuclear cytoplasmic ratio and surround cylindric cores of hyaline basal lamina material. The differential diagnosis includes other carcinomas, mostly adenocarcinoma, but the monotony of tumour cells and presence of basal lamina material is a helpful diagnostic indicator.

Sarcomas can involve the lung either as a primary growth or as a metastases. These include leiomyosarcoma, fibrosarcoma, malignant schwannoma, synovial sarcoma, liposarcoma, osteosarcoma and chondrosarcoma (Crosby, 1985; Kim, 1986).

Malignant Fibrous Histiocytoma is characterised by cells presenting singly or as poorly cohesive clusters.

The cells can be spindle shaped with oval to elongated nuclei resembling those seen in fibrosarcoma. Larger cells with pleomorphic nuclei and prominent nucleoli can also be present. These cells have foamy cytoplasm and appear histiocytic.

Tumour giant cells with multiple nuclei are also identified (Kawahara, 1988).

Ultrastructurally the tumours show histiocytic or myofibroblastic differentiation with cells containing lysosomes and fat droplets (Lee, 1984). Immunocytochemistry can be employed to assist in diagnosis, the neoplastic cells staining positive for alpha-1-antitrypsin, muramidase and KPI (CD68) lysosyme. The differential diagnosis includes primary and metastatic adenocarcinoma, melanoma, Hodgkin's disease and other sarcomas such as pleomorphic liposarcoma.

Epithelial and mesenchymal differentiation can be seen in FNA smears of Chondroid Hamartoma.

Diagnosis is based on the recognition of mature cartilage and/or fibromyxomatous fragments (Dunbar, 1989; Orell, 1992). Sheets of bronchial epithelium and fat may also be present.

Cartilage presents as dense, irregular, discrete structures with an almost hyalinised appearance.

Lacunae can be identified in thinner fragments. This cartilage needs to be distinguished from chest wall contaminants such as bone spicules and muscle fibres. Fibromyxoid material has a fibrillar texture and stains bright red with giemsa. Elongated, fusiform bipolar cells characteristic of fibroblasts can be seen embedded in this fibrillary substance. Diagnostic pitfalls in the identification of fibromyxoid material include fibrous tissue, mucous and clusters of epithelioid histiocytes (Dunbar, 1989). Cartilage can be identified in teratomas, dermoids and pulmonary blastomas and these lesions must be considered in the differential diagnosis (Dail, 1988).

Cytological diagnosis of metastatic involvement of the lung is dependent on knowledge of clinical history and comparison of cellular features with previous histological findings. Some metastatic malignancies have cytological features which can suggest a site of origin, however, it is not always possible to confidently exclude a primary neoplasm.

The cytological appearance of metastatic breast carcinoma can vary according to subtype and degree of differentiation. Ductal carcinoma can present as clusters of cells exhibiting nuclear uniformity, inconspicuous nucleoli and scant cytoplasm. They may present in indian-file arrangement similar to that described for small cell carcinoma. These cells also need to be distinguished from bronchioloalveolar carcinoma, reactive bronchiolar epithelium and macrophages. Lobular carcinoma of the breast can also have bland cytological features and may present singly and mimic malignant lymphoma (Johnston, 1976). Although not specific, immunocytochemical staining for oestrogen receptor protein or B72.3 may support the diagnosis. The cells show positive staining to gross cystic disease fluid protein-15 in approximately 50% of cases.

Metastatic renal cell carcinoma can also have bland nuclear features.

However, macronucleoli and irregular nuclei may be seen in poorly differentiated tumours. A characteristic feature is the presence of abundant finely vacuolated cytoplasm giving the cell a "clear-cell" appearance. The demonstration of intracytoplasmic glycogen and/or lipid helps in diagnosis. The differential diagnosis includes primary lung adenocarcinoma, especially bronchioloalveolar carcinoma, vacuolated macrophages and reactive bronchial epithelium. The tumour needs to be distinguished from other tumours which have a clear cell appearance and which may metastasize to the lung, for example adrenal cortical carcinoma, hepatocellular carcinoma and mucoepidermoid carcinoma of salivary glands.

The cytological features of metastatic colonic adenocarcinoma include the presence of cohesive clusters of cells.

These cells often showing well formed gland structures. The cells may be composed of elongated, hyperchromatic nuclei (Flint, 1992). Smears can show a background of necrosis and blood due to the tendency of colonic cancers to undergo central necrosis. Ultrastructural examination is not specific but the presence of short microvilli, rootlets and core filaments may suggest colonic origin.

The cells of metastatic malignant melanoma are characterised by markedly atypical hyperchromatic nuclei.

These cells contain macronucleoli. Intranuclear cytoplasmic pseudoinclusions may be seen. The cells usually present singly or in loose clusters and spindle shaped, bi- or multinucleated cells can be identified. The presence of cytoplasmic melanin is diagnostic and this can be confirmed with special stains.

Ultrastructurally, premelanosomes and melanosomes (type II and III) may be seen.

Immunostaining for S100, HMB-45 and vimentin is positive. Amelanotic lesions need to be distinguished from malignant lymphoma, undifferentiated carcinomas and sarcomas.

Malignant mesothelioma usually present as atypical cells having a mesothelial appearance.

Cytologic features include dense cytoplasm, distinct cell borders, bi-nucleation and multinucleation. Some of the cells may show a microvillus edge. Other cell patterns which can be seen on smears include balls of cells and papillary structures. Distinction from a well differentiated adenocarcinoma may be difficult, especially if a peripheral lesion with a bronchoalveolar pattern. Histochemical studies are of value eg presence of epithelial mucin excludes mesothelioma. Identification of hyaluronic acid within epithelial cells indicates mesothelioma. The tumour is usually positive for high molecular weight cytokeratin (cytoplasmic) and for Leu M1 (CD15).

The distinction between benign and malignant mesothelial cells can be suggested on EM.

Benign mesothelial cells show microvilli on the luminal aspect of the cell. However in mesothelioma, cells show aberrant or circumferential microvilli often in direct contact with collagen.

Metastatic transitional cell carcinoma can simulate metaplastic squamous epithelium and may lead to a false negative diagnosis (Lachman, 1994). The major difference between the two types of cells is the presence of prominent nucleoli and slight nuclear membrane irregularities in tumour cells.

Other malignancies which can present in cytological specimens obtained from the respiratory tract include metastatic prostatic and ovarian carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma and leukaemic infiltrates.

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