Pancreatic metastasis in a case of small cell lung carcinoma: Diagnostic role of fine-needle aspiration cytology and immunocytochemistry.

Small cell lung carcinoma represents a group of highly malignant tumors giving rise to early and widespread metastasis at the time of diagnosis. However, the pancreas is a relatively infrequent site of metastasis by this neoplasm, and there are only occasional reports on its fine needle aspiration (FNA) cytology diagnosis. A 66-year-old man presented with extensive mediastinal lymphadenopathy and a mass in the pancreatic tail. Ultrasound-guided FNA smears from the pancreatic mass contained small, round tumor cells with extensive nuclear molding. The cytodiagnosis was metastatic small cell carcinoma. Immunocytochemical staining showed that a variable number of neoplastic cell were positive for cytokeratin, chromogranin A, neurone-specific enolase and synaptophysin but negative for leukocyte common antigen. The trans-bronchial needle aspiration was non-diagnostic, but biopsy was suspicious of a small cell carcinoma. This case represents a rare metastatic lesion in the pancreas from small cell lung carcinoma, diagnosed by FNA cytology.

Introduction

Small cell lung cancer (SCLC) accounts for 20-25% of all bronchogenic carcinomas and is associated with the poorest 5-year survival of all histologic types.[1] It represents a group of highly malignant tumors, giving rise to early and widespread metastasis at the time of diagnosis at sites such as lymph nodes, adrenal glands, liver, lung, brain and bones.[2] The pancreas is a relatively infrequent site of metastasis from this neoplasm,[3] and reports on metastatic small cell carcinoma (SCC) in the pancreas, either of pulmonary or extrapulmonary origin, to be diagnosed by fine needle aspiration (FNA) cytology are very rare.[4-6] Here, we report a case that was diagnosed as metastatic SCC by ultrasound (US)-guided FNA cytology and immunocytochemical studies of a pancreatic mass.

Case Report

A 66-year-old man, a heavy smoker, presented with persistent cough, weight loss and superior vena cava syndrome. Computerized tomography (CT) scan of the chest revealed extensive mediastinal lymphadenopathy. Based on clinical and imaging findings, possibilities like lymphoma and SCC were considered. CT scan of the abdomen showed a mass in the pancreatic tail, suggestive of metastasis from a primary in the lung.

The pancreatic mass was subjected to US-guided FNA. The air-dried smears were stained routinely by May–Grünwald–Giemsa (MGG) stain and wet-fixed smears in 95% ethanol were stained by Papanicolaou method. The smears were highly cellular and contained small, round tumor cells with scanty cytoplasm, which showed extensive nuclear molding [Figure 1a and b]. The nuclei of the tumor cells were round to oval and had salt and pepper type chromatin. There was occasional micro-acinar formation. Rare cells with paranuclear blue inclusions and scattered apoptotic bodies were present. Some singly dispersed neoplastic cells resembled lymphoma cells and were accompanied by a few cytoplasmic fragments [Figure 1c]. Most of the tumor cells were found to have a positive reaction for pan-cytokeratin [Figure 1d], and a variable number were positive for neurone-specific enolase [Figure 1e] and chromogranin A. Occasional tumor cells were positive for synaptophysin, but all were negative for leukocyte common antigen. Based on cytomorphology and immunocytochemistry, the diagnosis was metastatic SCC.

Figure 1

Metastatic small cell carcinoma: Ultrasound-guided FNA of a pancreatic mass in a 66-year-old man: Cytomorphological features and immunocytochemical stainings on FNA smears. (a) The neoplastic cells show nuclear molding and have round to oval nuclei with a salt and pepper type chromatin pattern (Papanicolaou, ×400). (b) Highly cellular smear show small, round tumor cells with scanty cytoplasm, extensive nuclear molding, and mitotic activity (MGG, ×400). (c) Dissociated lymphoma-like tumor cells along with a few cytoplasmic fragments resembling lymphoglandular bodies are observed (MGG, ×1000). (d) Positive reaction for cytokeratin in most of the tumor cells (CK, ×400) (e) Positive reaction for neurone-specific enolase in a few neoplastic cells, including rare large cells (NSE, ×1000)

The patient was subjected to trans-bronchial needle aspiration (TBNA) and biopsy. The TBNA smears were non-diagnostic but trans-bronchial needle biopsy contained tissue fragments containing bronchial glands, closely associated with aggregates of small, round blue tumor cells. The neoplastic cells showed nuclear molding at places and formed occasional micro-acini. The histopathological diagnosis was suspicious of an SCC. The tumor cells were positive for chromogranin A, synaptophysin, CD57 and cytokeratin (Ck), but staining for CD 20 and CD3 was negative.

Discussion

Metastatic involvement of the pancreas is an infrequent clinical condition. On searching medical records of 850 patients with lung cancer, Maeno et al.[7] identified 26 (3.1%) patients with pancreatic metastasis. Yoon et al.[8] reported 53 pathologically proven metastatic tumors of the pancreas (MTPs); the primary malignancies were renal cell carcinoma (n=14), gastric cancer (n=11), colorectal cancer (n=5), lymphoma (n=4), non-SCLC (n=3), gastrointestinal stromal tumor (n=2), melanoma (n=2), SCLC (n=2), gallbladder cancer (n=2) and one case each of hepatocellular carcinoma, thymic carcinoid, liposarcoma, cholangiocarcinoma, osteosarcoma, breast cancer, duodenal cancer and ovarian cancer. Among 20 non-hematological metastases in the pancreas evaluated by FNA, Volmar et al.[5] observed 9 renal-cell carcinomas, 3 melanomas, 2 pulmonary small-cell carcinomas, 2 breast carcinomas and one each case of prostate carcinoma, colon adenocarcinoma, pulmonary squamous cell carcinoma and gastrointestinal stromal tumor. Layfield et al.[6] reported 17 metastatic malignancies to pancreas, which accounted for 0.73% of all pancreatic FNAs. The primary sites included eight renal cell carcinomas, four lymphomas, two squamous cell carcinomas (one from the lung and the other from the esophagus), one medullary thyroid carcinoma, one alveolar rhabdomyosarcoma and an SCLC.

The SCLC includes three morphologic categories in paraffin sections: (1) SCC, (2) mixed small cell/large cell and (3) combined SCC.[1] In our case, the smears were made mostly of small cells, interspersed with occasional large cells. The neoplastic cells had scant cytoplasm and stippled or salt-and-pepper type chromatin. Nuclear molding was conspicuous and scattered cells with paranuclear blue inclusions or apoptotic bodies were present throughout the smear. Extreme nuclear molding by clusters of small tumor cells is considered to be the most characteristic presentation of SCC; moreover, paranuclear blue inclusions, which are 1-4 μm spherical inclusions demonstrated by Romanowsky stain, may act as a diagnostically useful finding.[9] According to Arora et al.,[10] nuclear molding, cell size and scant, basophilic cytoplasm were highly sensitive and specific for distinguishing SCC from Non-SCC (NSCC). Other features, such as salt-and-pepper chromatin, crush artifact and apoptotic bodies, had also significantly high specificity; however, their low sensitivity precluded their usefulness in separating SCC from NSCC.

Difficulties may be observed in differentiating metastatic SCC from other small round cell tumors and primary pancreatic SCC from metastatic SCC. In the present case, we observed dissociation of neoplastic cells and presence of cytoplasmic fragments resembling lymphoglandular bodies, which are common features of non-Hodgkin lymphoma, but can be observed in a small percentage in other small round cell tumors.[9] Under such situations, a panel of immunohistochemical stains can be useful in differentiating SCC from various other small cell neoplasms.[4] In practical work-up of SCC, immunohistochemistry is useful to discern SCC from high-grade lymphoma; SCC labels with antibodies to high molecular weight cytokeratins, but not with antibodies to leukocyte common antigen (CD45).[11] In our case, the neoplastic cells in FNA smears were Ck+ and stain for LCA showed negative reaction, thus excluding the possibility of non-Hodgkin lymphoma. The most common immuno profile of metastatic SSC from a lung primary is positive staining with cytokeratin 7 and thyroid transcription factor (TTF)-1 and no reaction to Ck20.[12] However, immunohistochemical studies are found to have limited value in distinguishing a primary site from metastatic SCC.[4] According to Lin et al.,[13] immunohistochemistry has not proven useful in distinguishing primary periampullary SCC from metastatic SCLC. Although, a high percentage of lung primary cancer expresses TTF-1, this marker has variable positivity in patients with extrapulmonary SCC,[13] and the expression of TTF-1 has not been well explored in pancreatic SCC, with only one negative reported case in literature to date.[14] Moreover, cytokeratin (Ck7 and Ck20) switching can occur in the natural history of pulmonary SSC.[12]

In our case, the clinical suspicion was SCLC. Histology and immunohistochemical studies also favored the primary tumor as SCLC. The pancreatic FNA cytology was diagnosed as metastatic SCC, which was positive for pan-Ck, neurone-specific enolase, chromogranin A and synaptophysin. However, the immunohistochemical/ immunocytochemical panels did not include Ck7, Ck20 and TTF-1, which could have further confirmed the primary lung cancer.