A 61-year-old man was referred to our hospital because of rapid growth of a mass shadow revealed by chest radiography. The mass was diagnosed as pure small cell carcinoma by CT-guided needle biopsy, and the patient underwent chemotherapy. However, as the tumor showed no response, we considered the possibility of some other form of malignancy and performed surgery. Postoperatively, the mass was diagnosed as small cell carcinoma combined with small cell, spindle cell and squamous cell carcinoma. We report this case in view of the rarity of this combination of morphologic patterns in a primary bronchogenic carcinoma.
In the 1999 revised World Health Organization classification (third edition), combined small cell carcinoma is categorized as a small cell carcinoma variant and defined as small cell carcinoma containing non-small cell carcinoma components . Combined small cell lung carcinoma (SCLC) is relatively rare, accounting for 2–14% of all cases of SCLC [2–4], and a combination of small cell and spindle cell carcinoma is exceedingly rare. Preoperative diagnosis of mixed tumors is difficult and the prognosis of combined SCLC is worse than that of pure SCLC [3,4].
A 61-year-old man presented at a local clinic complaining of hemosputum, but as chest radiography revealed no abnormalities, he was released and followed up. Three months later, he again coughed out hemosputum and returned to the same clinic. This time, chest radiography revealed a 5×3.5-cm mass lesion in the right mid-lung field, and the patient was, therefore, referred to our department. Chest computed tomography (CT) performed on admission revealed a 4.0×3.5-cm mass in S1-2 of the right lung (Fig. 1), and also hilar adenopathy. Cranial magnetic resonance imaging, abdominal CT and bone scintigraphy revealed no abnormalities. Bronchoscopy revealed a tumor obstructing the upper lobe bronchus, but punch biopsy failed to confirm the diagnosis. CT-guided needle biopsy revealed small tumor cells with a high N/C ratio and minimal cytoplasm, and small areas of artefactually crushed cells and nuclei, a histological feature of small cell carcinoma. Although tumor markers such as carcinoembryonic antigen, cytokeratin 19 fragment, sialyl Lewis x antigen, neuron specific enolase and progastrin releasing peptide were negative, the tumor was diagnosed as pure SCLC based on the findings of CT-guided needle biopsy and the rapid enlargement of the tumor. Therefore, we administered chemotherapy (Cisplatin+Etoposide) designed for cT2N1M0 pure SCLC. However, the tumor showed no response. Accordingly, we considered the possibility of a malignant tumor other than pure SCLC, and performed surgery via a right anterolateral thoracotomy. Hilar lymph nodes in which metastasis had been suspected preoperatively were initially dissected, but the intraoperative pathological examination revealed no malignant cells, and these lymph nodes were considered to show merely reactive enlargement. Therefore, this case was judged as sT2N0M0 stage1b, and right upper lobectomy and lymph node dissection were performed.
The postoperative pathological examination revealed features of both small cell carcinoma and squamous cell carcinoma, namely alveolar proliferation of carcinoma cells with increased chromatin and round nuclei with a high N/C ratio, and abundant cytoplasm with intercellular bridges, respectively. In addition, in extensive parts of the tumor, cells with spindle-shaped or oval nuclei were seen to have proliferated in a fascicular or storiform pattern, and transition to epithelial cells was also evident in some areas (Fig. 2).
Immunohistochemical examination performed on each component showed negativity for cytokeratin 13, cytokeratin 18, chromogranin, leu7, neuron specific enolase, smooth muscle actin, myoglobin and desmin, positivity for vimentin, and partial positivity for CD34. The epithelial component was partially positive for epithelial membrane antigen. Based on these results, the patient was diagnosed as combined small cell carcinoma containing three malignant components: small cell carcinoma, squamous cell carcinoma and spindle cell carcinoma.
The patient's postoperative clinical course has been good. At 4 years after surgery, he is alive without any tumor recurrence.
In the present case, spindle cell carcinoma, small cell carcinoma and squamous cell carcinoma were observed in approximately 65, 30 and 5% of the tumor, respectively. Combination of small cell and spindle cell carcinoma is very rare, and only one case has been reported .
Because in this case only the small cell carcinoma component was obtained by CT-guided lung biopsy, it was initially difficult to distinguish this tumor from pure SCLC. In view of the evident hilar adenopathy, rapid enlargement of the tumor, and the result of CT-guided lung biopsy, we considered this tumor to be stage2 pure SCLC and administered appropriate chemotherapy. However, since the tumor response to chemotherapy was much worse than is typical for pure SCLC cases, and all the relevant tumor markers were negative, we considered the possibility of undifferentiated non-small cell carcinoma and decided to carry out surgery. Intraoperative pathological examination of the hilar lymph nodes, performed following thoracotomy, revealed no metastasis. Therefore, we considered curative surgery to be feasible, and performed right upper lobectomy.
In general, small cell carcinoma is more sensitive to chemotherapy than non-small cell carcinoma, but combined SCLC is often resistant to chemotherapy . This resistance is due to certain characteristics of the non-small cell carcinoma components. Patients with combined SCLC have a poorer prognosis than those with pure SCLC [3,4]. Satisfactory results cannot be obtained with only conventional chemotherapy and radiotherapy designed for small cell carcinoma. However, it has been reported that patients with stage1 combined SCLC who undergo surgery have a prognosis similar to that of patients with pure SCLC . As our patient has survived for a long time without any tumor recurrence, we consider that surgery should be performed proactively in appropriately selected cases. An especially important consideration is that if the clinical course appears to be atypical for pure SCLC, then the possibility of a pleomorphic tumor such as combined SCLC should be borne in mind, and the therapeutic strategy altered accordingly.