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Large-cell neuroendocrine carcinoma that presented with bone marrow replacement

An 84-year-old male smoker, who underwent left upper lobectomy for a lung adenocarcinoma six years earlier, was admitted to our institution due to loss of appetite and exertional dyspnea. Computed tomography scanning demonstrated a tumor shadow in the upper lobe of the right lung, mediastinal lymphadenopathy, and tumor shadows in the liver. His blood test revealed anemia (hemoglobin, 9.9 g/dL), thrombocytopenia (platelet count, 32 × 10/μL), and increased serum levels of lactate dehydrogenase (2,391 IU/L) and soluble interleukin-2 receptor (6,954 U/mL). Examination of the bone marrow smear showed large neoplastic cells, comprising 70% of nucleated cells, and the cells lacked expression of lymphoid and myeloid antigens on flow cytometry analysis. A bone marrow biopsy demonstrated that the marrow space was replaced by the proliferation of large neoplastic cells, and some areas exhibited an organoid nesting pattern. Immunohistochemistry revealing that neoplastic cells were positive for synaptophysin and chromogranin established the diagnosis of large-cell neuroendocrine carcinoma (LCNEC). This replacement of bone marrow with carcinoma cells is a rare presentation of LCNEC and abnormalities in laboratory test results resembled those in hematolymphoid tumors.


INTRODUCTION
Neuroendocrine carcinomas (NECs) are classified as large-cell neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). 1 LCNECs have been reported in several organs such as the lungs, breasts, urinary bladder, colon, gallbladder, ovaries, and uterine cervix. 2 The metastatic organ sites of LCNECs include the lymph nodes, liver, bone, lung, and brain. 2,3 To the best our knowledge, bone marrow involvement with LCNECs has rarely been described. Here, we report a case of LCNEC, in which carcinoma cells replaced the bone marrow. Laboratory test results revealed anemia, thrombocytopenia, and high levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), which resembled those in hematolymphoid tumors.

CASE REPORT
An 84-year-old male smoker was admitted to our in- stitution because of loss of appetite and exertional dyspnea for 1 month. Six years earlier, he had undergone lobectomy of the left upper lobe for lung adenocarcinoma.
One year ago, he developed another lung tumor shadow in the right upper lobe, which was treated by stereotactic body radiotherapy with a total dose of 50 Gy without a pathological diagnosis. For 60 years, he had smoked 20 cigarettes a day, and he had a history of angina pectoris.
On examination, his body temperature was 37.1°C, respiratory rate was 20 breaths/min, and oxygen saturation was 93%. In addition, his blood pressure and pulse rate were normal. There was no purpura or surface lymphadenopathy. Computed tomography (CT) scan with administration of a contrast material displayed a tumor shadow measuring 54 × 44 × 40 mm in the upper lobe of the right lung, mediastinal lymphadenopathy that compressed the superior vena cava, and multiple tumors in the liver (Figure 1). The patient's hemoglobin level was 9.9 g/dL (range, 13.1-17.0 g/dL), reticulocyte production index was 0.6 (0.6-1.3), white blood cell count was 8.58 × 10 3 /µL (3.50-8.50 × 10 3 /µL), and platelet count was 32 × 10 3 / µL (15.0-35.0 × 10 4 /µL). His white blood cell differential count was 35% lymphocytes, 18% monocytes, 44% segmented neutrophils, and 3% band neutrophils. There   Collectively, we diagnosed the patient as having LC-NEC, the primary site of which was possibly the right upper lobe of the lung based on the findings of the chest CT (as shown in Figure 1). The concentration of CY-FRA was 21.1 ng/mL (range, <3.5 ng/mL) and that of NSE was 945 ng/mL (range, <16.3 ng/mL). The concentrations of CEA and Pro-GRP were normal. However, the patient succumbed to the disease on the 22 nd day, and autopsy was not performed.

DISCUSSION
In this report, we described a rare presentation of LC- Distinguishing LCNECs from SCCs can be difficult in some cases because no single feature can be used to clearly segregate SCCs and LCNECs; hence, a combination of features must be taken into account. Moreover, its evaluation must be subjective to some extent. In one study, 12 there was a unanimous diagnostic agreement on 70% of SCCs and 40% of LCNECs in surgically resected neuroendocrine tumors of the lung that were independently reviewed by five pulmonary pathologists. Tumor cells in our patient did not have numerous nucleoli.
However, the distinction between SCCs and LCNECs has little clinical value because of the similar therapeutic protocol. 13 Some groups have suggested that SCCs and LCNECs in the lung should be combined into a single group in daily practice as a high-grade NEC. 14 The specimen from our patient was positive for CK20 and negative for TTF-1. CK20, which is a 46-kDa basic protein, is confined to intestinal epithelial cells, urothelial cells, and Merkel cells. 15 TTF-1 is a nuclear transcription factor that regulates cell growth and differentiation in thyroid, lung, and selected brain tissues. 16