Japanese Journal of Clinical Oncology 33:10-13 (2003)
© 2003 Foundation for Promotion of Cancer Research
Calcification in Large Cell Neuroendocrine Carcinoma of the Lung
1 Pathology Division, National Cancer Center Research Institute East, Kashiwa, Chiba and 2 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: The aim was to investigate the prevalence of intratumoral calcification in large cell neuroendocrine carcinoma (LCNEC) and to review computed tomography (CT) and histological findings.
Patients and methods: From August 1992 through March 2000, 35 out of 1183 surgically resected lung cancer patients were histologically diagnosed as having LCNEC at our institute. We reviewed the plain radiographs and CT scans of these 35 LCNEC patients. In LCNEC cases with intratumoral calcification, we examined the size, number, distribution and pattern of intratumoral calcifications visible on the CT scans and the histological features.
Results: Three cases (9%) exhibited calcification. The calcifications were recognized by CT scans alone. The CT scans showed punctate or eccentric intratumoral calcifications, which are considered to be a malignant feature, in all three cases. In two cases, the calcifications were histologically confirmed to be located within the necrotic areas of a tumor nest.
Conclusion: We found three LCNEC cases with intratumoral calcification. The prevalence of LCNEC calcification was similar to that in previous reports on lung cancer. The mechanism of the intratumoral calcification in our LCNEC cases is speculated to be dystrophic calcification.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The presence of calcifications in solitary pulmonary nodules on radiological examinations is generally considered to be evidence of a benign lesion. However, the widespread use of computed tomography (CT) scans has shown that calcifications in lung cancer are not rare (1–3). Large cell neuroendocrine carcinoma (LCNEC) is a category of neuroendocrine lung tumors proposed by Travis et al. in 1991 (4), that has been newly listed in the latest WHO classification of lung tumors (5).
We recently encountered a patient with LCNEC that exhibited a unique pattern of multiple punctate calcifications. LCNEC with calcification has not been reported previously. We retrospectively reviewed the CT findings of surgically resected LCNEC cases at our institute and found two other cases of LCNEC with calcification. In this paper, we describe the radiological and histological findings of these cases.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Between August 1992 and March 2000, 1183 lung cancer patients underwent surgical resections at the National Cancer Center Hospital East. Among them, 35 patients (3.0%) were histologically diagnosed as having LCNEC according to the criteria described in the WHO classification of lung tumors (5). The neuroendocrine morphology characterized by organoid nesting, trabecular, rosette-like and palisading patterns was examined using standard hematoxylin and eosin staining. Neuroendocrine differentiation was confirmed using the following immunohistochemical markers: chromogranin, synaptophysin and neural cell adhesion molecule. Von Kossa staining was used to confirm the presence of calcium histologically.
Two co-workers, who were experienced in CT scanning, reviewed the plain radiographs and CT scans of these 35 LCNEC patients and agreed by consensus on the imaging interpretation. Chest radiographs and CT scans were interpreted independently. Based on the interpretations of the CT scans, the size and location of the primary tumor and the size, number, distribution and pattern of intratumoral calcification were recorded.
Contrast-enhanced CT scans were performed using a X-Vision/SP system (Toshiba, Tokyo, Japan); contiguous 10 mm thick sections were obtained from the pulmonary apices to the bases in a supine position at full inspiration in all cases. Dynamic incremental scanning was always performed; scans were nearly always obtained after bolus injection of 100 ml of iopamidol (iopamiron, 300 mg I/ml) (Schering, Berlin, Germany) by an automatic injector. Contrast-enhanced or unenhanced 2 mm thick section images were available in 21 cases.
The location of the tumor was considered to be central when it was located in the inner one-third of the lung field on a CT scan and peripheral when located in the outer two-thirds. Intratumoral calcifications were determined by visual identification on the mediastinal window setting images (window width, 380–420 HU; level, 30–70 HU) of the CT scans. High attenuation area observed visually as opaque, bony structures was interpreted as calcification.
The medical records of all patients with calcified LCNEC were reviewed to determine if hypercalcemia was a possible cause of the metastatic calcifications.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Three (two men and one woman) out of 35 LCNEC patients (9%) exhibited intratumoral calcifications that were visible on CT scans (Table 1). The calcifications were not visible on the plain radiographs in these cases. Two patients (cases 1 and 3) were histologically confirmed to have intratumoral calicifications. In case 2, the calcification was extremely small and was barely detectable; even on thin-slice CT scan images; the presence of this calcification was not confirmed histologically.
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The clinical characteristics and CT findings are summarized in Table 1. All of the patients were heavy smokers (more than 20 pack-years). Cases 2 and 3 contracted pulmonary tuberculosis at the ages of 40 and 20 years, respectively. Serum parameters pertinent to metastatic calcification, such as the levels of calcium and alkaline phosphatase, were within normal limits. Cases 1 and 3 are alive and have shown no signs of recurrence. Case 2 died of gastric cancer 51 months after the surgical resection of LCNEC. All tumors were located in the peripheral lung field and were 3 cm or larger in size.
The CT and histological characteristics of the intratumoral calcifications are summarized in Table 2. The CT scans demonstrated eccentric calcification in cases 1 and 2 (Figs 1 and 2) and diffuse, punctate calcifications throughout the tumor in case 3 (Fig. 3a). In cases 1 and 3, the calcifications were confirmed to occur within the necrotic areas of the tumor nest (Fig. 3c).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Calcifications within solitary pulmonary nodules observed during radiological examination are usually suggestive of a benign lesion. The prevalence of visible lung cancer calcifications on chest radiographs has been reported to be 1% (6). However, CT scans are more sensitive at detecting calcification and the prevalence of calcifications detected using this imaging mode has been reported to be 6–10% (1–3). Roentgenograms of resected specimens exhibit calcifications in 16% of lung cancers (7). These data suggest that lung tumor calcification does not guarantee benignity. In the present study, intratumoral calcifications were identified on CT scans in three out of 35 (9%) patients with LCNEC. This rate is similar to those in previous reports on lung cancer.
The morphological features of calcification visible on CT scans are important for distinguishing between benign pulmonary nodules and malignant ones. Dense central, laminated or diffuse calcifications are characteristic of benign lesions and virtually exclude malignancy. Although punctate or eccentric calcifications are also sometimes observed in benign lesions, they are considered to be indicative of possible malignancy (8). The calcification patterns in our cases were consistent with these malignant features.
Four mechanisms of calcification have been suggested: (i) calcified scar tissue, degenerated bronchial cartilage or granulomatous disease is engulfed by the tumor, (ii) dystrophic calcification occurs within the areas of tumor necrosis, (iii) calcium is deposited within the tumor as a result of a secretary function of the carcinoma and (iv) metastatic calcification occurs as a result of hypercalcemia (3,7,9,10). Metastatic calcification usually occurs in normal lung tissue (alveolar septums, bronchial and vascular walls), the kidney and the stomach (9). The precise mechanisms of dystrophic and metastatic calcification remain undefined. In cases 1 and 3, the calcifications were microscopically confirmed to occur within the necrotic areas at the center of tumor nests and were not found in normal lung tissue. Although cases 2 and 3 had a past history of pulmonary tuberculosis, we could not detect any histological findings suggesting that the tumor had engulfed a pre-existing calcified granuloma. Serum levels of calcium and alkaline phosphatase were within normal limits in all patients. These findings suggest that the mechanism of calcification in these cases was dystrophic calcification.
Some investigators have reported that the histologic subtypes of lung cancer are not correlated with calcification (1,3). However, Kurihara et al. (2) reported that intratumoral calcification was found in three of 13 (23%) small cell carcinomas, which was more frequent than that in other subtypes. They also suspected that the mechanism of calcification in small cell carcinomas was dystrophic calcification. Both small cell carcinoma and LCNEC exhibit extensive areas of necrosis within tumor nests (5). Thus, it seems reasonable to speculate that the calcification mechanism in cases of LCNEC is dystrophic calcification.
In summary, we encountered three cases of LCNEC with intratumoral calcifications visible on CT scans. The prevalence of calcifications in patients with LCNEC was 9%, which is similar to that in previous reports on lung cancer. The mechanism of intratumoral calcification in our LCNEC cases was speculated to be dystrophic calcification.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Atsushi Ochiai, Pathology Division, National Cancer Center Research Institute East, 6–5–1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. E-mail: aochiai@east.ncc.go.jp
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REFERENCES |
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Received July 12, 2002; accepted October 21, 2002
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