Eur J Cardiothorac Surg 2002;23:457-460
© 2002 Elsevier Science NL
Pulmonary large-cell neuroendocrine carcinoma (LCNEC)
René Hagea,
Kees Seldenrijkb,
Peter de Bruinb,
Henry van Swietenc,
Jules van den Boscha*
a Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
b Department of Pathology, St Antonius Hospital, Nieuwegein, The Netherlands
c Department of Thoracic Surgery, St Antonius Hospital, Nieuwegein, The Netherlands
Received 8 October 2002;
received in revised form 9 December 2002;
accepted 16 December 2002.
* Corresponding author. Tel.: +31-30-6092428; fax: +31-30-6052001
e-mail: j.vandenbosch{at}antonius.net
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Abstract
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Objective: The experiences on the treatment of seven consecutive patients with large-cell neuroendocrine carcinoma (LCNEC) were studied, observed over 6 years from 1992. Since LCNEC was recognized as a separate histological entity, only very few series have been reported. Together with the carcinoids (atypical and typical) and the small-cell lung carcinoma (SCLC), it forms the spectrum of neuroendocrine tumors. Methods: Between 1992 and 1997, seven patients who underwent surgical resection were diagnosed as LCNEC postoperatively. Mean age was 65 years (range 54–77 years), five patients were male, all patients were heavy smokers. One patient was staged as IA, four as IB, one as IIIB and one as IV. Results: In five patients, preoperative diagnosis was unknown, in one squamous cell carcinoma and in one adenocarcinoma was suspected. There were four lobectomies, two bilobectomies and one resection of the lingular division with a wedge resection of the upper division of the left upper lobe. Three patients received adjuvant chemotherapy and one, adjuvant radiotherapy. Survival ranged from 7 to 39 months. There are no patients currently alive. Conclusions: LCNEC is a high-grade neuroendocrine tumor with a poor prognosis. In our patients, after surgical resection or multimodality treatment, all have developed widespread metastatic disease with a rapidly fatal course. Due to the rarity of this tumor, the incidence, prognosis and optimal treatment remain to be determined.
Key Words: Large-cell neuroendocrine carcinoma • Large cell • Neuroendocrine • Pulmonary • Carcinoma
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1. Introduction
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Neuroendocrine tumors of the lung can be placed in a biological spectrum, ranging from the relatively low-grade malignant typical carcinoids (TC) and atypical carcinoids (AC) to the large-cell neuroendocrine carcinoma (LCNEC) and the highly malignant small-cell lung carcinoma (SCLC). LCNEC, a very rare tumor, was proposed as a separate category by Travis et al. in 1991 [1], recognizing a distinct high-grade neuroendocrine tumor category with biological and light microscopical characteristics between the intermediate-grade AC and the high-grade SCLC. LCNEC was then defined as: (a) neuroendocrine morphology by light microscopy; (b) large tumor cells with a low nuclear–cytoplasmic ratio, polygonal shape, finely granular eosinophilic cytoplasm, coarse chromatin and frequent nucleoli; (c) high mitotic rate (more than 10 mitoses per 10 high power fields); (d) frequent tumor necrosis and (e) neuroendocrine features by immunohistochemistry or electron microscopy, or both.
In the past, probably most LCNEC must have been diagnosed as SCLC, AC (poorly differentiated), adeno- or squamous cell carcinoma. Although the incidence of LCNEC probably is very low, the exact incidence of LCNEC is not known. In a series of Jiang et al. [2], 22 LCNEC were diagnosed out of 766 reviewed surgically resected primary lung cancers. Since there is no information about LCNEC in patients who did not undergo resection and also because preoperative diagnosis is extremely difficult to make, the exact incidence remains to be determined. Because in the literature, there are only a small number of studies describing LCNEC, we analyzed seven patients diagnosed as having LCNEC [1–8].
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2. Materials and methods
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Between 1992 and 1997, 695 patients underwent thoracic surgery at the St Antonius Hospital, Nieuwegein, The Netherlands. Among those patients, seven were diagnosed with LCNEC. We retrospectively obtained clinical information and follow-up, by reviewing the medical records (Table 1). The surgical resection specimens of all patients were reviewed. At the time of diagnosis, the average patient age was 65 years (range 54–77). Five patients were male and two female. All patients were smokers. According to the International System for Staging of Lung Cancer, one patient was stage IA, four, IB, one, IIIB and one, IV [9]. The diagnosis of LCNEC on the resection specimen was made by using the criteria proposed by Travis et al. [1], using hematoxylin–eosin stained slides of formalin-fixed and paraffin-embedded tissue sections. Immunohistochemical stains included the general neuroendocrine markers, using polyclonal antibodies to synaptophysin (Dako, Glostrup, Denmark), chromogranin A (Boehringer Mannheim, Mannheim, Germany), neuron-specific enolase (NSE) (Dako) and CD56 (123C3) (Monosan, Uden, The Netherlands). Also a panel of AE1/3 (Hybritech Inc, San Diego, USA), thryroid transcription factor 1 (TTF1) (Microm, Francheville, France) and carcinoembryonic antigen (CEA) (Boehringer Mannheim) was applied (Table 2). Histologic sections were available for all seven patients. Due to the small number of cases, no formal statistical analysis of these data was made.
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Table 1. Pathological stage, initial pre-and postoperative diagnosis, treatment and survival of seven patients retrospectively diagnosed as LCNECa
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3. Results
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Five patients presented with thoracic pain, two patients complained of a non-productive cough. One of the patients also had an episode of hemoptysis. Anorexia and weight loss were documented in three patients. In five patients, preoperative diagnosis was unknown, in two a non-small-cell lung carcinoma (NSCLC) was supposed (one adenocarcinoma, one squamous cell carcinoma) (Table 1). For routine staging, mediastinoscopy was done in all patients, and was negative in all cases. Four patients were treated by lobectomy, two underwent bilobectomy (one in combination with a CABG) and one underwent a resection of the lingular division with a wedge resection of the upper division of the left upper lobe. The postoperative period was uncomplicated, and there was no postoperative hospital mortality. Three patients received postoperative chemotherapy. One patient received three cycles of CDE (cyclophosphamide, doxorubicin and etoposide); chemotherapy was discontinued thereafter because of severe hematological toxicity, which disappeared with the suspension of therapy. He then presented with sympomatic brain metastases within 2 years after the original diagnosis. Another patient, presented with concomitant LCNEC and skin metastasis, received six courses of CDE, which resulted in stable disease with a duration of 12 months. Because of progression thereafter, she was treated with two cycles of streptozotocin (STZ) and 5-fluorouracil (5-FU) but died soon thereafter due to symptomatic brain metastases. The third patient received palliative chemotherapy with six cycles of STZ and 5-FU, when metastases in the lung, liver and vagina were found, indicating progressive disease. Unfortunately, while chemotherapy was given, progressive disease developed.
One patient received postoperative local radiotherapy, followed 4 months later by palliative cranial radiotherapy because of symptomatic brain metastases. Three patients did not receive adjuvant therapy; one was clinically not fit to undergo chemotherapy, the other was initially misdiagnosed as a large-cell lung carcinoma with curative resection, and with the last patient chemotherapy was not discussed for unknown reason. One patient was staged as stage IA (pT1N0M0), four IB (pT2N0M0), one IIIB (pT4N1M0) and one IV (pT2N0M1). By light microscopy, all resection specimens had the neuroendocrine characteristics (organoid, trabecular, rosette or palisading growth patterns). Cytologic features were large cell size, a low nucear–cytoplasmic ratio and frequent nucleoli. The mitotic rate was greater than 10/10 high-power field (HPF). There also was extensive necrosis. Neuroendocrine features were seen with immunohistochemistry (Table 2). In two patients with LCNEC, also a component of SCLC was seen. In two other patients, there was LCNEC with a NSCLC component. All seven patients eventually presented with metastatic disease and no patients are currently alive.
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4. Discussion
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LCNEC is a poorly differentiated high-grade neuroendocrine tumor with a very poor prognosis, in other series not significantly different from SCLC, but worse than AC. All patients described with LCNEC were smokers, many of them with a huge number of pack years. The male predominance in our series has been confirmed by other reports in literature [1–3]. The real incidence of LCNEC is not known, and since the original description of LCNEC by Travis in 1991, only small series of LCNEC have been described [1]. The diagnosis of LCNEC is difficult because at first neuroendocrine differentiation has to be recognized by light microscopy, and the differential diagnosis includes SCLC, AC and NSCLC, especially poorly differentiated adeno-or squamous cell carcinoma. In our seven patients, the preoperative diagnosis of LCNEC could not be made. A surgical resection specimen is almost always necessary for diagnosis of LCNEC, although diagnosis has been confirmed by percutaneous needle biopsy as well [3]. Since four of seven LCNEC cases in our series also had a non-LCNEC component, small biopsies are obviously problematic in achieving an exact preoperative diagnosis in all cases. Standard work-up leading to diagnosis should always include at least chest X-ray, CT thorax and abdomen, bronchoscopy and mediastinoscopy. If preoperative diagnosis of LCNEC could be made, for example, by percutaneous needle biopsy, CT brain and bone scan would strongly be recommended. Most distant metastases occur in brain, liver and bone, and demonstrating metastatic disease could prevent unnecessary surgical resection. However, non-surgical procedures almost never lead to the diagnosis of LCNEC.
It would, therefore, be very interesting to retrospectively review all SCLC, AC and NSCLC, but unfortunately the diagnosis of LCNEC is almost impossible without resection specimens. In the study of Jiang, only 22 cases were found when 766 resection specimens were reviewed (2.87%). Eighteen had been previously classified as NSCLC. For LCNEC, Jiang et al. found a 1- and 5-year survival rate of 58.8 and 44.8%, respectively, while this was significantly better with 86.2 and 54.4%, respectively, for NSCLC. Compared to our patients, the survival in the study of Jiang et al. seems very high. Although we have no certain explanation for this suggested survival difference, our patients showed LCNEC with a SCLC component (n=2) and a NSCLC component (n=2). Also, in four out of seven patients, CEA was positive. It has been suggested that CEA expression might be associated with a poor survival in neuroendocrine tumors [1]. In 1986, a study reported CEA positivity as a predictive treatment failure in atypical carcinoids, perhaps some LCNEC were included in this study, as Travis already suggested [1,10]. However, these considerations remain speculative. There is only one study with stage-corrected survival rates, recently published by Takei et al. [8]. This study shows a 5-year survival of 67, 75, 45 and 0% for stage I, II, III and IV, respectively. With 87 patients diagnosed as LCNEC, this is the largest series ever published. Dresler et al. also studied LCNEC, but they did not adhere to the Travis criteria, and, therefore, most probably have included a wide range of neuroendocrine tumors other than LCNEC [4].
Because of the small number of cases, and often retrospective studies, the optimal therapy for LCNEC is not known. The data of prognosis of LCNEC, reported by Travis and Jiang, only include patients who underwent surgery, so the effect on survival of chemo-and/or radiotherapy as (neo-) adjuvant treatment is unknown. Also, chemotherapy protocols often change in time and can also vary between different hospitals, therefore, hampering proper comparison. Another difficulty is that pathological tumor node metastases (TNM) stage often is not reported. In a recent study of Yamanishi et al. [5], six cases of LCNEC were described, when reviewing resection specimens of SCLC. Unfortunately, the number of revised resection specimens is not mentioned. They reviewed resection specimens of patients who underwent surgery for SCLC, because Travis had described in his study that disagreement between pathologists occurred most commonly when differentiating LCNEC from SCLC [6] in a series of 40 neuroendocrine carcinomas. However, the number of patients who underwent surgery for SCLC in our hospital is very limited, and we did not find any LCNEC in our 100 patients where resection specimens revealed the diagnosis (with recent revision) of SCLC postoperatively [11]. These 100 patients were only 4.7% of all patients with bronchogenic carcinoma who underwent pulmonary resection in our hospital between 1977 and 1994. Thus, in searching for LCNEC as previously misdiagnosed tumors, one should not only consider surgical resection specimens of ‘SCLC’, but also adeno-and squamous cell carcinoma. In the future, genetic differences might help to distinguish LCNEC and SCLC. A study with comparative genomic hybridization (CGH) in 13 LCNEC and five SCLC/LCNEC showed that gains of chromosomal material differ between LCNEC and SCLC [12]. A gain of chromosomal region 3q was seen in 66% of all SCLC and in all SCLC/LCNEC and only once in LCNEC. The question is, whether a gain of 3q drives tumor development toward SCLC. An interesting observation is that in other tumors, such as cervical carcinomas, a gain of 3q has been correlated with tumor progression [13].
It can be concluded that LCNEC is a very rare aggressive neuroendocrine tumor with a remarkably dismal prognosis and a high propensity to metastasize. Even when diagnosed and treated in the earliest stage, disease free survival remains very low. The real incidence, prognosis and optimal treatment for this tumor are still not clearly established. Since LCNEC has been recognized as a separate pathologic category in the WHO classification, probably in the near future more results on the behavior of LCNEC can be expected.
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References
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- Heselmeyer K., Schrock E., du Manoir S., Blegen H., Shah K., Steinbeck R., Auer G., Ried T. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc Natl Acad Sci USA 1996;93:479-484.[Abstract/Free Full Text]
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Abstract
1. Introduction
