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Primary Sclerosing Neuroendocrine Carcinomas of the Lung
A Clinicopathologic and Immunohistochemical Study of 10 Cases

Neda Kalhor MD, Saul Suster MD, Cesar A. Moran MD
DOI: http://dx.doi.org/10.1309/AJCPIRV02WXSLHZK 618-622 First published online: 1 April 2010


We describe 10 cases of primary well-differentiated neuroendocrine carcinomas (carcinoid tumor) of the lung with extensive sclerotic changes. The patients were 6 women and 4 men from 20 to 69 years of age. Clinically, patients had symptoms of bronchial obstruction such as cough, dyspnea, and chest pain. Surgical resection of the tumors was accomplished in all the cases. Histologically, all tumors corresponded to the well-differentiated type; however, in 4 cases, lymph node metastases were present. Immunohistochemically, all tumors showed positive staining for neuroendocrine markers, including chromogranin, synaptophysin, CD56, and broad-spectrum keratin. Follow-up information showed that 8 patients were alive after a period ranging from 1 to 5 years. The cases presented highlight an important feature of neuroendocrine carcinomas of the lung not previously addressed, one that may pose a problem not only in the diagnosis but also in the grading of these neoplasms.

Key Words:
  • Carcinoid
  • Neuroendocrine
  • Lung
  • Sclerosis
  • Immunohistochemistry

Primary neuroendocrine carcinomas of the lung represent an important group of tumors that may show a wide range of histopathologic features. More important is the fact that in many circumstances, the histologic grade of the tumor may be used to determine the course of therapy that may provide the most benefit for the patients. Therefore, it is important to be familiar with the current criteria for diagnosis and grading systems in order to properly assess the degree of differentiation in these tumors.1 Regardless of the classification system used,16 neuroendocrine tumors in the lung may show unusual histopathologic features that pose questions regarding whether a tumor should be classified as low or intermediate grade. To illustrate this importance, we present a group of tumors that is characterized mainly by the presence of extensive areas of sclerosis, which not only obscures the true nature of the neoplasm but, in some cases, also could be construed as a feature of a higher-grade neoplasm.

Our experience with 10 such tumors is presented. We highlight the pitfalls in the diagnosis of these tumors when they manifest with extensive sclerosis, mainly when dealing with small biopsy specimens.

Materials and Methods

This study is based on 10 cases of well-differentiated neuroendocrine carcinomas (carcinoid tumor). All cases were encountered during a review of 105 cases of resected neuroendocrine carcinomas from 1988 to 2003. In 2 cases, the previous biopsy material was also analyzed. H&E-stained sections of the tumors were available in all cases, varying from 3 to 8 per case, and paraffin blocks were also available to perform immunohistochemical studies. Histochemical studies for Masson trichrome and amyloid were performed in all cases. A review of the clinical information and follow-up was performed in all cases studied.

For immunohistochemical studies, unstained sections obtained from paraffin blocks of the tumor were available and were used to stain against antibodies for broad-spectrum keratin (dilution 1:50; DAKO, Carpinteria, CA); chromogranin (dilution 1:100; DAKO), synaptophysin (dilution 1:200; DAKO), CD56 (dilution 1:200; NeoMarkers, Fremont, CA), CD117 (dilution 1:100; DAKO), thyroid transcription factor-1 (dilution 1:100; DAKO), and calcitonin (prediluted; DAKO). Control samples were run concurrently.


Clinical Features

The most salient clinical features are presented in Table 1. The patients were 6 women and 4 men from 20 to 69 years of age. In 8 patients, the clinical symptoms were those of cough, chest pain, and dyspnea, while 2 patients were asymptomatic. Of the tumors, 7 had a central bronchial location, and 3 were located in the periphery of the lung; 6 were located in the right lung and 4 in the left lung. Complete surgical resection of the tumor was performed in all cases. In 4 cases, lymph node metastasis was identified in peribronchial lymph nodes (N1).

View this table:
Table 1

Pathologic Features

Grossly, the tumors varied in size from 1.4 to 3.8 cm in greatest dimension. The tumors were well circumscribed and light brown, and, at the cut surface, showed a homogeneous surface without evidence of necrosis and/or hemorrhage.

In 2 cases, the biopsy material was available for review. In one case, the tumor displayed prominent sclerotic changes with only clusters of neoplastic cells embedded in the fibrocollagenous stroma, whereas in the second case, the tumor displayed prominent ectatic blood vessels and sclerotic changes with only a cluster of neoplastic cells embedded in the fibrocollagenous stroma Image 1.

Image 1

Biopsy specimen from a sclerotic neuroendocrine carcinoma of the lung. A, Note the presence of clusters of neoplastic cells embedded in a fibrocollagenous stroma (H&E, ×10). B, Low-power view showing prominent sclerotic changes with prominent dilated vascular structures (H&E, ×10).

In the resected specimens, all tumors showed similar histopathologic features. They showed prominent sclerotic changes, and, in some cases, the fibrocollagenous stroma was also mixed with fibroelastotic changes. Within this stroma, clusters of neoplastic neuroendocrine cells were easily seen Image 2. In 3 cases, the neoplastic spindle cell proliferation was composed of spindle cells, whereas in 7 cases, the features were more of the conventional type of neuroendocrine carcinoma, namely round cells with scant cytoplasm, round to oval nuclei, and inconspicuous nucleoli. No evidence of necrosis or hemorrhage was identified in any of the cases. In addition, no vascular permeation of tumor cells was identified in any of the cases. Mitotic activity was not increased, with cases showing 0 or 1 mitotic figure per 10 high-power fields or 1 or 2 mitotic figures per 50 high-power fields examined when such a count was possible owing to the extent of collagenous stroma. Nevertheless, the overall qualities of the tumors, namely an organized nested pattern without nuclear atypia, were more in keeping with low-grade tumors.

Histochemical stains for amyloid were negative in all cases, and Masson trichrome showed variable staining in the dense fibrocollagenous or fibroelastotic tissue. Immunohistochemical studies were performed in all cases showing tumor cells positive for pankeratin, chromogranin, and synaptophysin Image 3. In addition, in 5 cases, immunohistochemical staining for thyroid transcription factor-1 showed positive nuclear staining; CD117 (c-Kit) showed nuclear labeling in scattered cells (no more than 1%); and CD56 showed positive staining. A calcitonin immunostain was negative in all cases.

Image 2

A, Lobectomy specimen showing a central neuroendocrine carcinoma with prominent sclerotic changes (H&E, ×5). B, Sclerotic neuroendocrine carcinoma showing areas of prominent sclerosis and more viable spindle cell neoplasm (H&E, ×30).

Image 3

A, Cluster of neoplastic cells showing positive staining for chromogranin (×40). B, Cluster of neoplastic cells showing positive staining for synaptophysin (×40).

Follow-up information showed that 8 patients were alive at 1 to 5 years, and 2 patients were lost to follow-up.


The existence of unusual features in neuroendocrine carcinomas of the lung is well known, and, in the majority of cases, unusual features such as the presence of metaplastic bone, pigment, mucoid material, and spindle cell morphologic features710 are rarely thought to represent a difficulty in diagnosis, whether in assessing the true nature of the tumor or in properly addressing the degree of differentiation. However, the presence of extensive areas of sclerosis in a neuroendocrine carcinoma of the lung may pose a significant problem in arriving at a specific diagnosis and also in properly assessing the specific histologic grade for the tumor. This difficulty may be more apparent in biopsy specimens in which the material available for diagnosis may show essentially sclerosis or fibrosis with only focal areas of viable diagnostic material. It is mainly in these circumstances that one needs to consider the possibility of sclerosing neuroendocrine tumor to avoid unnecessary delay in treatment.

As seen in the cases presented, these tumors may occur in any age group and, in addition, may not be limited to tumors confined to the lung parenchyma. In 3 of our cases, the tumor had spread to involved hilar lymph nodes, which represents another unusual feature associated with this sclerosing variant of neuroendocrine carcinomas of the lung. However, based on the follow-up obtained for the patients, although short in some cases, it does not seem that the tumors behaved more aggressively. One important point that requires careful attention is that in some of these cases, the initial diagnosis was not that apparent in the biopsy sample obtained, whereas in some cases, the extensive sclerosis was interpreted as necrosis or as a feature to upgrade the tumor to an intermediate grade (moderately differentiated tumors to atypical carcinoids). However, with this in mind, one must be careful to evaluate the presence of sclerosis and to not interpret such a finding as a feature to upgrade these tumors, which currently is not part of the criteria for upgrading a tumor from well to moderately differentiated (carcinoid to atypical carcinoid).

In the recent past, the presence of extensive sclerosis has been observed in other thoracic tumors, some of them of the neuroendocrine type. Plaza et al11 described 19 cases of sclerosing paragangliomas and alluded to the same problem—that these tumors may mimic a higher grade neoplasm. Although none of those tumors was located in the lung, some of the tumors described were mediastinal tumors. Needless to say, paragangliomas and neuroendocrine carcinomas may show similar immunophenotypes, which, at times, in limited biopsy material can pose considerable difficulty in making an unequivocal diagnosis. Other tumors that have also been described as showing extensive sclerosis are mediastinal parathyroid adenomas.12 Once again, these tumors may share a similar immunophenotype with neuroendocrine carcinomas that may, on certain occasions, pose a problem in arriving at a specific diagnosis. Based on the extensive sclerosis already described in other neuroendocrine tumors, it is possible that such a feature may be related to regressive changes by the tumor.

As described in paragangliomas and ectopic mediastinal parathyroid adenomas, the cellularity in some of these cases may be quite scant, with overwhelming sclerotic changes. Nevertheless, as we documented in 3 of our cases, the presence of extensive areas of sclerosis should not be equated with a limited tumor because in 3 of our cases, the tumor also spread to lymph nodes, even though the cellularity in the primary tumor was scant.

Possible conditions that may enter into the differential diagnosis of sclerosing neuroendocrine carcinomas include the so-called hyalinizing granuloma of the lung,13 infection, and other non–small cell carcinomas and invasive mediastinal tumors that may show sclerotic changes. Primary paragangliomas of the lung are rare tumors14,15 that, although sharing similar morphologic and immunohistochemical features with neuroendocrine carcinomas, in the majority of cases show negative staining for epithelial markers such as keratin. In cases of hyalinizing granuloma of the lung, the lesion will display increased fibrocollagen and inflammatory infiltrate but will lack neuroendocrine cellular proliferation. In addition, the use of immunohistochemical stains for neuroendocrine markers such as chromogranin and synaptophysin will show negative staining. Mediastinal tumors that may show prominent sclerotic changes include thymomas and ectopic parathyroid tumors.12,16 However, in these settings, the presence of an anterior mediastinal mass will lead to a more correct interpretation.

Finally, it is important to highlight that the presence of prominent sclerotic changes in neuroendocrine carcinomas of the lung does not represent a feature that requires an upgrade of a tumor from well to moderately differentiated. Unfortunately, in some cases, the presence of prominent sclerosis may be misinterpreted as possible necrotic change. Thus, considerable effort should be made not to upgrade these tumors based on the presence of extensive sclerosis.

We have described an unusual variant of neuroendocrine carcinoma of the lung and highlighted the importance of keeping such a feature in the differential diagnosis of sclerotic lesions of the lung. Careful morphologic analysis of these cases, along with the use of immunohistochemical studies, will lead to a correct interpretation.


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