Typical Pulmonary Carcinoid Research Articles

Differential Expression of ErbB Receptors on Typical Pulmonary Carcinoid Cancers

Lung cancer is the leading cause of cancer-related death inthe United States. Pulmonary typical carcinoid (TC) cancers are part of a spectrum of neuroendocrine lung cancers which includes small cell lung cancer (SCLC). Besides surgery, there are limited treatment options available for patients with these cancers, emphasizing the need for the development of new treatments. The c-erbB family of receptor tyrosine kinases (ErbB1-4) mediate cellular responses to growth factors and interact with downstream signaling pathways to promote tumorigenesis through abnormal cell proliferation. ErbB1 (EGFR) has received considerable attention in NSCLC since somatic mutations in the tyrosine kinase domain correlated with responsiveness to gefitinib. In NSCLC, breast, and ovarian cancer, ErbB2/ErbB3 heterodimers have been found to be expressed and signal to downstream pathways such as ERK. ErbB4 has been shown to promote proliferation or differentiation of neural tumors (ependymoma, gliomas, and meningiomas), ovarian cancer, and osteosarcoma. We recently examined the expression of ErbB receptors on TC cancers by quantitative real-time RT-PCR and immunoblotting. TCs have high expression of ErbB3 with moderate expression of ErbB1 and ErbB4 and lack expression of ErbB2. This contrasts with atypical carcinoids and SCLC which have high expression of ErbB4 with minimal expression of ErbB3 and lack expression of ErbB1 and ErbB2. We believe that investigation of ErbB signaling in pulmonary carcinoids will lead to new insights into the biology of these cancers, the understanding of which could lead to the development of novel treatments. Supported by funds from Mayo Foundation.

Typical and Atypical Pulmonary Carcinoid Tumor Overdiagnosed as Small-Cell Carcinoma on Biopsy Specimens: A Major Pitfall in the Management of Lung Cancer Patients

Typical and Atypical Pulmonary Carcinoid Tumor Overdiagnosed as Small-Cell Carcinoma on Biopsy Specimens: A Major Pitfall in the Management of Lung Cancer Patients

Large cell neuroendocrine carcinoma of the uterine cervix with cytogenetic analysis by comparative genomic hybridization: a case study

Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a newly introduced category of the revised World Health Organization classification. We reported a case of cervical LCNEC with cytogenetic analysis by comparative genomic hybridization (CGH). The cervical tumor showed moderately increased mitotic activity (8-14 mitotic figures per 10 high-power fields) and focal necrosis, which made it problematic to differentiate from atypical carcinoid. CGH analysis failed to detect chromosome 11q loss that has been reported to be characteristic of pulmonary atypical carcinoids. Furthermore, chromosome 3q amplification, which has been detected frequently in pulmonary small cell carcinomas and LCNECs but not in pulmonary typical and atypical carcinoids, was the most remarkable chromosomal aberration. Although CGH reports are extremely rare in neuroendocrine tumors of the uterine cervix, specific chromosomal aberrations may be useful in their distinction.

Nuclear and environment morphometric profile in tumor size and nodal metastasis of resected typical pulmonary carcinoid

As the biologic behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and extracellular matrix invasion, Bcl2 and extracellular matrix density have been targeted as potentially useful tumor markers. In this study, we sought to validate the importance of Bcl2 and ECM density and to study the relationships of Bcl2 and ECM density with clinical factors and other tumor or stromal markers. We examined Bcl2 and several other markers in tumor tissues from 55 patients with surgically excised pulmonary typical carcinoid. We used histochemistry, immunohistochemistry, and morphometry to evaluate the amount of tumor staining for Bcl2 and ECM; the surrogate markers for aggressive potential for our study were tumor size and lymph node metastasis determined at diagnosis. Multivariate logistic model analysis demonstrated that after surgical excision control, tumor size was significantly related to nodal metastasis ( P=0.01), but quantitative staining of the tumor for Bcl2 and ECM added prognostic information and was as strongly prognostic as tumor size ( P<0.01). Cutpoints at the median staining of 3.1% and 9.8 μm 2 for Bcl2 and ECM, respectively, divided patients into two groups with distinctive risk for nodal metastasis. Those with Bcl2>3.1% and ECM<9.8 μm 2 had high risk for nodal metastasis. We concluded that tumor staining for Bcl2 and ECM in resected PTC is strongly related to tumor size and nodal metastasis. Patients with >3.1% and <9.8 μm 2 staining in their tumors comprise a subset with a high hazard for nodal metastasis and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.

The use of Alu-PCR to distinguish between typical pulmonary carcinoids versus classic midgut carcinoids.

Although histologically 'typical' pulmonary and 'classic' midgut carcinoids are similar, the small intestine tumors are more aggressive than their pulmonary counterpart. We believe that in contrast to pulmonary carcinoids arising from Kulchitsky cells, 'classical' midgut carcinoids develop from crypt stem cells that differentiate into endocrine ('classical') or exocrine-endocrine ('non-classical' adenocarcinoid) tumors. The different progenitor cells may determine different malignant potentials between these types of carcinoids. To identify genetic differences between 'classical' midgut and typical pulmonary carcinoids using an Alu-PCR genomic profiling method, we reviewed 54 cases of carcinoid tumors that were surgically removed at Hartford Hospital from 1996 through 2001. Histologically these cases were selected into three groups: i) foregut or pulmonary carcinoids, ii) 'classic' midgut carcinoids of small intestine and iii) multiple typical pulmonary carcinoids. Genomic-profiling of DNA from these cases was performed using an Alu-PCR method. Metastases were observed in 18/20 'classical' intestinal carcinoid tumors, 3/30 pulmonary carcinoids, and 0/4 multiple pulmonary carcinoids. These results confirm that pulmonary carcinoids behave in a more benign fashion than intestinal carcinoid tumors. Using Alu-PCR to profile tumor cell genomic DNA, we showed that 68% of small intestine carcinoids and 58% of pulmonary carcinoids had allelic banding patterns suggestive of either amplification or deletion of gene sequences. Alu-PCR demonstrated loss or gain of genetic sequences that were unique for each examined group. These findings strongly suggest that pulmonary carcinoids differ from their intestinal counterparts.

Typical and Atypical Pulmonary Carcinoids: Outcome in Patients Presenting With Regional Lymph Node Involvement

Typical pulmonary carcinoid tumors are well-differentiated neuroendocrine tumors that are associated with good patient survival rates, while atypical carcinoid tumors are more aggressive and have worse patient survival rates. Because these tumors rarely involve the thoracic lymph nodes at presentation, it is currently unknown to what extent the presence of thoracic lymph node metastases at the time of diagnosis influences patient survival. A computerized search of the medical records for pulmonary carcinoid tumor at the Mayo Clinic from 1976 to 1997 revealed 517 patients, from which we identified 36 patients with pulmonary carcinoid tumors involving regional thoracic lymph nodes but without distant disease. For each patient, we reviewed the tumor histology, stage, and outcome. In addition, because the histologic criteria for the diagnosis of carcinoid tumors had changed significantly during the time of the study, we reexamined all of the histologic specimens using the current World Health Organization (WHO) criteria for classifying pulmonary neuroendocrine tumors. After reclassification with the WHO criteria for neuroendocrine tumors, 23 patients had typical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, 19 patients had no evidence of disease (NED), 2 patients had developed systemic metastases (SM) and are still alive, and 2 patients had died. Eleven patients had atypical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, four patients had NED, seven patients had developed SM within a median time of 17 months, and six patients with SM died shortly thereafter (median survival time, 25.5 months), while one is still alive. Two patients had been reclassified with large cell neuroendocrine carcinoma at the time of this review; both of these patients had developed SM (at 4 months and 21 months after diagnosis) and had died (at 15 months and 21 months after diagnosis, respectively). These data suggest that patients with atypical pulmonary carcinoid tumors with regional lymph node metastases have a high likelihood of developing recurrent disease if treated with surgical resection alone and have significantly worse outcome (p < 0.001) compared to those patients with typical carcinoid tumors with thoracic lymph node involvement.

DNA topoisomerase II-alpha in pulmonary carcinoid tumors.

Fifty-four pulmonary carcinoid tumors of surgically treated patients were diagnosed according to modified Arrigoni histological criteria (WHO 1999). Forty-seven typical (TC) and seven atypical carcinoids (AC) formed the basic groups. Four subgroups were selected from the TCs and consisted of cases with higher tumor size (T2) or those associated with nodal involvement (N1), tumor satellites, and tumorlets. Subgroup tumors were regarded as affections with possible increased proliferation potential. The proliferate activity was examined immunohistochemically by topoisomerase II-alpha (clone SWT3D1) on paraffin material and calculated by the number of positive nuclei per 10 HPF. The topoisomerase expression was found to be statistically different in both principal groups made up of typical and atypical carcinoids with a mean value of 49 and 135 positive nuclei per 10 high power field in TC and AC, respectively. The remaining subgroups of the TCs associated with examined characteristics (larger tumor diameter, metastases, satellites, tumorlets) were not found to be statistically different. The topoisomerase II-alpha is a marker giving valuable information about the diagnosis of pulmonary typical and atypical carcinoids.

Spontaneous Partial Expectoration of an Endobronchial Carcinoid

Typical pulmonary carcinoid tumors often present as proximal endobronchial masses discovered during the evaluation of cough and/or hemoptysis. We present a case of a carcinoid tumor that presented with spontaneous partial expectoration. A review of the literature revealed 16 cases of expectoration of fragments from various primary and metastatic tumors. Our case appears to be the first report of the expectoration of a carcinoid tumor.

Nuclear pleomorphism in typical carcinoid tumours of the lung: problems in frozen section interpretation.

Pulmonary typical carcinoid tumours are generally easy to diagnose with their uniform cells, carcinoid growth pattern and lack of mitoses. However, nuclear pleomorphism, which is common in other neuroendocrine tumours, is not emphasized in pulmonary carcinoid tumours. Three cases of typical carcinoid tumours, because of marked nuclear pleomorphism on frozen section, were misdiagnosed as non-small cell carcinomas.

Primary tumors of the lung other than lung cancer

Neoplasms of the lung other than lung cancer are rare and have varying biologic behavior. Diffuse malignant mesothelioma remains a difficult clinical problem, with efforts directed at combined modality therapy. A nude mouse xenograft model may hold promise in the identification of active chemotherapy agents. Continuing evidence suggests that typical and atypical pulmonary carcinoids represent a spectrum of neuroendocrine disease, with small cell lung cancer representing the most virulent subtype. Therapy for advanced invasive thymoma includes neoadjuvant chemotherapy, surgery, and postoperative radiation. Nonseminomatous germ cell neoplasms of the mediastinum respond much less favorably to cisplatin-based chemotherapy than do similar tumors arising elsewhere, and new advances in treatment are needed. Rare mesenchymal tumors usually respond favorably to surgical excision.