Histopathology 2008, 52, 348–354. DOI: 10.1111/j.1365-2559.2007.02952.x
Differential expression of neural-cadherin in pulmonary epithelial tumours D L Zynger, N D Dimov, L C Ho, W B Laskin & A V Yeldandi Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Date of submission 6 July 2007 Accepted for publication 22 August 2007
Zynger D L, Dimov N D, Ho L C, Laskin W B & Yeldandi A V (2008) Histopathology 52, 348–354
Differential expression of neural-cadherin in pulmonary epithelial tumours Aims: Neural (N)-cadherin belongs to a group of transmembrane molecules with a crucial role in tissue morphogenesis and maintenance of an epithelioid phenotype and increased N-cadherin expression is implicated in tumour progression and dedifferentiation. The aim was to determine whether evaluation of N-cadherin in pulmonary tumours might assist in identifying lesions with more aggressive potential. Methods and results: One hundred and fifty-five pulmonary lesions were analysed for N-cadherin expression using immunohistochemistry, including neuroendocrine hyperplasia (n = 3), typical carcinoid (n = 59), atypical carcinoid (n = 12), small cell lung carcinoma (n = 11), large cell neuroendocrine carcinoma (n = 12), adenocarcinoma (n = 35) and squamous cell carcinoma (n = 23). Lymph node status was correlated
with immunohistochemical expression. N-cadherin expression was demonstrated in all cases of neuroendocrine hyperplasia, 96% of typical carcinoids, 83% of atypical carcinoids, 63% of the small cell lung carcinomas and 32% of large cell neuroendocrine carcinomas. Over 90% of the adenocarcinomas and 100% of the squamous cell carcinomas were negative. Increased N-cadherin expression in typical carcinoids was associated with negative lymph node status (P < 0.001). Discussion: N-cadherin is differentially expressed in pulmonary tumours and is predominantly observed in neuroendocrine lung lesions with high expression in typical and atypical pulmonary carcinoids. The level of expression of N-cadherin between types of lung tumours does not appear to indicate malignant potential or aggressive behaviour.
Keywords: atypical carcinoid, N-cadherin, neuroendocrine, pulmonary, typical carcinoid Abbreviations: AC, atypical carcinoid; ADC, adenocarcinoma; LCNC, large cell neuroendocrine carcinoma; NEH, neuroendocrine hyperplasia; SCC, squamous cell carcinoma; SCLC, small cell lung carcinoma; TC, typical carcinoid
Introduction Cadherins are a family of calcium-dependent homophilic adhesion molecules that are localized to the zonula adherens.1 More than 30 cadherins have been identified and named according to the tissue in which they were first observed.2 N-cadherin is expressed during mammalian embryogenesis and angiogenesis and is found in neural crest cells, with reduced Address for correspondence: Debra L Zynger, MD, Department of Pathology, Feinberg 7-325B, Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine, 251 East Huron Street, Chicago, IL 60611, USA. e-mail:
[email protected] 2008 The Authors. Journal compilation 2008 Blackwell Publishing Limited.
expression during cell migration.3–5 Neoplastic cells with de novo or up-regulated N-cadherin expression have demonstrated increased motility and metastatic potential.6–9 A possible role of N-cadherin in tumoral angiogenesis has been suggested.6–9 Furthermore, some neoplasms undergo a transition from E-cadherin to N-cadherin during tumour progression and dedifferentiation.10–12 Pulmonary neuroendocrine tumours encompass a broad range of phenotypically diverse neoplasms with a spectrum of clinical outcomes. Included within this category are the low-grade typical carcinoid (TC), the intermediate-grade atypical carcinoid (AC) and the extremely aggressive small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNC).13
N-cadherin IHC in pulmonary tumours
Although the majority of TC behave non-aggressively, metastatic spread has been documented in 5–10% of cases.13 Within neuroendocrine tumours, prognosis appears to be related to the degree of differentiation: AC tend to have a worse prognosis than TC, and in turn LCNC and SCLC both have the most dismal prognoses.13 Although the current mainstay of therapy for most pulmonary neoplasms is surgical resection, the unique exception is SCLC, in which chemotherapy is preferred due to the frequent presence of metastases at the time of diagnosis.14,15 As the impact on patient care is significant, the ability to differentiate between SCLC and other lesions on biopsy is crucial. However, the frequent presence of crush artefact, in addition to the often minute nature of the biopsy specimen, often makes accurate diagnosis a challenge.16 Identification of a marker to separate high-grade from low-grade lesions, or SCLC from non-small cell lung carcinoma, would be useful. N-cadherin has been described as a marker which is up-regulated in more aggressive lesions.6–9 N-cadherin expression in the spectrum of lung tumours, particularly in neuroendocrine tumours, has not yet been evaluated. Using immunohistochemistry, we investigated N-cadherin expression in primary lung lesions, including neuroendocrine hyperplasia (NEH), TC, AC, SCLC, LCNC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC), in order to determine if this marker is differentially expressed in pulmonary tumours and could have diagnostic or prognostic utility.
Materials and methods c a s e s el ec t i on One hundred and fifty-five lung lesions accessioned between 1990 and 2006 at Northwestern Memorial Hospital (Chicago, IL, USA) were retrieved electronically from the surgical pathology files and included NEH, TC, AC, SCNC, LCNC, ADC and SCC. NEH had a neuroendocrine growth pattern and cellular features, but were 80% of tumours. Approximately two-thirds of SCLC and one-third of LCNC expressed N-cadherin, with a significantly lower intensity of reactivity than for TC or AC. N-cadherin has not been previously described in any pulmonary neuroendocrine tumours and there are only a few reports of N-cadherin expression in neural or endocrine tumours at other sites. Within the adrenal gland, most pheochromocytomas, adrenal cortical adenomas and a minority of adrenal cortical carcinomas express N-cadherin.21 The majority of small cell carcinomas from various sites were positive for N-cadherin, and it has been suggested that loss of N-cadherin in these tumours may be a bad prognostic indicator.22 Furthermore, the majority of Merkel cell carcinomas and astrocytomas express N-cadherin.23,24 Our data showed a higher level of N-cadherin in more differentiated neuroendocrine neoplasms as well as a correlation between negative lymph node status and increased expression of N-cadherin in TC. Therefore, N-cadherin expression in lung neuroendocrine tumours as well as certain neural or endocrine tumours at other locations may be due to the acquisition of neuroendocrine features during carcinogenesis and may not signify
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aggressive behaviour, in contrast to numerous previously studied non-neuroendocrine carcinomas.6–12 Larger series need to be conducted to determine if loss of N-cadherin expression has prognostic utility for TC. It will also be interesting to see if in larger series the correlation between increased expression and negative lymph node status will be observed in other lung neuroendocrine tumours such as AC, SCLC or LCNC. In addition to its potential prognostic value, N-cadherin can be used as an additional lung marker for TC or AC, especially in small biopsy specimens, which were included in this study and demonstrated strong positivity. The sensitivity of N-cadherin for carcinoids was similar to traditional neuroendocrine markers such as neuron-specific enolase, chromogranin A and synaptophysin, as well as newer markers such as microtubule-associated protein-2.25,26 N-cadherin expression in pulmonary lung tumours appears to be predominately restricted to neuroendocrine lesions. Most ADC did not express N-cadherin and all SCC were negative. N-cadherin could be used to help rule out ADC and SCC, as few of these tumours were immunoreactive, similar to chromogranin, CD56 and polysialylated neural cell adhesion molecule, and appears to be more specific than synaptophysin, neuron-specific enolase or microtubule-associated protein-2 for neuroendocrine lesions.25–29 Our data are similar to those of prior investigations, which described a minority of pulmonary ADC and SCC with N-cadherin expression. Reports of N-cadherin reactivity in pulmonary ADC have ranged from 0 to 45%.30–34 There has been only one prior study of N-cadherin in lung SCC, which showed 20% of cases with positivity.27 Differences between percent positivity may reflect use of different antibody clones, antibody concentrations, antigen retrieval methods or scoring techniques. This is the first study of N-cadherin immunohistochemistry in the spectrum of lung tumours. We have demonstrated differential expression of N-cadherin in histological types of pulmonary epithelial tumours regarding both frequency of positivity and intensity of reactivity, with higher expression in more differentiated lesions. Our data have shown that the majority of TC and AC express N-cadherin, whereas most ADC and SCC are negative. The positivity of TC and AC for N-cadherin indicates that it is a reliable immunohistochemical marker for these tumours. The presence of N-cadherin in pulmonary neuroendocrine tumours may be due to neuroendocrine differentiation of the precursor cell and does not appear to convey aggressive behaviour as demonstrated in other non-neuroendocrine malignancies.
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