Pulmonary neuroendocrine (NE) proliferations are a diverse group of disorders which share distinct cytological, architectural and biosynthetic features. Tumours composed of NE cells are dispersed among different tumour categories in the WHO classification of tumours and as such do not conform to a singular group with regards to treatment and prognosis. This is reflected by the highly variable behaviour of NE proliferations, ranging from asymptomatic, for instance in diffuse idiopathic pulmonary NE cell hyperplasia and tumourlets, to highly malignant cancers such as small cell lung cancer and large cell NE carcinoma. In this review NE proliferations are described as distinct entities ranging from low grade lesions to high grade cancers. The differential diagnoses are considered with each of the entries. Finally, mention is made of tumours which may show some NE features.

Lung cancer in never-smokers was recognised as a distinct clinical entity around the mid-2000s because these patients tended to be Asian women and diagnosed at a younger age with a preponderance of adenocarcinoma and better survival outcome despite a more advanced stage of presentation. It was soon discovered that lung cancer in never-smokers had a higher prevalence of activating EGFR mutations and we tend to classify lung cancer by smoking status for screening purpose. With the discoveries of many actionable driver mutations such as activating EGFR mutations and ALK rearrangement in adenocarcinoma of the lung we have switched to classifying non-small cell lung cancer into different individual molecular subgroups based on the presence of a dominant driver mutation. Although many actionable driver mutations are found in never-smokers with adenocarcinoma, this review will summarise that a substantial proportion of patients with these actionable driver mutations had a previous smoking history. Alternatively among the driver mutations that are associated with smoking history, a fair amount of these patients were never-smokers. Thus smoking status should not be used as a screen strategy for identifying driver mutations in clinical practice. Finally smoking history may have predictive and/or prognostic significance within individual molecular subgroups and identifying the difference according to smoking history may help optimise future targeted therapy.

The pathological diagnoses and classification schemes for thyroid carcinoma have changed over the past 20 years and continue to do so. New entities have been described and molecular analyses have suggested better characterisation and grouping of certain tumours. Because some of the lesions have been named differently by different authors, clinicians and patients may be confused as to what a specific patient's lesion represents. In this review, we discuss the thyroid tumours of follicular origin which are clinically unusual but important to recognise as their behaviour may be aggressive, they may not respond to radioiodine treatment and they may cause significant mortality. This paper describes these important but rare lesions, their pathological features, important clinicopathological correlations, molecular correlates and prognostic implications.

Smoking-related interstitial fibrosis (SRIF) is a common, histologically striking finding in smokers that must be distinguished from the idiopathic interstitial pneumonias and other chronic interstitial fibrosing lesions. It is characterised by marked thickening of alveolar septa by fibrosis composed of thick collagen bundles that have a distinctive hyalinised quality and often are admixed with variable numbers of hyperplastic smooth muscle fibres. There is minimal accompanying inflammation. This fibrosis is usually most prominent in subpleural and centrilobular parenchyma, but can be present elsewhere as well. It is accompanied by emphysema and respiratory bronchiolitis. Most patients are asymptomatic or only mildly symptomatic, and the clinical course is stable in most. This paper reviews the pathologic features of SRIF in detail, its differentiation from more ominous interstitial fibrosing processes, and the clinical implications of its diagnosis.

OBJECTIVES:

To investigate the pathological and clinical meaning of p63 in extranodal nasal type NK/T cell lymphoma (NKTCL).

METHODS:

We detected p63 and p53 expression using immunohistochemistry staining in 84 cases of NKTCL from Southern of China, an area with a well known high incidence of nasopharyngeal carcinoma, which is closely associated with Epstein-Barr virus infection. Moreover, we analysed the relationship between p63 and p53 expression and the clinicopathological features of NKTCL.

RESULTS:

Our results first showed that p63 expression was found in 14.3% (12/84) of NKTCL compared with 6.6% (2/30) in reactive lymphoid hyperplasia of nasopharynx. p63 Expression rate in NKTCL was significantly higher than that in reactive lymphoid hyperplasia of nasopharynx (p=0.016). NKTCL patients with p63 positivity had poorer 5-year overall survival rate (29.2%) than that (49.9%) of p63 negativity. p53 expression was found in 33.3% (28/84) of NKTCL. Our data showed that p53 expression was significantly associated with tumour stage (p=0.016) and international prognostic index (p=0.026) in patients with NKTCL. Cox regression test showed that p53 expression rate and international prognostic index score were statistically independent prognostic factors for NKTCL patients (p=0.002 and p=0.016, respectively). Our results suggest that p63 and p53 might play a role in pathogenesis of NKTCL.

This is a general overview of KRAS, its structure and role in pertinent cancers. Also its role in determining adjuvant therapy is discussed.

Breast cancer represents a heterogeneous group of diseases with varied presentation, morphological and biological features, behaviour, and response to therapy. Management of breast cancer relies on availability of robust predictive and prognostic factors to support decision making. Identifying and validating the prognostic and predictive value of a given marker is based on studying its association with clinical outcome with or without consideration for therapy, respectively. In the field of cancer research, clinical outcome is determined by assessing certain time-dependent events: 'endpoints' such as tumour progression, recurrence and patient mortality. Guidelines for reporting tumour markers have been published and there is a perception that outcome determination in breast cancer is well documented. However, reviewing the literature has highlighted the varied use of definitions used in clinical outcome measures and there are pitfalls in outcome analysis. This may have contributed to the discrepancies in the literature and to the inconsistent conclusions seen in published studies assessing the same markers. Identification of these pitfalls is expected to improve prognostic and predictive marker assessment. Here issues related to outcome determination in breast cancer including definitions and pitfalls and some critical views are presented.

Due to the advanced progress in personalised therapy concepts for non-small cell lung cancer (NSCLC), we applied the ion semiconductor sequencing (ISS) approach to molecular diagnosis of NSCLC, analysing a set of therapy relevant gene loci. DNA from macrodissected tumour samples of formalin fixed biopsies was used for PCR amplification of EGFR exons 18, 19, 21 and KRAS exon 1. A total of 128 PCR products were analysed by conventional termination sequencing as well as by ISS. Sensitivity of ISS was additionally determined using 100-10 000 copies of reference mutants. All somatic mutations detected by direct Sanger sequencing were also identified by ISS. No additional mutants were detected. Running samples with limited copies of mutated alleles revealed high sensitivity, detecting less than 10% (2500 copies) mutants in a human wild type background. In conclusion, multiplexed mutation analyses by ISS is an efficient technology that can easily be linked to existing PCR approaches in molecular pathology.

AIMS:

In lung cancer with anaplastic lymphoma kinase (ALK) gene rearrangement, accurate diagnosis is essential to identify patients who can be treated with a specific kinase inhibitor. Sensitive ALK immunostaining can provide nearly complete concordance with gene rearrangement status and is expected to serve as a surrogate biomarker for tailored treatment with an ALK inhibitor. In the present report, we describe aberrant ALK expression in a small proportion of pulmonary neuroendocrine carcinomas (NECs) that do not have ALK gene alteration.

METHODS:

A total of 227 pulmonary NECs were assembled on tissue microarrays and were subjected to highly sensitive ALK staining methods.

RESULTS:

We observed focal positivity with heterogeneous intensity in 2 (2.9%) of 69 small-cell carcinomas and 1 (0.9%) of 106 large-cell NECs. In contrast, 52 carcinoid tumours were all negative for ALK expression. Neither ALK rearrangement nor amplification was observed using fluorescence in situ hybridisation, and no somatic mutation was detected in three ALK positive NECs.

CONCLUSIONS:

Thus, this aberrant expression is probably of a wild-type ALK and a potential pitfall when implementing sensitive ALK immunohistochemistry in the molecular diagnosis of lung cancer.