In non-small cell lung cancer, epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have a major impact upon the level of response to treatment with specific tyrosine kinase inhibitors. This review describes the molecular basis of ALK inhibition, summarizes current data on the effectiveness and safety of ALK inhibition therapy, describes the different testing methodologies with their advantages and disadvantages, provides a suggested testing algorithm and puts forward a proposal for an external quality assessment program in ALK testing. Electronic supplementary material The online version of this article (doi:10.1007/s00428-012-1281-4) contains supplementary material, which is available to authorized users.

Rearrangements of the ROS1 gene occur in 1–2 % of non-small cell lung cancers (NSCLCs). Crizotinib, a highly effective inhibitor of ROS1 kinase activity, is now FDA-approved for the treatment of patients with advanced ROS1-positive NSCLC. Consequently, focus on ROS1 testing is growing. Most laboratories currently rely on fluorescence in situ hybridisation (FISH) assays using a dual-colour break-apart probe to detect ROS1 rearrangements. Given the rarity of these rearrangements in NSCLC, detection of elevated ROS1 protein levels by immunohistochemistry may provide cost-effective screening prior to confirmatory FISH testing. Non-in situ testing approaches also hold potential as stand-alone methods or complementary tests, including multiplex real-time PCR assays and next-generation sequencing (NGS) platforms which include commercial test kits covering a range of fusion genes. In order to ensure high-quality biomarker testing, appropriate tissue handling, adequate control materials and participation in external quality assessment programmes are essential, irrespective of the testing technique employed. ROS1 testing is often only considered after negative tests for EGFR mutation and ALK gene rearrangement, based on the assumption that these oncogenic driver events tend to be exclusive. However, as the use of ROS1 inhibitors becomes routine, accurate and timely detection of ROS1 gene rearrangements will be critical for the optimal treatment of patients with NSCLC. As NGS techniques are introduced into routine diagnostic practice, ROS1 fusion gene testing will be provided as part of the initial testing package.

Our results show that TNBC have higher i.t. VEGF levels compared with non-TNBC. Ongoing clinical trials will answer if therapy directed towards angiogenesis may be an alternative way to improve outcome in this poor prognosis group.

We present a series of 23 cases of a distinctive, hitherto poorly recognized low-grade adenocarcinoma, with several histologic features reminiscent of papillary carcinoma of the thyroid, and which mostly but not exclusively occurs in the tongue. All the tumors were unencapsulated and were divided into lobules that were composed mainly of cribriform and solid growth patterns. Therefore, we propose the name "cribriform adenocarcinoma of minor salivary gland origin (CAMSG)." All the patients were adults with a mean age at diagnosis of 55.8 years (range, 25 to 85 y). Fourteen of the 23 tumors were localized in the tongue, 3 in the soft palate, 2 in the retromolar buccal mucosa, 3 in the lingual tonsils, and 1 in the upper lip. Fifteen patients of 23 had synchronous metastases in the cervical lymph nodes at the time of diagnosis, bilateral in 3 cases. In 3 patients, the nodal metastasis was the first evidence of disease, later investigation revealing primary neoplasms in the base of tongue and tonsil, respectively. In addition, 1 patient developed a cervical lymph node metastasis 8 years after excision of a primary tumor of the tongue. Data on treatment and follow-up were available in 14 cases. The patients were treated by radical excision with clear margins (12 cases) or by simple excision (2 cases). Neck dissection was performed in 10 patients; 9 received radiotherapy, but none were treated by chemotherapy. Clinical follow-up ranged from 2 months to 13 years (mean, 6 y and 5 mo). Twelve patients are alive with no evidence of recurrent or metastatic disease after treatment, 1 patient died 2 years after surgery without evidence of tumor, and 1 patient is alive with recurrent tumor of the palate.

Napsin A is an aspartic proteinase expressed in lung and kidney. We have reported that napsin A is expressed in type II pneumocytes and in adenocarcinomas of the lung. The expression of napsin was examined in 118 lung tissues including 16 metastases by in situ hybridisation. Napsin was expressed in the tumour cell compartment in 33 of 39 adenocarcinomas (84.6%), in two of 11 large cell carcinomas and in one lung metastasis of a renal cell carcinoma. Expression of napsin was found to be associated with a high degree of differentiation in adenocarcinoma. Immunohistochemistry was performed for three proteins currently used as markers for lung adenocarcinoma : surfactant protein-A, surfactant protein-B and thyroid transcription factor-1. Thyroid transcription factor-1 showed the same sensitivity (84.6%) as napsin for adenocarcinoma, whereas surfactant protein-A and surfactant protein-B showed lower sensitivities. Among these markers, napsin showed the highest specificity (94.3%) for adenocarcinoma in nonsmall cell lung carcinoma. We conclude that napsin is a promising marker for the diagnosis of primary lung adenocarcinoma. Lung cancer is the leading cause of cancer mortality in the world and one of the top incidence of cancers in Europe and the US (Black et al, 1997;Wingo et al, 1999). Lung cancer has a poor prognosis and even for patients with operable disease, the 5-year survival rate is 14% in the US (Landis et al, 1998). Nonsmall cell lung cancer (NSCLC), essentially consisting of adenocarcinoma, squamous cell carcinoma (epidermoid carcinoma) and large cell carcinoma, accounts for approximately 80% of all lung cancers (Travis et al, 1995). The incidence of pulmonary adenocarcinoma has been increasing and adenocarcinoma is now the most common histologic subtype in the US (Charloux et al, 1997;Landis et al, 1998).The lung is also a common site for metastases from tumours growing at other sites. From a clinical point of view, it is important to distinguish between primary lung adenocarcinoma and metastatic adenocarcinoma in the lung since treatment protocols differ depending on the origin. Primary lung adenocarcinoma develops from type II pneumocytes and from bronchiolar nonciliated secretory cells (Clara cells). Surfactant apoproteins, including surfactant protein-A (Sp-A) and surfactant protein-B (Sp-B) are used as markers for lung adenocarcinoma and thyroid transcription factor-1 (TTF-1) is used as a marker for lung adenocarcinoma, large cell carcinoma, small cell carcinoma and thyroid carcinoma (Kaufmann and Dietel, 2000b).Recently, a new aspartic proteinase, napsin A, was cloned and shown to be expressed in lung and kidney (Tatnell et al, 1998). Our group and another group have shown that napsin A is identical to the protein spots TAO1/TAO2 detected by two-dimensional gel electrophoresis of lung adenocarcinoma, and that napsin A is expressed in type II pneumocytes and lung adenocarcinomas (Chuman et al, 1999;Hirano et al, 2000). However, the detailed expression patterns of napsin A in association with other m...