ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma

Popat, Sanjay; González, David; Min, Toon; Swansbury, John; Dainton, Melissa; Croud, James; Rice, Alexandra; Nicholson, Andrew G.

doi:10.1016/j.lungcan.2011.07.017

Cited by 48 publications

(33 citation statements)

References 18 publications

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“…With these procedures in place, a suggested strategy could involve screening of all non-squamous lung tumors with ALK immunohistochemistry. Positive immunohistochemistry cases, or negative cases with clinicopathologic features indicative of higher pre-test likelihood of ALK rearrangement, for example, patients who have never smoked with advanced NSCLC of adenocarcinoma histology and EGFR and KRAS wild type (36% of this enriched population are reported to be ALK rearrangement positive 33 ), or signet ring or mucinous histologic features, 19,29,47,48 could be evaluated using ALK FISH. The use of these integrated rigorous molecular screening methodologies may enable accurate, efficient and cost-effective identification of lung cancer patients likely to benefit from targeted anti-ALK therapies.…”

Section: Discussionmentioning

confidence: 99%

Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization

et al. 2013

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Rearrangements of anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) define a molecular subgroup of tumors characterized clinically by sensitivity to ALK tyrosine kinase inhibitors such as crizotinib. Although ALK rearrangements may be detected by reverse transcriptase-PCR, immunohistochemistry or fluorescence in situ hybridization (FISH), the optimal clinical strategy for identifying ALK rearrangements in clinical samples remains to be determined. We evaluated immunohistochemistry using three different antibodies (ALK1, 5A4 and D5F3 clones) to detect ALK rearrangements and compared those with FISH. We report the frequency and clinicopathologic features of lung cancers harboring ALK translocations in 594 resected NSCLCs (470 adenocarcinomas; 83 squamous carcinomas, 26 large cell carcinomas and 15 other histological subtypes) using a tissue microarray approach. We identified an ALK gene rearrangement in 7/594 cases (1%) by FISH and all anti-ALK antibodies correctly identified the seven ALK-positive cases (100% sensitivity), although the intensity of staining was weak in some cases. These data indicate that the use of antibodies with high sensitivity and avidity to ALK may provide an effective pre-screening technique to complement the more expensive and labor-intensive approach of ALK FISH testing.

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Section: Discussionmentioning

confidence: 99%

Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization

et al. 2013

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“…Despite some level of morphologic similarity, SRCA do not show a biologic link to ALK gene rearranged lung adenocarcinomas with signet ring features [22,23], MASC [8] or soft tissue type myoepitheliomas [6]. Of note, one case of a parotid myoepithelial carcinoma harboring the ALK gene rearrangement was presented in the 2012 College of American Pathologists (CAP) annual meeting [24].…”

Section: Discussionmentioning

confidence: 99%

Secretory Myoepithelial Carcinoma: A Histologic and Molecular Survey and a Proposed Nomenclature for Mucin Producing Signet Ring Tumors

Bastaki

Purgina

Đačić

et al. 2014

Head and Neck Pathol

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Signet ring cell (mucin producing) adenocarcinoma is a rare low grade salivary gland malignancy. While currently designated as an adenocarcinoma, myoepithelial differentiation has been implied in previously reported cases. We herein perform a survey of our cases of signet ring cell adenocarcinoma and review the literature in order to refine categorization of this rare tumor. Five cases were retrieved. One was reclassified as a mammary analogue secretory carcinoma, leaving four that fulfilled the criteria for signet ring cell adenocarcinoma: the presence of prominent signet ring or vacuolated cells arranged in islands, interconnecting strands, cords or sheets in a myxoid or hyaline stroma, or pools of mucin. An extensive panel of histochemical and immunohistochemical stains and fluorescence in situ hybridization (FISH) (modeled after common phenotypes and molecular alterations seen in signet ring and myoepithelial tumors at other sites) was performed. The male-to-female ratio was 3:1. The mean age was 56 years (range 18-81). Sites involved included buccal mucosa (2), soft palate (1) and deep parotid (1). Perineural and angiolymphatic invasion were present in three and two cases respectively. One patient was lost to follow up and the remainder were alive and without disease at time of last follow up (mean 38 months). All cases showed mucicarmine positive vacuolated/signet ring cells embedded in a myxoid stroma. Three cases showed at least focal p63 staining and two cases showed positivity for calponin. Membranous E-cadherin was retained in all cases. FISH was negative for ETV6, EWSR1, and ALK1 rearrangements in all four cases. Based on the current series and the previously reported cases, it is evident that signet ring adenocarcinomas have a dual secretory and myoepithelial phenotype and thus as a whole more appropriately designated as 'secretory myoepithelial carcinoma.' They behave in a fairly indolent fashion and do not share the major molecular alterations seen in other signet ring and myoepithelial tumor types.

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“…In addition, studies directly comparing alternative tests such as IHC with FISH are ongoing, [7][8] including at my own institution (unpublished observation). The outcomes of these comparisons and the clinical data from the phase II trial need to be collected and carefully evaluated, perhaps in an independent registry.…”

Section: Discussionmentioning

confidence: 99%

Treating Anaplastic Lymphoma Kinase–Positive Lung Cancer in the Weeks After the US Food and Drug Administration Approval of Crizotinib

Pennell¹

2012

JOP

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On August 26, 2011 the US Food and Drug Administration (FDA) approved the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor crizotinib (Pfizer; New York, NY) for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with translocations of the ALK gene as determined by an FDA-approved companion genetic test. 1 The approval was based on a high response rate in 255 patients with ALK-positive NSCLC treated with the drug as part of two early-phase trials. [2][3] This is the first new FDA-approved drug for advanced NSCLC in the last 5 years, to our knowledge, and there is much enthusiasm about the approval among patients and practitioners.As an oncologist specializing in the treatment of patients with lung cancer, I had suspected that crizotinib would be approved sometime in 2011. However, I also worried that there would be growing pains in prescribing this new (and expensive) drug for a small, genetically defined subpopulation. When a new drug is approved, the pharmaceutical company usually does not yet have mass production up and running and starts out with a limited supply produced for research purposes. For crizotinib the drug was initially made available only through three specialty mail-order pharmacies. In addition, insurance companies need time to develop policies for coverage of crizotinib in a molecularly defined (ALK-positive) patient population. As it turns out, all of my concerns would come to life in the form of three young men in just the first couple of weeks after the approval. One Story of FrustrationThe first patient was a 35-year-old male neversmoker who was referred in mid-August 2011 after his local oncologist discovered that his tumor was ALK positive. My institution had been participating in the phase II clinical trial of crizotinib in patients with ALK-positive NSCLC, and we had several patients on this trial-some referred from many hours away. This patient was quite symptomatic, with a cough and increasing shortness of breath, having rapidly progressed through first-line chemotherapy. In this setting, second-line chemotherapy has only a small chance of helping, and patients with ALK-positive disease tend not to respond to erlotinib, the only other approved second-line drug. 4 Fortunately, we had an alternative.There was an issue with his enrollment when his tumor tissue came back negative for the ALK translocation by the company's central laboratory. The trial was originally designed to only enroll patients who were confirmed to have ALK-positive disease by the central laboratory, which was using the companion diagnostic test eventually submitted and approved by the FDA (Vysis ALK Break Apart Fluorescent In Situ Hybridization [FISH] Probe Kit; Abbott Molecular, Des Plaines, IL). However, there are several different ways to test for ALK positivity: immunohistochemistry (IHC), which detects expression of the fusion protein; reverse transcriptase polymerase chain reaction, which identifies the fusion gene transcript with high sensitivity; and break apart FISH, which...

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ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma

Cited by 48 publications

References 18 publications

Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization

Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization

Secretory Myoepithelial Carcinoma: A Histologic and Molecular Survey and a Proposed Nomenclature for Mucin Producing Signet Ring Tumors

Treating Anaplastic Lymphoma Kinase–Positive Lung Cancer in the Weeks After the US Food and Drug Administration Approval of Crizotinib

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