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Joshua K. Sabari, John V. Heymach, and Beth Sandy

An understanding of the biology of uncommon epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) is evolving. These mutations are important for the selection of targeted therapy and the development of resistance. The advent of genomic profiling has led to guideline-recommended molecular testing to identify patients with NSCLC who carry uncommon EGFR mutations to aid in the selection of appropriate targeted therapy. This article discusses the efficacy and safety of current and emerging targeted therapies for the treatment of uncommon EGFR mutations in NSCLC to aid in developing patient-specific treatment plans.

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Lirong Liu, Fangfang Hou, Yufeng Liu, Wenzhu Li, and Haibo Zhang

More than 20 types of ALK fusion variant subtypes have been identified, including different fusion partner genes or EML4-ALK fusions with different breakpoints. However, different ALK fusions show different sensitivities to ALK-tyrosine kinase inhibitors (ALK-TKIs) and the emergence of rare fusions brings great challenges to the target therapy in clinic. We report a rare EML4-ALK (E6;A18) fusion in a patient with lung adenocarcinoma that responded well to alectinib. This is the second case of this rare variant reported but the first report of response to an ALK-TKI. This evidence is the first to show that alectinib may be effective for this rare fusion type of non–small cell lung cancer, and these findings have important implications for drug selection in patients with this subtype. Further studies are needed to understand the function of this variant.

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Karen L. Rech and Rong He

Histiocytic neoplasms, including Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), present a diagnostic challenge due to nonspecific fibroinflammatory infiltrates and a diverse clinical presentation. The pathologist can play a key role in classification of these disorders through multidisciplinary collaboration and correlation of pathologic features with clinical and radiologic findings. The histopathologic differential diagnosis is broad, requiring knowledge of the possible diagnoses at each specific anatomic site, and a careful assessment to exclude other inflammatory and neoplastic disorders. An immunohistochemistry panel including CD163, CD1a, langerin, S100, Factor XIIIa, OCT2, and BRAF V600E can provide definitive diagnosis in LCH and RDD, whereas ECD requires classic clinical features as well as confirmation of an activating MAPK pathway mutation by genetic studies.

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Presenter: Matthew J. Matasar

Despite a growing therapeutic arsenal to treat relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), outcomes remain poor. Only approximately half of patients with this disease are eligible to receive curative autologous stem cell transplant, and of those, only half will be cured. Moreover, for patients who are transplant-ineligible, there are few effective options. Dr. Matthew J. Matasar discussed the current unmet needs in the treatment of patients with R/R DLBCL, treatment strategies in the second- and third-line settings, and emerging therapeutic options.

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Michael A. Cilento, Nicola K. Poplawski, Sellvakumaram Paramasivam, David M. Thomas, and Ganessan Kichenadasse

PARP inhibitors are orally administered antineoplastic agents that affect the homologous recombination (HR) repair pathway, and are approved by the FDA for the treatment of ovarian, breast, pancreatic, and prostate cancers. This report presents a case of recurrent endometrial carcinoma occurring in a woman with a germline pathogenic PALB2 whole-exon deletion. This uncommon finding in a patient with endometrial carcinoma provided the opportunity to use a management strategy of PARP inhibition with olaparib, resulting in a prolonged response to treatment; however, disease progression eventually occurred. Further studies are required to elucidate the mechanisms underlying resistance to PARP inhibition, and the potential future treatment options in this setting. Current recommendations for risk management of female carriers of PALB2 variants focus on breast and ovarian cancer risk. This case raises the additional question of a potential role for risk-reducing hysterectomy in female carriers of PALB2 variants.