BACKGROUND: Pulmonary mucoepidermoid carcinoma (PMEC) is a rare lung malignancy, especially in combination with ALK mutations, whose clinical presentation lacks specificity and for which there are no standardized treatment guidelines.
METHODS: We report a case of a patient with PMEC-predominant primary lung cancer combined with an ALK mutation.
METHODS: One patient was diagnosed with PMEC combined with ALK mutation.
METHODS: After diagnosis by puncture pathology, the patient was treated with oral targeted drugs.
RESULTS: The patient\'s cough and fever were controlled, her diet improved significantly, and she gained 20 pounds in 6 months. During this period, the primary and metastatic foci in the lungs were significantly reduced on repeat chest CT.
CONCLUSIONS: PMEC combined with ALK mutation is an extremely rare primary lung cancer, and the diagnosis is mainly based on pathology, histology and immunohistochemistry. The application of molecularly targeted drugs to patients with mutations can significantly improve the prognosis of patients with PMEC, which is expected to be a new breakthrough in the treatment of PMEC.

BACKGROUND: Screening for anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) is crucial for identifying patients eligible for targeted therapy. The FDA-approved ALK (D5F3) immunohistochemistry (IHC) assay, used with the OptiView Amplification Kit, demonstrates excellent sensitivity and specificity in detecting these patients. However, the clinical significance of resulting focal positivity remains unclear, and ALK (D5F3) expression unrelated to ALK fusion is observed in some cases of neuroendocrine differentiation. This study aims to validate these findings with molecular testing and contribute to the accurate interpretation of ALK (D5F3) IHC results.
METHODS: A total of 1619 patients diagnosed with NSCLC and neuroendocrine carcinoma were evaluated using ALK (D5F3) IHC. For cases with strong but focal expression and those with diffuse strong positivity in neuroendocrine differentiation, ALK fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) tests were performed.
RESULTS: Seven out of 1109 adenocarcinomas (0.6%) and six out of 289 squamous cell carcinomas (2.1%) exhibited strong focal ALK (D5F3) expression. Nine out of 209 neuroendocrine carcinomas (4.3%) showed homogeneously strong ALK (D5F3) expression. All these cases, including adenocarcinoma with neuroendocrine differentiation and combined small cell carcinoma, were negative for ALK fusions by FISH and/or NGS.
CONCLUSIONS: This study demonstrates that strong but focal ALK (D5F3) immunostaining and strong expression in neuroendocrine differentiation may not indicate ALK fusion. By considering these findings, we can improve the accuracy of patient selection for targeted therapy by minimizing false-positive interpretations of ALK (D5F3) staining.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare and highly aggressive lymphoma with characteristic ALK rearrangements. Various fusion genes involving ALK have been demonstrated, but the influence of the ALK fusion partners on ALK protein expression and the genetic characteristics of ALK+ LBCL remain relatively unknown. In this study, we conducted an extensive clinicopathological and molecular analysis on seven cases of ALK+ LBCL to explore the correlation between ALK fusion genes and ALK protein expression, thereby enriching the genetic characteristics of this tumour. We integrated the findings from clinical, histopathological/immunophenotypic, and molecular studies, including three samples subjected to next-generation sequencing, and six cases underwent RNA-based ALK fusion gene detection. We identified five distinct types of ALK fusion genes, including CLTC, NPM1, PABPC1, SEC31A, and TFG. Notably, only the NPM1::ALK fusion showed nuclear and cytoplasmic ALK staining, and the remaining four fusion genes resulted in cytoplasmic ALK staining. Our analysis revealed that the CLTC::ALK fusion resulted in a unique cytoplasmic perinuclear Golgi zone focal granular heterogeneous staining pattern of ALK. Additionally, we identified six potentially clinically significant gene mutations, including TET2, CHD2, DTX1, KMT2D, LRP1B, and XPO1. Furthermore, in all cases, the absence of 5-hydroxymethylcytosine (5hmC) was observed. We present seven cases of ALK+ LBCL, discussing the correlation between fusion genes and ALK protein expression, and enhancing our understanding of the genetic attributes of this tumour. This study also shows the loss of 5hmC in nearly all seven ALK+ LBCL cases, independently of TET2 mutations.

BACKGROUND: Distant metastases from lung cancer are commonly found in the brain, bone, and liver. Metastases to the breast from non-mammary malignancies are extremely rare, and their clinical presentations remain unclear.
METHODS: We herein report a case of bilateral breast metastases from anaplastic lymphoma kinase-positive advanced lung cancer in a 51-year-old Japanese male patient. During the course of systemic treatment for advanced lung cancer, computed tomography revealed bilateral breast enlargement without contrast enhancement, a finding consistent with gynecomastia. While other metastatic lesions responded to chemotherapy, both breast masses grew vertically like nodules. The breast masses were immunohistochemically diagnosed as metastases from lung cancer and were removed surgically. Simultaneous bilateral breast metastases from malignancies of other organs, like ones in this case, have rarely been described.
CONCLUSIONS: It is important to keep in mind that breast metastases from nonmammary malignancies are a possible explanation for unusual breast findings in a patient with a history of malignancies.

OBJECTIVE: Patients with metastatic or advanced non-small cell lung cancer (NSCLC) need biomarker testing, including, in most cases, anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and PD-L1, to identify options for targeted therapies and to optimally incorporate immune checkpoint inhibitors into therapeutic regimens. We sought to examine real-world patterns of biomarker testing, quantify interphysician practice variation, and correlate testing with clinical outcomes.
METHODS: We extracted real-world data from a nationwide electronic health record-derived deidentified database from 17,165 patients diagnosed with advanced NSCLC between 2018 and 2021 and receiving care in the community setting. We analyzed data using descriptive analyses, fixed- and mixed-effects logistic regression models, and proportional hazard models.
RESULTS: Only 67% of all 17,165 patients and 77% of patients with nonsquamous, metastatic NSCLC had ALK, EGFR, and PD-L1 testing within 90 days of diagnosis. Later diagnosis year (2019-2021 compared with 2018) was associated with higher rates of ALK, EGFR, and PD-L1 testing; stage IIIB/C disease (compared with stage IV), squamous histology, and Black or African American race were associated with lower rates. Interphysician variation was substantial with a median odds ratio between physicians (adjusted for patient factors) of 1.78 for ALK, EGFR, and PD-L1 testing. Patients with nonsquamous, metastatic NSCLC had significantly prolonged survival if tested with all three biomarkers (median, 364 days for all three v 180 for none of the three; hazard ratio, 0.67; P < .001).
CONCLUSIONS: Rates of biomarker testing appear suboptimal with substantial interphysician variation. Testing correlates with improved survival, although causality cannot be proven from this study. Additional work is needed to address the underlying causes of suboptimal test ordering.

A 57-year-old male underwent an open right radical nephrectomy in 2015 for a 3-cm kidney tumor which was classified at the time as a combined tubulocystic and collecting duct carcinoma. One of six nodes was positive for metastatic carcinoma and the patient received adjuvant carboplatin/gemcitabine chemotherapy. In 2020, he developed enlarging retroperitoneal adenopathy and underwent a retroperitoneal lymph node dissection with 11 of 13 nodes in the resected specimen positive for the previously described renal carcinoma, followed by adjuvant radiotherapy. In November 2022, he again underwent surgery for further locoregional recurrence with resection of a right psoas mass lesion and right hemicolectomy. Pathology on this occasion was reclassified as anaplastic lymphoma kinase-rearranged renal cell carcinoma (ALK-RCC). Shortly afterward, a restaging CT revealed multiple liver metastases and evidence of further disease recurrence in the right renal bed. He commenced alectinib with a complete radiological response and has continued on it for 12 months at the time of writing this report. To our knowledge, there are only five prior reports of ALK-RCC treated with targeted ALK inhibitor therapy in the literature. We report this case to highlight the importance of recognizing and diagnosing this rare RCC subtype since it has significant therapeutic implications. Furthermore, to our knowledge, this patient has had the longest follow-up reported to date in the literature so far. A concerted effort by the histopathology and oncology community is needed to gather more data on the incidence and treatment outcomes of these tumors so that progress can be made in optimizing their management. It is important to consider novel and emerging entities from the most recent WHO 2022 classification, many of which are defined by molecular characteristics with associated therapeutic implications.

Anaplastic lymphoma kinase (ALK) is detected in both normal and oncological developmental tissues. Among ALK-related tumors, superficial ALK-rearranged myxoid spindle cell neoplasm (SAMS) is a rare, soft tissue tumor characterized by the immunophenotypical co-expression of CD34 and S100. Here, we describe a patient with this rare tumor and outline its clinical and radiological characteristics. A 28-year-old woman with diabetes, hypertension, and panic disorder presented with discomfort caused by a rubbery mass on the left buttock that had persisted for 10 years. Computed tomography revealed a multilobulated hypodense mass with small internal enhancing foci, posing challenges for the exact diagnosis of the lesion. The entire lesion was excised with clear resection margins. An 8.0 × 6.0 cm, well-circumscribed tumor with a lobular growth pattern was observed in the deep subcutaneous tissue. Light microscopy revealed epithelioid, ovoid, and spindle-shaped cells with a reticular cordlike pattern. Immunohistochemistry results were positive for S100, CD34, and vimentin. Break-apart fluorescence in situ hybridization assay results for ALK were also positive. These findings were consistent with those of SAMS. This case suggests that SAMS should be considered when identifying large nonspecific masses during clinical and imaging evaluation.

BACKGROUND: With multiple targeted therapies approved for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), it is increasingly important to understand outcomes with various sequences of next-generation ALK tyrosine kinase inhibitors (TKIs). We describe contemporary sequencing patterns and treatment effectiveness of first-line (1L) and second-line (2L) treatments in patients who received second-generation ALK TKIs in the 1L treatment of ALK-positive NSCLC in the United States.
METHODS: A cohort of adults with ALK-positive advanced NSCLC who initiated treatment with 1L alectinib or brigatinib between June 2017 and April 2021 in the Flatiron Health electronic health record-derived de-identified database were followed through April 2023. Time to treatment discontinuation (TTD) in 1L and 2L, TTD on 1L plus 2L sequential therapy (TTD2), and total time on sequential ALK TKI therapy (including beyond 2L) were evaluated.
RESULTS: Patients (N=273) were followed up for a median duration of 28.9 months. Among patients who discontinued 1L therapy, 22% died after 1L discontinuation (median time from discontinuation to death, 4.0 months) without receiving 2L therapy. Median (95% confidence interval [CI]) TTD was 21.9 (15.2-25.8) and 7.3 (5.3-10.2) months in 1L and 2L, respectively. Median (95% CI) TTD2 was 29.4 (25.1-36.1) months and total time on sequential ALK TKI treatment was 28.0 (23.6-32.9) months.
CONCLUSIONS: In this large real-world study, TTD2 and the total time on sequential ALK TKIs was approximately 2.5 years. The high attrition rate from 1L to 2L and the longest clinical benefit observed with 1L therapy support using the drug with the longest 1L effectiveness up front in patients with ALK-positive advanced NSCLC.

BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients.
METHODS: A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease.
CONCLUSIONS: This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer.

UNASSIGNED: Anaplastic lymphoma kinase (ALK) gene-rearrangements are identified in about 3-5% of non-small cell lung cancers (NSCLC), and ALK-rearranged NSCLC is to be considered an oncogene-addicted cancer with peculiar clinical characteristics.
UNASSIGNED: Several ALK inhibitors have been studied and approved for use in the treatment of advanced ALK-rearranged NSCLC with reported superiority in terms of efficacy and safety profile compared with chemotherapy. Second- and third-generation ALK inhibitors (alectinib, brigatinib, and lorlatinib) offer to NSCLC patients a clinically meaningful prolongment of survival with a very good quality of life profile. However, resistances to these agents always occur, with less satisfying options for second-line treatments. Direct comparisons among these agents are not available, and the choice among brigatinib, alectinib, and lorlatinib as first-line treatment remains challenging. Very recently, alectinib has been demonstrated to improve efficacy outcomes compared with chemotherapy also in resected stage IB-IIIA ALK-rearranged NSCLC, extending the clinical benefit offered by ALK inhibitors also to the adjuvant setting.
UNASSIGNED: Future development of ALK inhibitors in NSCLC treatment includes the search for optimal management of acquired resistance to first-line treatments and the extension of use of ALK inhibitors also to neoadjuvant and preferably to perioperative setting.