Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) ...chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003-2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as "NSCLC-t", comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; "NSCLC-pt", with pemetrexed treatment only; and "SCLC-t", consisting of etoposide chemotherapy.A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n
20) and SCLC-t in 38% (n
48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0-9.9) months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0-6.9) months (hazard ratio 2.51, 95% CI 1.39-4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0-8.5) months (hazard ratio 1.66, 95% CI 1.08-2.56; p=0.020).In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC-pt and SCLC-t chemotherapy.
Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these ...diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g., menin 1 gene MEN1), and few affect genes of the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto-oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.
Aims
Cutaneous metastases of internal malignancies occur in 1–10% of cancer patients. The diagnosis can sometimes be challenging, especially in cases with an unknown primary cancer.
Materials and ...methods
A retrospective case review was performed including all cases of skin metastases from primary internal malignancies diagnosed at the Department of Pathology at the Maastricht University Medical Centre+ from 2007 to 2021. The clinicopathological data were collected and immunohistochemical and molecular diagnostic tests were performed to confirm the primary origin of the metastases.
Results
We identified 152 cases (71 female; 31 male patients) of cutaneous metastases of internal malignancies. 28 patients (20 women and 8 men) were diagnosed with multiple cutaneous metastases. Among the female patients, the most common primary tumour was breast cancer (50% of the cases), followed by lung (13.6%), gynaecological (7.3%), and gastrointestinal origin (7.3%). Among the male patients, the most common primary sites were gastrointestinal and lung origin (altogether, 50% of the cases). In 19 patients, the cutaneous metastasis was the first presentation of a clinically silent internal malignancy (18.6%), of which most (78.9%) represented metastatic lung carcinomas. Finally, metastasizing patterns were different across tumour types and gender.
Conclusion
Breast, lung, gastrointestinal, and gynaecologic cancers are the most common primary tumours demonstrating skin metastases. Infrequently, cutaneous metastases can be the first clinically visual manifestation of an underlying not yet diagnosed internal malignancy; therefore, occasional broad immunohistochemical profiling, molecular clonal analysis, and a continuous high level of awareness are necessary for a precise diagnosis of cutaneous metastases of internal malignancies.
Background
Molecular tumor boards (MTBs) provide rational, genomics‐driven, patient‐tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and ...recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands.
Materials and Methods
MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision‐making method, reporting, and registration of the MTBs was completed through on‐site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy.
Results
Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type–specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%).
Conclusion
MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a “Dutch MTB model” for an optimal, collaborative, and nationally aligned MTB workflow.
Implications for Practice
Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing.
Worldwide, molecular tumor boards (MTBs) differ in terms of scope, composition, methods, and recommendations. This article assesses differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands.
Background
The prognostic reliability of the UICC's TNM classification (8th edition) for human papillomavirus (HPV)‐positive tonsillar squamous cell carcinomas (TSCCs) compared to the 7th edition was ...explored, and its improvement by using additional anatomical and nonanatomical parameters.
Methods
One hundred and ten HPV‐positive and 225 HPV‐negative TSCCs were retrospectively analyzed. Survival was correlated with patient and tumor characteristics (7th and 8th edition UICC TNM classification).
Results
In HPV‐positive TSCCs, the 8th edition UICC's TNM classification correlated better with prognosis than the 7th edition. Also, smoking status was a stronger prognosticator of survival than UICC staging. Non‐ or former smokers had a 5‐year overall survival of 95.1% regardless of tumor stage. Furthermore, age (>65 years), cN3, and M1 classification were significant prognostic factors.
Conclusion
The prognostic value of the 8th edition UICC's TNM classification improved significantly when compared to the 7th edition. Nonetheless, further improvement is possible by adding nonanatomical factors (smoking, age >65 year) and separating N0‐N2 from N3.
Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated ...OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi‐omics data (whole‐exome‐, whole‐genome‐, RNA sequencing and Epic 850K‐methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K‐methylation analysis was cross‐validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTPhigh vs OTPlow group, likelihood‐ratio test P = 1.5 × 10−2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (FDR < 0.05 and β‐value effect size > .2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (log‐rank test P = .0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels.
What's new?
Patients with pulmonary carcinoids that have low expression of the gene OTP (Orthopedia Homeobox) tend to have a worse prognosis. However, no mutations or genomic modifications have been found that explain the difference in OTP expression. Here, the authors analyzed DNA methylation data, and they found that changes in DNA methylation patterns were associated with the difference in OTP expression levels. These findings may suggest a role for epigenetic therapies in pulmonary carcinoid patients in the future.
Background
The goal of this review was to present an overview of the currently identified molecular parameters in head and neck squamous cell carcinoma (HNSCC) of nonsmokers and nondrinkers (NSND).
...Methods
Following the PRISMA guidelines, a systematic search was performed using the electronic databases PubMed, Embase, and Google Scholar.
Results
Of the 902 analyzed unique studies, 74 were included in a quantitative synthesis and 24 in a meta‐analysis. Human papillomavirus (HPV) was reported as a molecular parameter in 38 studies, followed by p16 and TP53 (23 and 14 studies, respectively). The variety of other molecular parameters concerned sporadic findings in small numbers of NSND.
Conclusions
HNSCC in NSND is more often related to HPV and p16 overexpression compared to tumors of smokers‐drinkers. In a third of virus‐negative tumors, TP53 mutations were detected with a mutational profile associated with aging and ultraviolet light exposure rather than to tobacco consumption.
Different studies have shown that HPV16‐positive OPSCC can be subdivided based on integration status (integrated, episomal and mixed forms). Because we showed that integration neither affects the ...levels of viral genes, nor those of virally disrupted human genes, a genome‐wide screen was performed to identify human genes which expression is influenced by viral integration and have clinical relevance. Thirty‐three fresh‐frozen HPV‐16 positive OPSCC samples with known integration status were analyzed by mRNA expression profiling. Among the genes of interest, Aldo‐keto‐reductases 1C1 and 1C3 (AKR1C1, AKR1C3) were upregulated in tumors with viral integration. Additionally, 141 OPSCC, including 48 HPV‐positive cases, were used to validate protein expression by immunohistochemistry. Results were correlated with clinical and histopathological data. Non‐hierarchical clustering resulted in two main groups differing in mRNA expression patterns, which interestingly corresponded with viral integration status. In OPSCC with integrated viral DNA, often metabolic pathways were deregulated with frequent upregulation of AKR1C1 and AKR1C3 transcripts. Survival analysis of 141 additionally immunostained OPSCC showed unfavorable survival rates for tumors with upregulation of AKR1C1 or AKR1C3 (both p <0.0001), both in HPV‐positive (p ≤0.001) and ‐negative (p ≤0.017) tumors. OPSCC with integrated HPV16 show upregulation of AKR1C1 and AKR1C3 expression, which strongly correlates with poor survival rates. Also in HPV‐negative tumors, upregulation of these proteins correlates with unfavorable outcome. Deregulated AKR1C expression has also been observed in other tumors, making these genes promising candidates to indicate prognosis. In addition, the availability of inhibitors of these gene products may be utilized for drug treatment.
What's new?
Oropharyngeal squamous cell carcinoma (OPSCC) is often associated with high‐risk human papillomavirus infection, especially HPV16, but the clinical relevance of viral integration in a subset of these tumors remains unclear. Here the authors describe transcriptional signatures of metabolic reprogramming including increased expression of the aldo‐keto‐reductases AKR1C1 and AKR1C3 proteins in OPSCC cells regardless of HPV status. Tumors with upregulation of these proteins were strongly associated with poor prognosis suggesting prognostic as well as therapeutic implications for OPSCC patients beyond HPV16 infection.
Aims
Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic ...sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20–30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets.
Methods and results
In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non‐EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation‐negative IMTs mutations or fusions – as yet unreported in primary IMT – were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease mean survival 8 months (4–15 months), whereas only one of 14 classical IMT patients succumbed to disease mean follow‐up time 52 months (2–204 months); P < 0.01.
Conclusion
This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.
Twenty primary abdominal inflammatory myofibroblastic tumours, including four epithelioid inflammatory myofibroblastic sarcomas, were analysed showing mostly kinase fusions, including a novel RRBP1::ALK fusion and FGFR1 translocation. In kinase fusion‐negative IMTs, we expand the molecular profile to genes related to the RTK/PI3K/AKT pathway, rendering further opportunities for targeted therapy.
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