Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia.

Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis.

Evaluation of Pharyngeal Background Mucosa in Patients with Superficial Hypopharyngeal Carcinoma.

OBJECTIVES/HYPOTHESIS: Transoral surgery (TOS) has become increasingly popular for patients with superficial hypopharyngeal squamous cell carcinoma (SCC). However, the number of patients in whom metachronous multiple SCC of the head and neck (HNSCC) occurs has also increased. In this study, we investigated whether multiple lugol-voiding lesions (LVLs) in the pharyngeal background mucosa observed during TOS would be a biomarker of metachronous HNSCC. STUDY DESIGN: Retrospective study. METHODS: We examined 362 patients who underwent TOS for superficial hypopharyngeal carcinoma. Endoscopic images were reviewed in a blinded fashion by two endoscopists. LVLs in the pharyngeal mucosa were graded as follows: A, no lesions; B, 1 to 4 lesions; and C, ≥5 lesions per endoscopic view. RESULTS: Cumulative incidence curves of secondary HNSCC in the groups of grades A, B, and C revealed 3-year incidence rates of 14.4%, 18.8%, and 29.3%, respectively (P = .001 for A vs. C and P = .002 for B vs. C). Cumulative incidence curves of third HNSCC in the groups of grades A, B. and C revealed 5-year incidence rates of 3.9%, 9.8%, and 19.6%, respectively (P = .001 for A vs. C and P = .006 for B vs. C). Cumulative incidence curves of fourth HNSCC in the groups of grades A, B, and C revealed 7-year incidence rates of 0%, 2.3%, and 13.2%, respectively (P = .025 for A vs. C and P = .009 for B vs. C). CONCLUSIONS: Multiple LVLs in the pharyngeal mucosa increase the risk of development of metachronous multiple HNSCC. LEVEL OF EVIDENCE: 3 (nonrandomized, controlled cohort/follow-up study) Laryngoscope, 131:2036-2040, 2021.

Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016.

Importance: To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs). Objective: To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs. Design, Setting, and Participants: Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020. Exposures: Receipt of immunotherapy or other anticancer agents. Main Outcomes and Measures: The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs. Results: Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population. Conclusions and Relevance: In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.

Patterns of Prior and Subsequent Neoplasms in Children and Adolescents With Soft Tissue Sarcomas.

BACKGROUND: The occurrence of prior, concurrent and subsequent neoplasms (SN) represents a serious problem in children and adolescents with soft tissue sarcomas. Pathogenic germline variants contribute to the diagnosis of multiple neoplasms in sarcoma survivors. MATERIALS AND METHODS: The records of 748 children and adolescents, diagnosed with soft tissue sarcomas and registered in trials/registries by the cooperative soft tissue sarcoma (Cooperative Weichteilsarkom Studie) group, were reviewed for the occurrence of SNs. Reference histology review was available for all cases; the presence of oncogenic fusions known at the time of diagnosis was confirmed for fusion-positive (F+) entities. RESULTS: Concurrent or subsequent SNs developed in 13 of 473 survivors of fusion-negative (F-) sarcomas, for an 8-year cumulative SN incidence of 5% in survivors of F- sarcomas. In contrast, only 1 of 278 survivors of F+ sarcoma developed an SN. Twenty of 748 patients with soft tissue sarcomas had a history of prior neoplasms. Six of 14 patients who developed SNs after their index sarcomas met Chompret criteria for Li-Fraumeni syndrome. Nine of 20 patients who had tumors before their index sarcoma diagnosis had neurofibromatosis type 1 or neurofibromatosis type 1 spectrum tumors. CONCLUSION: Sarcoma phenotype/genotype and the sequence and nature of prior and subsequent neoplasms provide a window into underlying germline genetic susceptibilities in children and adolescents with soft tissue sarcomas.

Risk and subtypes of secondary primary malignancies in diffuse large B-cell lymphoma survivors change over time based on stage at diagnosis.

BACKGROUND: Previous studies have shown an increased risk of secondary primary malignancies (SPMs) after diffuse large B-cell lymphoma (DLBCL) treatment. Whether stage of DLBCL at diagnosis affects the subtypes of SPMs that occur has not been previously described. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients aged >18 years diagnosed with primary DLBCL from 1973 to 2010 and categorized by early stage (ES) (stage I-II) or advanced stage (AS) (stage III-IV) disease. Differences in overall and location-specific SPM incidence by stage and time since diagnosis were assessed in 5-year intervals using a Fine-Gray hazards model. Overall survival was compared using the log-rank test. A Cox proportional hazards model was used to assess differences in survival. RESULTS: In total, 26,038 patients with DLBCL were identified, including 14,724 with ES and 11,314 with AS disease. The median follow-up was 13.3 years. Overall, 13.0% of patients developed SPM, with a higher but nonsignificantly increased risk of SPM development in those who had ES disease compared with those who had AS disease (14% vs 11.6%; P = .14). During the first 5 years after diagnosis, patients who had ES disease had a higher risk of SPM than those who had AS disease, specifically colorectal, pancreas, breast, and prostate SPMs. During the period from 10 to 15 years after diagnosis, patients who had AS disease had a higher risk of SPM than those who had ES disease, specifically hematologic SPMs. Development of SPM was found to significantly increase the risk of death regardless of stage at diagnosis. CONCLUSIONS: In this large, population-based study, distinctly different subtypes and temporal patterns of SPM development were identified based on stage of DLBCL at diagnosis. The current study merits consideration of tailored site-specific and time-specific surveillance for patients with DLBCL according to stage and time interval since diagnosis.

Impact of age at diagnosis of head and neck cancer on incidence of metachronous cancer.

BACKGROUND: Metachronous cancer in patients with head and neck cancer (HNC) is common and is associated with a poor prognosis. We aimed to evaluate the incidence of metachronous cancer at different sites according to age at diagnosis of index HNC. METHODS: We collected data on 2011 patients with oral cancer, oropharynx cancer, hypopharyngeal cancer, and laryngeal cancer as index cancers using the Osaka International Cancer Institute Cancer Registry database between 2005 and 2016. Among these, we analyzed 1953 patients after excluding 5 patients who were not followed-up and 53 patients with simultaneous multiple index cancers. We evaluated the cumulative incidence of metachronous cancer in the esophagus, lung, and other sites according to age at diagnosis of the index HNC using the Kaplan-Meier method. Multivariate logistic regression analysis was performed to identify factors that influenced the incidence of metachronous cancers following HNC. RESULTS: The cumulative incidence of metachronous esophageal cancer in young patients (< 65 years) was significantly higher than that in old patients (≥ 65 years) (12.1% vs 8.5% at 5 years, and 16.5% vs 11.2% at 10 years; p = 0.015). On the other hand, the cumulative incidence of the other cancers in young patients was significantly lower than that in old patients (7.8% vs 12.2% at 5 years, and 13.9% vs 15.3% at 10 years; p = 0.017). The cumulative incidence of lung cancer was not significance according to age at diagnosis of the index HNC. In the multivariate analysis, histological type (squamous cell carcinoma) and lesion location (hypopharynx and larynx) were independently associated with metachronous cancers. Moreover, age at diagnosis of the index HNC (< 65 years), histological type (squamous cell carcinoma) and lesion location (hypopharynx) were significant predictors of metachronous esophageal cancer incidence and lesion location (hypopharynx) was a significant predictor of metachronous lung cancer incidence. CONCLUSION: Risk stratification of metachronous cancers with age and other predictors may help to properly manage patients with HNC. TRIAL REGISTRATION: The present study is a non-intervention trial.

Post-radiation sarcoma: A study by the Eastern Asian Musculoskeletal Oncology Group.

The oncologic risk of ionizing radiation is widely known. Sarcomas developing after radiotherapy have been reported, and they are a growing problem because rapid advancements in cancer management and screening have increased the number of long-term survivors. Although many patients have undergone radiation treatment in Asian countries, scarce reports on post-radiation sarcomas (PRSs) have been published. We investigated the feature and prognostic factors of PRSs in an Asian population. The Eastern Asian Musculoskeletal Oncology Group participated in this project. Cases obtained from 10 centers were retrospectively reviewed. Patients with genetic malignancy predisposition syndrome, or who had more than one type of malignancy before the development of secondary sarcoma were excluded. Forty-two high-grade sarcomas among a total of 43 PRSs were analyzed. There were 29 females and 13 males, with a median age of 58.5 years; 23 patients had bone tumors and 19 had soft tissue tumors. The most common primary lesion was breast cancer. The median latency period was 192 months. There were no differences in radiation dose, latency time, and survival rates between bone and soft tissue PRSs. The most common site and diagnosis were the pelvic area and osteosarcoma and malignant fibrous histiocytoma for bone and soft tissue PRSs. The median follow-up period was 25.5 months. Five-year metastasis-free and overall survival rates were 14.5% and 16.6%, and 39.1% and 49.6% for bone and soft tissue PRSs. Survival differences depending on initial metastasis and surgery were significant in soft tissue sarcomas. Although this study failed to find ethnic differences, it is the largest review on PRS in an Asian population. As early recognition through long-term surveillance is a key to optimal management, clinicians should take efforts to understand the real status of PRS.

Prostate cancer survivors: Risk and mortality in second primary cancers.

To assess etiological and clinical consequences of second primary cancers (SPCs) in prostate cancer (PC) patients, we followed newly diagnosed patients to identify men who were diagnosed with a SPC and recorded their causes of death. We used the Swedish Family-Cancer Database to assess relative risks (RRs) and causes of death in SPCs until the year 2015 in patients with a PC diagnosis between 2001 and 2010. Among a total of 4.26 million men, 76 614 were diagnosed with PC at the median age of 71 years. Among them, 8659 (11.3%) received a subsequent diagnosis of SPC after a median follow-up of 4 years. The most common SPCs were colorectal, skin, bladder, and lung cancers, melanoma, and non-Hodgkin lymphoma. The ranking was almost identical with first cancers among elderly men in Sweden. The RR for SPCs in prostate-specific antigen-detected PC was approximately equal to RR in other PC. Mortality patterns of PC patients were distinct depending on the presence or absence of SPC. Among patients with SPC, 47.8% died as a result of the corresponding SPC, followed by other causes (22.2%) and PC (18.1%). For patients without SPC, PC and non-neoplastic causes almost matched each other as the main causes of death (48.5% and 47.8%). The results suggest that SPCs appear autonomous from primary PC and reflect incidence and mortality of first cancers in general. SPC was the most common cause of death in patients with SPC; close to half of the patients died due to SPC. For improved survival in PC patients, prevention and early detection of SPCs would be important, and the present results suggest that risk factors for SPC in PC are the same as those for first cancer in general.

Second primary colorectal cancer after the initial primary colorectal cancer.

BACKGROUND: Initial primary colorectal cancer (IPCRC) has a high risk of developing into second primary colorectal cancer (SPCRC). Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) have different characteristics and are considered to be two different entities. However, the different risks for SPCRC in categorized tumor sites and SPCRC subcategorized sites have not been fully elucidated to date. We aimed to compare incidence and survival of IPCRC and SPCRC and characterize the risk factors of SPCRC while also comparing the different SPCRC characteristics. METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data to compute standardized incidence ratios (SIR) in order to estimate risk of SPCRC after IPCRC diagnosis. The most prominent risk factors for SPCRC were measured by multivariate regression analysis and the temporal trend of SPCRC incidence was assessed with Joinpoint regression. Survival of patients with SPCRC and IPCRC was compared by Kaplan-Meier analysis. RESULTS: Patients with IPCRC were 1.73 times more likely to develop SPCRC (SIR = 1.73, 95% CI 1.69-1.78). SPCRC incidence declined since the first 8 years of IPCRC diagnosis to baseline. We demonstrated poorer survival with SPCRC compared with IPCRC while second RCC resulted in better survival compared with second LCC. Black ethnicity, age range 70-79, and LCC were associated with the highest risk of developing SPCRC. CONCLUSION: The characteristic differences between second LCC and RCC were relatively narrow. Furthermore, in those with SPCRC, RCC had the best survival outcome.

Type of second primary malignancy after achieving complete response by definitive chemoradiation therapy in patients with esophageal squamous cell carcinoma.

BACKGROUND: While the standard treatment for stage II-III (non-T4) esophageal squamous cell carcinoma (ESCC) is neoadjuvant therapy followed by esophagectomy, definitive chemoradiation therapy (dCRT) is an option to treat ESCC patients who reject or may not tolerate surgical treatment. Second primary malignancy (SPM) is a problem for long-term survivors after achieving complete response (CR) by dCRT. METHODS: The source of the subjects in this study was the patients with stage II/III (excluding T4 disease) ESCC (UICC6th) who underwent dCRT from 2000 to 2011 at the National Cancer Center Hospital, Japan. SPM, defined as malignancy newly detected at different site from the initial disease, was checked in patients who achieved CR by the initial dCRT. RESULTS: Among the 285 patients with stage II/III (excluding T4 disease) ESCC who underwent dCRT, 185 patients achieved CR. SPM was detected in 49 patients (median time to developing SPM, 41.5 months), accounting for 19.3% (95% CI 0.137-0.257) as the 5-year cumulative risk of SPM. SPMs were head and neck cancer (n = 12), gastric cancer (n = 12), esophageal cancer (n = 7), lung cancer (n = 5), colon cancer (n = 4), diffuse large B-cell lymphoma (n = 3), bladder cancer (n = 2), small intestinal cancer (n = 1), cholangiocarcinoma (n = 1), malignant melanoma (n = 1), and breast cancer (n = 1). There were no significant differences in baseline characteristics between the patients who developed SPM (n = 49) and others (n = 136). CONCLUSIONS: Because second primary malignancy developed often after achieving CR by dCRT for ESCC, it should be followed carefully.

Second primary acute lymphoblastic leukemia in adults: a SEER analysis of incidence and outcomes.

We conducted a surveillance epidemiology and end results (SEER)-based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (≥18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5-year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de-novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age ≥65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5-year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10-1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58-1.95, P < 0.001). Hematological-1M sites had significantly higher SIRs (hematological-SIR 7.35; solid-SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5-year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer.

The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. METHODS: A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. RESULTS: It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. CONCLUSIONS: Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.

The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification.

INTRODUCTION: Application of tumor, node, and metastasis (TNM) classification is difficult in patients with lung cancer presenting as multiple ground glass nodules or with diffuse pneumonic-type involvement. Clarification of how to do this is needed for the forthcoming eighth edition of TNM classification. METHODS: A subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee conducted a systematic literature review to build an evidence base regarding such tumors. An iterative process that included an extended workgroup was used to develop proposals for TNM classification. RESULTS: Patients with multiple tumors with a prominent ground glass component on imaging or lepidic component on microscopy are being seen with increasing frequency. These tumors are associated with good survival after resection and a decreased propensity for nodal and extrathoracic metastases. Diffuse pneumonic-type involvement in the lung is associated with a worse prognosis, but also with a decreased propensity for nodal and distant metastases. CONCLUSION: For multifocal ground glass/lepidic tumors, we propose that the T category be determined by the highest T lesion, with either the number of tumors or m in parentheses to denote the multifocal nature, and that a single N and M category be used for all the lesions collectively-for example, T1a(3)N0M0 or T1b(m)N0M0. For diffuse pneumonic-type lung cancer we propose that the T category be designated by size (or T3) if in one lobe, as T4 if involving an ipsilateral different lobe, or as M1a if contralateral and that a single N and M category be used for all pulmonary areas of involvement.

The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification.

INTRODUCTION: Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. METHODS: A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. RESULTS: Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor-T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location-with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. CONCLUSION: We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses. METHODS: Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review. RESULTS: Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review. CONCLUSIONS: Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer.

Second Primary Malignancies in CTCL Patients from 1992 to 2011: A SEER-Based, Population-Based Study Evaluating Time from CTCL Diagnosis, Age, Sex, Stage, and CD30+ Subtype.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a diverse group of extranodal non-Hodgkin lymphomas with malignant T lymphocytes localizing in the skin. CTCL can mainly be classified as mycosis fungoides, Sézary syndrome, or primary cutaneous CD30+ lymphoma. Patients with CTCL have an increased risk of developing second primary malignancies. OBJECTIVE: Our objective was to analyze the overall incidence of second primary malignancies in patients with CTCL by age, sex, stage, and the primary cutaneous CD30+ lymphoproliferative subtype of CTCL, as this group has usually been excluded from previous analyses. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate CTCL cases diagnosed between 1992 and 2011. We calculated the multiple primary standardized incidence ratio, comparing the observed incidence of second primary malignant neoplasms in the CTCL patient population versus the general population. RESULTS: CTCL is associated with an overall increased risk of cancers. This incidence is greatest within the first year of diagnosis. The risk of secondary Hodgkin disease is greatest in patients aged ≥60 years; the risk of secondary non-Hodgkin lymphoma is greatest in patients aged 20-39. Males demonstrated a significantly increased risk of developing Hodgkin lymphoma, while females showed a significantly increased risk of developing bronchopulmonary malignancy. Overall, secondary malignancy incidence was significantly elevated for stage I and IV CTCL. Patients with CD30+ CTCL had a significantly higher incidence of Hodgkin lymphoma, non-Hodgkin lymphoma, and urinary cancers than the general population. CONCLUSION: Occult secondary malignancies, particularly lymphomas, should be considered in adult CTCL patients, including those with the CD30+ subtype.

Therapy-related myelodysplasia and acute myeloid leukemia.

Therapy-related leukemia (myelodysplasia and acute myeloid leukemia-t-MDS/AML) is a well-known complication of conventional chemoradiotherapy used to treat a variety of primary malignancies including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), sarcoma, and ovarian and testicular cancers. The median time to development of t-MDS/AML is 3-5 years, with the risk decreasing markedly after the first decade. t-MDS/AML is the major cause of non-relapse mortality after autologous hematopoietic cell transplantation (HCT) for HL or NHL. The magnitude of risk of t-MDS/AML is higher, and the latency is shorter after HCT, compared to conventional therapy. Two types of t-MDS/AML are recognized depending on the causative therapeutic exposure: an alkylating agent/radiation-related type and a topoisomerase II inhibitor-related type. Inter-individual variability in the risk for development of t-MDS/AML suggests a role for genetic variation in susceptibility to genotoxic exposures. Treatment of t-MDS/AML with conventional therapy is associated with a uniformly poor prognosis, with a median survival of 6 months. Because of the poor response to conventional chemotherapy, allogeneic HCT is recommended. Current research is focused on developing risk prediction and risk reduction strategies.