Risk of Second Primary Malignancies in Patients With Follicular Lymphoma: A United States Population-based Study

BackgroundWith the improving outcomes of patients with follicular lymphoma (FL), it is imperative to focus on survivorship issues, including the development of second primary malignancies (SPMs). We used a large US database to measure the risk of SPMs among FL survivors.Materials and MethodsWe used the Surveillance, Epidemiology, and End Results-13 registry to identify FL patients from 1992 to 2011. We calculated the risk of SPMs, developing ≥ 6 months after diagnosis, using the standardized incidence ratio (SIR) and absolute excess risk. We calculated the cumulative incidence of SPMs using the competing risk method and risk factors for SPMs using univariate and multivariate methods.ResultsOf a total of 15,517 patients with FL followed up for a median of 71 months, 1540 (9.9%) developed SPMs, with a SIR of 1.08 and absolute excess risk of 11.3 per 10,000 person-years. A significantly increased risk was noted for Hodgkin lymphoma (SIR, 5.85), acute myeloid leukemia (SIR, 4.88), and the following sites: oral cavity and pharynx (SIR, 1.43), stomach (SIR, 1.43), lung and bronchus (SIR, 1.35), melanoma of skin (SIR, 1.38), other nonepithelial cancers of the skin (SIR, 2.88), urinary bladder (SIR, 1.24), and kidney/renal pelvis (SIR, 1.43). The cumulative incidence of SPMs was 11.06% at 10 years. Multivariate regression showed that age > 65 years (SIR, 1.57; P < .001), male gender (SIR, 1.43; P < .001), and receipt of radiation (SIR, 1.24; P = .001) predicted a higher rate of SPMs.ConclusionPatients with FL have increased risk of both hematologic and solid malignancies. Risk factors for SPMs include advanced age, male gender, and receipt of radiation therapy.     

Second Malignancies Following Treatment in non-Hodgkin's Lymphoma

Second malignancies represent an important iatrogenic complication of the treatment of hematologic and other neoplasms. In this review we summarize the literature relating specifically to malignancies developing in the wake of treated non-Hodgkin's lymphoma (NHL). In these patients, the risk of myelodysplastic syndrome (MDS) and acute non lymphocytic Leukemia (ANLL) is reported to be increased 10-105 fold over that of the general population. Factors in the development of MDS and ANLL include basic defects in cellular immunity in NHL patients as well as treatment with alkylating agents and low dose total body irradiation. Biologically these secondary MDS and ANLLs are characterized by specific cytogenetic abnormalities and results of treatment are poor. Currently bone marrow transplantation offers the only potential cure.

There is no clear statistical evidence that solid tumors occur more frequently after NHL. However, bladder carcinoma, in cyclophosphamide treated patients, and lung cancer have been reported by some to occur with an increased incidence. Further investigation of the molecular events leading to the occurrence of second malignancies in NHL patients and the role played by oncogenes and tumor suppressor genes in this process is still needed.     

Survival of Patients With Second Primary Hodgkin Lymphoma

IntroductionThe increased risk for second malignancies after Hodgkin lymphoma (HL) diagnosis is well known. However, to our knowledge, no study has investigated the outcomes of patients diagnosed with HL after an antecedent malignancy (HL-2). We aimed to investigate overall survival (OS), disease-specific survival (DSS), and correlates of survival in HL-2 using the Surveillance, Epidemiology and End Results (SEER) database.Patients and MethodsHL-2 patients (n = 821) identified from the 2000-2014 SEER-18 registries were compared to first primary HL patients (HL-1, n = 31,355) from the same registries. Multivariable, propensity score–matched (PSM), and competing risks regression analyses were conducted to assess the effect of antecedent malignancy on survival.ResultsHematologic (n = 309, 37.6%), prostate (n = 169, 20.6%), and breast (n = 76, 9.3%) malignancies were common antecedent malignancies in HL-2. Median latency between antecedent malignancy and HL diagnosis was 39 months. Median ages at HL diagnosis for HL-1 and HL-2 were 36 and 66 years, respectively (P < .001). The 5-year OS and HL-DSS rates for HL-2 versus HL-1 were 53.2% versus 82.7% and 79.1% versus 90.9%, respectively (P < .001). On multivariable analysis, antecedent malignancy was associated with decreased OS (hazard ratio [HR] = 1.27; 95% confidence interval [CI], 1.13-1.42; P < .001). With PSM balancing across covariables, antecedent malignancy was associated with decrements in HL-DSS (HR = 1.46; 95% CI, 1.12-1.92; P = .006) and OS (HR = 2.09; 95% CI, 1.74-2.51; P < .001).ConclusionThe decrement in DSS in HL-2 relative to HL-1 may be related to biological differences in HL, age, and/or other unanalyzed factors. Further study of HL-2 patients is warranted.     

Primary CNS Lymphoma in Immunocompetent Patients

Primary central nervous system lymphoma (PCNSL) constitutes a rare group of extranodal non‐Hodgkin's lymphomas (NHLs), primarily of B cell origin, whose incidence has markedly increased in the last three decades. Immunodeficiency is the main risk factor, but the large majority of patients are immunocompetent. Recent evidence suggests a specific tumorigenesis that may explain their particular clinical behavior compared with systemic NHL. The addition of i.v. high‐dose methotrexate (MTX) chemotherapy to whole‐brain radiotherapy (WBRT) has considerably improved the prognosis, leading to a threefold longer median survival time compared with WBRT alone and represents the current standard of care. However, this combined treatment exposes the patient, especially the elderly, to a high risk for delayed neurotoxicity. In the older population (>60 years), there is growing evidence that MTX‐based chemotherapy alone as initial treatment is the best approach to achieve effective tumor control without compromising patient quality of life. In the younger population, the risk for neurotoxicity is much lower, and this strategy is controversial because it may be associated with higher relapse rates. Future efforts should focus on the development of new polychemotherapy regimens allowing the reduction or deferral of WBRT in order to minimize the risk for delayed neurotoxicity. In this setting, intensive chemotherapy with autologous blood stem cell transplantation was recently demonstrated to be feasible and efficient as salvage therapy and is currently being evaluated as part of primary treatment. This review highlights the recent advances in the pathogenesis and treatment of PCNSL in the immunocompetent population.     

Increased Risk of Second Primary Malignancies in Patients with Gynecological Cancer: A Swedish record-linkage study

The Stockholm-Gotland Cancer Register was used to study the risk of developing second primary malignancies (SPM) in women diagnosed with cancer of the uterine cervix, uterine corpus and ovaries during the period 1958-1992. Among 5 325 patients with uterine cervix cancer, 619 developed SPM. Standardized incidence ratio (SIR) was 1.29 (95% confidence interval (CI) 1.19-1.39). Significantly increased risks were observed for cancer of the colon, rectum, lung, vulva, kidney and bladder. A total of 4 815 women with uterine corpus cancer were followed and 660 SPM were found. The overall SIR was 1.21 (95% CI 1.12-1.30) with significantly increased risk for cancer of the colon, ovary, vulva and bladder. The incidence of leukemia was also significantly elevated (SIR = 3.03; 95% CI 1.70-5.00). Among 5060 patients with ovarian cancer, 379 SPM were found (SIR 1.49; 95% CI 1.34-1.64). Increased risks of cancer of the colon, rectum, breast, uterine corpus, bladder and leukemia were observed. All three primary sites showed elevated risks of cancer of the colon and bladder. For patients with a primary cancer of the corpus and ovary an elevated risk of leukemia was also noted. The conclusion from these findings is that SPM to some extent can be explained by previously known factors, i.e. treatment and common risk factors. However, further studies concerning the role of common etiology, for instance hereditary and hormonal factors, are needed to increase the knowledge on the etiology of second primary malignancies.     

Multiple Primary Malignancies in Patients with Head and Neck Cancer

During the 15 years from 1967 to 1981, 3, 162 patients withcarcinoma of the head and neck were treated with radiation therapy.Among them, 262 patients (8.3%) developed two or more independentmalignancies. There were 80 patients with prior cancer. Theoverall incidence of second malignancies in patients who hadradiation therapy was 5.8%. The incidences were 8.9, 7.7, 5.2and 1.7% of index cancer in the larynx, pharynx, oral cavityand paranasal sinus, respectively. Second primaries were observedin the head and neck (36%), digestive tract (35%), lung (19%)and the remaining 10% in other bodily sites. Of the 1, 486 patientswho survived for five years or more after radiation therapy,only 10 (0.7%) developed second malignancies within the previousradiation field.     

The Risk of Second Primary Malignancies in Patients With Lung Neuroendocrine Tumors: A Population-Based Study on SEER Database

PurposeWe investigated the at-risk sites of second primary malignancies (SPMs) and evaluate the risk factors of SPMs among lung neuroendocrine tumors (LNETs) survivors by using the surveillance, epidemiology, and end results (SEER) database.MethodsPropensity-score matching was performed to conduct a case-control study from the surveillance, epidemiology, and end results (SEER) database. Cox regression analysis and multiple primary standardized incidence ratios were performed to investigate the risk factors of occurrence of SPMs among patients with LNETs.ResultsOf 3,206 patients with LNETs after matching, 539 developed SPMs. The risk of developing SPMs was higher in older patients (55–74 vs ≦54: hazard ratios [HR] 1.875; age ≧75 vs ≦54: HR 2.713), higher-stage of LNETs (regional vs localized: HR 1.387; distant vs localized: HR 2.732) and recent periods of diagnosis (2004–2014 vs 1984–1993: HR 1.735). Patients with SCLC, TC and LENEC had a higher risk for SPMs compared to general population. Lung and bronchus, larynx and some digestive organs had higher risk for SPMs while some sex hormone related organs like prostate, breast, and female reproductive system had a lower incidence of SPMs.ConclusionsPatients with LNETs had overall higher risks of SPMs than general population. Different types of second primary malignancies occurred in different periods after LNETs were diagnosed. Further investigations are required to screen different second primary malignancies for those with primary LNETs.     

Second Primary Neoplasms in Thyroid Cancer Patients

To determine risk patterns for second primary neoplasms after the occurrence of thyroid cancer, we conducted a retrospective cohort study of 3321 thyroid cancer patients who were operated and histologically confirmed at the Noguchi Thyroid Clinic and Hospital Foundation between 1946 and 1985. They were followed from the date of operation through the end of 1990 with an observation period from 45 to 5 years. The average observation period of the patients was 13.4 years and the follow-up rate reached 98%. The standardized mortality ratio (SMR) was computed to assess possible risk increase by cancer site. In this computation, the time period less than 5 years after operation was omitted to reduce the influence of deaths related to the original thyroid cancer. A total of 103 deaths from malignant neoplasms other than thyroid cancer were observed during this time period (SMR=1.6, 95% confidence interval [CI]=1.3–2.0). Analyses of site-specific cancer mortality revealed significantly elevated risks for the central nervous system (SMR=16.1, CI=5,2–37.6) and respiratory organs (SMR=2.6, CI=1.5–4.1). Based on a review of available medical records with histological findings, we concluded that the risk increases for these sites were most likely to be attributable to second primary neoplasms. Whether or not the patients had received radiotherapy was not significantly associated with elevated risk. Further investigations are needed to clarify the risk factors responsible for the above findings.     

原发性肺淋巴瘤17例回顾性分析

目的:探讨原发性肺淋巴瘤（PPL）的临床特点、确诊手段、病理及治疗、预后。方法:回顾性分析1999年6 月至2008年12月河南省肿瘤医院收治的17例原发性肺淋巴瘤患者的临床特点、诊断、病理类型、治疗,应用Kaplan-Meier 法行生存分析和Log-rank 检验法行差异显著性检验。统计学分析应用SPSS10.0 软件完成。结果:17例患者中7 例女性,10例男性;年龄29～73岁,中位发病年龄56岁;按照WHO2001淋巴瘤病理分类系统,全组患者均为非霍奇金淋巴瘤,其中9 例为黏膜相关淋巴组织淋巴瘤（MALTL）;PPL 占同期收治恶性淋巴瘤病例数的0.81% ,占同期收治原发于结外淋巴瘤病例数的4.74% ;随访5.2～93个月,中位随访时间为62.5 个月。全组患者5 年总生存率为62.5% ,黏膜相关淋巴组织淋巴瘤（MALTL）和非黏膜相关淋巴组织淋巴瘤（non-MALTL）的5 年总生存率分别为75% 和50% ,差异具有统计学意义（P=0.047）。 结论:PPL 临床上非常少见,症状及影像学表现不特异,容易误诊,获取足够具有代表性的组织标本进行病理学检查是确诊的关键。PPL 的治疗原则尚无统一标准,由于其病理类型大多为低度恶性的MALT,因此预后较好。      

Second Primary Cancers Following Non-Hodgkin's Lymphoma in Japan: Increased Risk of Hepatocellular Carcinoma

We evaluated the risk of development of second primary cancers, with particular reference to subsequent hepatocellular carcinoma (HCC), in 592 patients diagnosed as non-Hodgkin's lymphoma (NHL), at Osaka Medical Center for Cancer and Cardiovascular Diseases. During 1978–1994, 2,163 person-years of observation were accrued, and 27 of the patients developed a second primary cancer, yielding an observed-to-expected ratio (O/E) of 1.53 [95% confidence interval (CI) = 1.01–2.23]. Significant excess risk was noted for primary liver cancer (PLC; O/E=4.36, 95% CI=1.99–8.28; O =9) and non-lymphocytic leukemia (O/E=26.17, 95% CI=5.26–76.46; O=3). The excess risk of PLC was relatively constant within the first 10 years after the NHL diagnosis. Patients who received chemotherapy as the NHL treatment had a significantly increased risk of PLC (O/E=5.91, 95% CI =2.70–11.23; O=9). Their clinical reports indicated that all nine patients with PLC were diagnosed as HCC, and eight of them had clinical and/or histologic evidence of cirrhosis at the time of HCC diagnosis. None of the nine patients had a history of blood transfusion between the first NHL treatment and the diagnosis of HCC. These findings suggested that Japanese NHL patients might have an increased risk of developing HCC, and they indicated the importance of medical surveillance for liver malignancies, as well as subsequent leukemias. Possible explanations for the excess risk of subsequent HCC are discussed.     

Risk of Second Primary Female Genital Malignancies in Women with Breast Cancer: a SEER Analysis

Breast cancer survivors are at an increased risk of second primary cancers, and the risk factors for the latter may have clinical significance. The aims of our study were to evaluate the incidences and risk factors of second primary female genital cancers (corpus uteri, cervix uteri plus ovary) in a large cohort of breast cancer survivors. Using the Surveillance, Epidemiology, and End Results (SEER) database, we examined the standardized incidence ratio (SIR) and risk factors for second primary female genital cancers observed between 2000 and 2014. Breast cancer survivors had increased SIRs for second corpus uteri cancers and second ovarian cancers and a decreased SIR for second cervical cancers (SIR 1.17, 1.12, and 0.64, respectively). Risk factors of second corpus uteri cancers were the age at first cancer diagnosis, race (black vs. white, aHR?=?1.142 95% CI 1.005–1.298), and progesterone receptor (PR) status (PR+ vs. PR?, aHR?=?1.131 95% CI 1.004–1.273). In addition, the risk of second ovarian cancer was positively associated with age while inversely associated with race (black vs. white, aHR?=?0.691 95% CI 0.555–0.859) and estrogen receptor (ER) status (ER+ vs. ER?, aHR?=?0.655 95% CI 0.544–0.788). Age, race, and hormone receptor status are risk factors of developing second female genital cancers among breast cancer survivors. Older age, black race, and a PR+ status in survivors are associated with a higher risk of second corpus uteri cancers. Additionally, older age and an ER? status should increase vigilance for potential second ovarian cancers.     

Characterization of Second Primary Malignancies in Mucosa-Associated Lymphoid Tissue Lymphomas: A SEER Database Interrogation.

Introduction: Second primary malignancies (SPMs) are long-term complications in cancer survivors. Mucosa-associated lymphoid tissue (MALT) lymphomas are indolent extra-nodal marginal zone lymphomas, the majority of which typically have long-term survival. In this study, we investigated the incidence and pattern of SPMs in adult patients diagnosed with MALT lymphomas between January 2000 and December 2016.Methods: Using the SEER-18 database and multiple primary standardized incidence ratio (MP-SIR) session of SEER stat software for statistical analysis, we assessed SPMs in MALT lymphomas.Results: During this time, a total of 12,500 cases of MALT lymphomas were diagnosed, of which 1466 patients developed 1626 SPMs (O/E ratio: 1.48, 95% CI:1.41-1.55, P<.001). The median latency period for development of SPMs was 54 months (range 6-201 months). Secondary non-Hodgkin lymphomas, as defined by SEER as distinct from the primary lymphoma, was the most common SPM with 299 cases, followed by lung cancer (O/E ratio: 6.15, 95% CI:5.47-6.89, P<.0001). There were 898 SPMs that developed between 6- 59 months (O/E ratio: 1.47, 95% CI:1.37-1.57, P<.0001) and 728 after 60 months latency (O/E ratio: 1.5, 95% CI:1.39-1.61, P<.0001) after diagnosis of the primary MALT lymphomas. An increased incidence of both solid and hematologic cancers occurred in patients as early as 6 months after diagnosis of MALT lymphoma.Conclusion: These findings indicate that despite the indolent nature of most MALT lymphomas, there is an increased risk for SPMs warranting long-term follow up.