Neuro-Oncology Neuro-Oncology 17(1), 129– 135, 2015 doi:10.1093/neuonc/nou105 Advance Access date 19 June 2014
Second malignancies in patients with primary central nervous system lymphoma Jun Wang, Jose S. Pulido, Brian Patrick O’Neill, and Patrick B. Johnston Department of Hematology, First People’s Hospital of Changde, Changde, China (J.W.); Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota (J.S.P.); Department of Neurology, Mayo Clinic, Rochester, Minnesota (B.P.O.); Division of Hematology, Mayo Clinic, Rochester, Minnesota (P.B.J.)
Background. Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma with distinctive biological behaviors. The evolving treatment of PCNSL has greatly improved the outcome for patients with this disease and has stimulated interest in second malignancies (SMs) in patients diagnosed with PCNSL. Methods. The records of 129 cases of PCNSL at Mayo Clinic, diagnosed between January 1, 1988, and November 26, 2012, were reviewed. Data on clinical characteristics, laboratory parameters, treatments, outcomes, and SMs were collected. The mean follow-up time was 44.8 months (range, 0.5 –240 months; median, 28.0 months). Results. Altogether, 28 cases with 30 (23.26%) SMs were identified. Twenty (15.50%) patients had prior or synchronous SM. Ten (7.76%) patients developed a subsequent primary cancer after PCNSL. The most common sites of prior or synchronous SMs were prostate (4/20), skin (4/20), and gastrointestinal (3/20). The most common site of the subsequent SM was skin (4/10). Two cases were identified with both prior SM and subsequent SM. Conclusions. Second malignancies in cases with PCNSL were not uncommon and occurred in nearly a quarter of our cohort. Nonmelanoma skin cancers were frequently seen. Therefore, screening for SMs should also be considered in long-term follow-up of patients with PCNSL. In addition, the high incidence of subsequent cancer, synchronous cancer, and frequently seen nonmelanoma skin cancers may all indicate an immunosuppressed state in patients with PCNSL. Keywords: primary central nervous lymphoma, second malignancies.
Long-term survival has been achieved in many malignancies, including lymphoma, due to substantial progress in therapeutic strategies. Thus, second malignancies (SMs) in these long-term survivors have been extensively studied to investigate the late side effects of treatment and increase understanding of the etiology and biology of different malignancies. According to recent studies, patients with non-Hodgkin lymphoma (NHL) are more likely to develop SMs, with a relative risk from 1.14 – to 1.47 over the general population.1 – 6 Solid tumors, especially lung cancer, brain cancer, renal cancer, bladder cancer, melanoma, Hodgkin lymphoma, and acute myelogenous leukemia (AML), are reported as the most frequent SM.2,6 Moreover, risks for SM vary between different subtypes of NHL. Specifically in the case of HIV-negative diffuse large B-cell lymphoma (DLBCL), the risk of hematological malignancies, especially acute myelogenous leukemia, were significantly increased,
whereas nonhematologic malignancies did not exhibit significant elevation.7 Prior studies have noted an increased risk of developing NHL in patients diagnosed with other malignancies.8 Although mechanisms underlying SM are not fully understood, common predisposing factors, genetic mutation, defect in or suppression of the immune system, and treatment such as chemotherapy, autologous stem cell transplantation (ASCT), and radiation therapy have been implicated as factors in immunocompetent patients.6 Primary central nervous system lymphoma (PCNSL) is an uncommon extranodal NHL variant with an incidence of 0.46 per 100 000 patients per year.9 It refers to lymphomas arising exclusively in the central nervous system (ie, the brain parenchyma, spinal cord, eyes, cranial nerves, and/or meninges). As PCNSL represents 3% of primary brain cancers, its rarity makes it challenging to study. Between the years 1970 and
Received 30 December 2013; accepted 11 May 2014 # The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Corresponding Author: Patrick B. Johnston, MD, PhD, Mayo Clinic, Department of Hematology, 200 First St SW, Rochester, MN 55905. (johnston. [email protected]).
Wang et al.: Second Malignancies in PCNSL
Materials and Methods After obtaining IRB approval, the records of 129 PCNSL cases at Mayo Clinic (Rochester, Minnesota) between January 1, 1988, and November 26, 2012, were reviewed. The diagnoses of PCNSL and SM were confirmed histopathologically in all cases. Bone marrow biopsy and PET-CT and/or CT scans were done in each patient to determine the stage and to exclude systemic lymphoma. HIV was tested as a routine. Data were collected on clinical characteristics, laboratory parameters, treatments, outcomes, and occurrences of SM. Malignancies diagnosed 6 months or more before the diagnosis of PCNSL were considered
to be prior second cancers. Malignancies diagnosed 6 months or more after the diagnosis of PCNSL were considered to be subsequent second cancers. Malignancies diagnosed simultaneously or within a 6-month interval of PCNSL diagnosis were considered to be synchronous second cancers.11 All cases were followed from the diagnosis of lymphoma to death, emigration, or the end of the study, whichever occurred first. The mean follow-up time was 44.8 months (range, 0.5 – 240 months; median, 28.0 months). CNS lymphoma secondary to systemic lymphoma or lymphocytic leukemia was excluded from this study.
Results Of the 129 PCNSL cases, 65 were male, and 64 were female. The mean age at diagnosis of lymphoma was 58.3 years (median, 61.0 y; range, 9 – 87 y). Except for 2 cases of T-cell lymphoma, the remaining (98.45%) cases were all B-cell types, including 2 cases of posttransplantation lymphoproliferative disorders. Large B-cell lymphoma was found in 113 cases (87.60%). HIV was negative in all but one case in the entire group, and that patient was excluded from the SM analysis. At a mean follow-up of 44.8 months, 69 (53.49%) patients died. The characteristics of the cases are summarized in Table 1. In total, 28 cases with 30 (23.26%) SMs were identified. All were HIV negative, and there were no autoimmune disorders detected in this group. Except for one case with mantle cell lymphoma and another with follicular lymphoma involving the CNS only, the remainder of cases identified with SMs had
Table 1. Characteristics of patients Characteristics
Total Sex Male Female Age at diagnosis, years ,30 30– 49 50– 69 70– 79 ≥80 Mean Median Range Follow-up (months) Mean Median Range ,1 years 1 –5 years .5 years Death
130
All Patients
Patients with Second Malignancy
No. of Patients
Percent of Patients
Prior No. of Patients
Subsequent No. of Patients
129
100%
20
10
65 64
50.39 49.61
11 9
7 3
4 29 64 26 6
3.10 22.48 49.61 20.16 4.65
0 0 13 5 2 67.5 67.0 50 –84
0 2 5 3 0 62.5 43–72
58.3 61.0 9 – 87
44.8 28.5 0.5– 240 43 50 36 69
33.33 38.76 27.91 53.49
1 6 13 15(75.00%)
0 2 8 2(20.00%)
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2000, PCNSL comprised mostly patients with AIDS, whereas the incidence of PCNSL has increased significantly in the immunocompetent population over the past decades. Approximately 95% of PCNSLs are mature DLBCLs. PCNSL shares some features in common with systemic DLBCL but has a different profile with regard to biology, histopathology, and pathogenesis that may result in its distinctive clinical response to therapy and its poor prognosis.10 In the past few years, evolving therapies, such as high-dose methotrexate, rituximab, and high-dose chemotherapy followed by ASCT, have greatly improved long-term survival for patients with PCNSL. However, few data have been reported about second cancers in patients with PCNSL except for some sporadic case reports. To address this unmet clinical gap, we reviewed the Mayo Clinic database of all PCNSL cases over a 24-year period.
Wang et al.: Second Malignancies in PCNSL
Table 2. Prior and synchronous cancers Site
Time Between the Diagnosis of 2 Malignancies ,6 m
6 m– 1 y
1 2
5 y–9 y
≥10 y
Total
1 1
2 1
1 1 1 1
4 4 3 2 2 2 1 1 1 20
1 2 2 1
1 1 8
0
Site
1 y –4 y
2
5
5
Abbreviations: ENT, ear-nose-throat; GI, gastrointestinal; m, month; NMSC, non-melanoma skin cancers; y, year.
large B-cell lymphoma. SM was not identified in the 2 cases with a posttransplantation lymphoproliferative disorder. Twenty cases were found with a history of prior or synchronous SM (see Table 2); 11 were males, and 9 were females. The mean age at diagnosis of PCNSL was 67.5 years (median, 67 y; range, 50–84 y). The latency of the 2 cancers was ,6 months in 8 cases, and these were classified as synchronous primary malignancies. Two patients developed PCNSL within the first 4 years of the prior malignancy, followed by 5 more patients during the following 5 years and another 4 patients after 10 years. One patient had a remote history of prior skin cancer without a documented date. The most common sites of the prior or synchronous second cancers in our study were prostate (4/20), skin (4/20), and gastrointestinal (GI; 3/20). The 4 skin cancers were all nonmelanoma skin cancers (NMSCs). Of the 3 GI cancers, 2 were in the colon. We also found 2 cases each of breast, head and neck, and thyroid cancers. Lung, uterine, and kidney cancers were not as common, with one case each (Table 2). Treatment for the prior cancers included surgery in 17 cases and radiation in 2 cases (1 with breast cancer and 1 with tonsillar cancer; Table 3). None of the 20 patients had received any chemotherapy before developing PCNSL, and 15 (75%) had died by the end of the study. In those with synchronous cancers, the mortality was 87.5% (7/8). Altogether, 10 patients developed a subsequent primary cancer after developing PCNSL (see Table 4); 7 of them were males, and 3 were females. Median age at diagnosis of PCNSL was 62.5 years (range 50 – 84 y). Four underwent highdose chemotherapy and autologous stem cell transplant (ASCT). The interval between ASCT and development of subsequent second cancer was a median of 3 years (range 0.5 –7 y). Six patients were diagnosed with subsequent cancers within the first 4 years after development of PCNSL. The numbers of subsequent cancers decreased as time went on, with 4 cases during the 5 –9 year interval and no cases after 10 years. The most common sites of the subsequent cancers in our study were skin cancers (4/10). We also found 2 cases involving the GI tract and one case each in lung, prostate, breast, and AML (Table 3). Eight of the 10 patients had previously received
Neuro-Oncology
Treatment of First Primary Malignancy Surgery Alone
Prostate 4 Skin (NMSC) 4 GI 2 Breast 1 ENT 1 Thyroid 1 Lung 1 Uterine 1 Kidney 1 Total 16
Radiotherapy Chemotherapy* No Treatment
1 1 1 1
2
0
2
Abbreviations: ENT, ear-nose-throat; GI, gastrointestinal; NMSC, non-melanoma skin cancers. *With or without surgery.
Table 4. Subsequent cancers Site
Time Between the Diagnosis of the 2 Malignancies ,1 year
Skin (NMSC) GI Prostate Breast AML Lung Total
1 y –4 y
5 y–9y
≥10 y
Total
0
4 2 1 1 1 1 10
4 2 1 1
0
1 1 6
4
Abbreviations: AML, acute myelogenous leukemia; GI, gastrointestinal; NMSC, non-melanoma skin cancers; y, year.
chemotherapy for PCNSL: 4 had received radiation, and 3 were treated with combined modality. One patient had been treated with rituximab alone. Of the 29 patients treated with ASCT for PCNSL, 4 (13.79%) developed subsequent cancers after autologous transplant. One patient had also received radiation for relapse after transplant. The latency between transplant and second cancer ranged from 0.5 – 7years. The conditioning regimens were non-TBI based. The 4 subsequent cancers were one each: NMSC, breast cancer, lung cancer, and prostate cancer (see Table 5). Two (20%) of the 10 patients had died by the end of the study. Two cases were identified with both prior cancer and subsequent cancer. One case was a male, aged 72 years at the time he was diagnosed with PCNSL. He had a history of histologically confirmed prostate cancer 8 years prior to PCNSL and was treated with surgery only for the prostate cancer. He achieved his first complete remission (CR) for PCNSL with chemotherapy containing methotrexate, rituximab, and temozolomide and was maintained with temozolomide. The lymphoma recurred
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Prostate Skin (NMSC) GI Breast ENT Thyroid Lung Uterine Kidney Total
Table 3. Treatment of the prior or synchronous primary malignancy in patients with primary central nervous system lymphoma
Wang et al.: Second Malignancies in PCNSL
Table 5. Treatment of primary central nervous system lymphoma in patients with subsequent cancers Site
Chemotherapy Alone
Chemotherapy and ASCT
1 1
1
Chemotherapy and Radiotherapy
Radiotherapy Alone
Chemotherapy, ASCT, and Radiotherapy
1
Other
1
1 1 1 1
2
1 3
2
1
1
1
Abbreviations: AML, acute myelogenous leukemia; ASCT, autologous stem cell transplantation; GI, gastrointestinal; NMSC, non-melanoma skin cancers.
2 years later in the testicle. He managed to achieve his second CR after resection and 30 Gy of local radiation in 15 fractions. He was diagnosed with AML 4 years after his lymphoma and died from the disease with no additional therapy. The other case was a female who had PCNSL diagnosed at the age of 65 years. She had been diagnosed with lung cancer 9 years before the PCNSL. Surgery was performed for her lung cancer without any radiation or chemotherapy. She underwent anthracycline-containing chemotherapy combined with radiation for treatment of the PCNSL and achieved a first CR. She was treated with methotrexate, rituximab, and temozolomide for relapse 3 years later but only achieved a partial remission. She developed GI-type 3A hilar cholangiocarcinoma at the age of 69 years and entered hospice care.
Discussion Previous studies have described SMs in patients with NHL. This current study focused on the SMs that developed in 129 patients identified with PCNSL. These are the most data related to SM in patients with PCNSL. In this study, we found that SMs were not uncommon in this population, with a total proportion of 23.26% (30/129). Not only were subsequent malignancies observed (7.75%), as in other studies of the NHL population, but a significant number of prior cancers (9.30%) and synchronous cancers (6.20%) were also identified. Recent studies1,2,6,7,12 – 16 have reported that patients with NHL are at high risk for subsequent malignancy, with an overall rate of 4.2% –8.8%. We cannot compare the standard incidence ratio (SIR) in this study with other studies, nor can we reach a conclusion due to the limited sample size in this study. However, given the high percentage and the relative short follow-up time, these percentages may actually be an underestimation of the true incidence. It is reasonable to suspect that these patients may have had a higher risk of second cancers than non-PCNSL NHL patients. Male sex has been considered a risk factor for SM in NHL patients in some studies,2,16 but other studies have proposed a similar or higher overall risk for females.1,6 In our study, the male:female ratio of the 129 patients with PCNSL was 1.02:1,
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whereas it was 1.50:1 for patients with SM. The ratio was similar (1.56:1) when sex-specific cancer sites were excluded, indicating a possible male preference. The initial purpose of the previous studies in secondary malignancies was to investigate the delayed effects of treatment. In this study, most of the subsequent cancers can be explained as late effects of treatment according to previous reports. Whole brain radiation or chemotherapy is the first-line therapeutic strategy for PCNSL. Chemotherapy is an established risk factor for SM after NHL. AML, bladder cancer, and lung cancer have been reported to be the most frequent SMs in patients treated with chemotherapy, especially those with alkylating agents.7,17 Radiation has been associated with a significantly elevated risk of secondary lung cancer, bladder cancer, thyroid cancer, and female breast cancer.1,2,5,6 As far as non-HIV-related diffuse large B-cell lymphoma is concerned, only the risk of developing AML was significantly elevated.7 Despite the alkylator-based chemotherapy regimen in 8 patients, AML was observed in only one patient 4 years after diagnosis of PCNSL. Bladder cancer was not observed as a SM, which may have been due to the small sample size in this study. NMSC appeared to be a predominant SM in this study. Interestingly, this cancer was excluded from most of the previous registry-based studies of SM in patients with NHL because of the incomplete data entered into the databases.1,2,4 – 7,18 Out of the 10 cases with subsequent cancers, 4 secondary NMSCs were identified. We cannot exclude the late effects of radiation since one patient had been exposed to radiation, and the skin lesions were located in the radiation fields. ASCT has also been introduced recently to achieve durable complete remissions in PCNSL patients. SM is a big concern after stem cell transplantation since it is the most common cause of nonrelapse mortality. T-MDS/AML and solid tumors are the most frequently seen. The incidence of solid tumors following ASCT varies from 0.2% – 4% at 20 years.19 The risk for (therapy-related myelodysplastic syndrome) t-MDS/AML seems to be highest in the first decade after transplantation, whereas the risk for solid tumors persists for at least 20 years.20 In this report, second solid tumors such as lung cancer, prostate cancer, and skin cancer were seen in 13.8% patients (4/29) after ASCT. The latency between transplant and second
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Skin (NMSC) GI Prostate Breast AML Lung Total
Treatment of Primary Central Nervous System Lymphoma
Wang et al.: Second Malignancies in PCNSL
Neuro-Oncology
immunosuppressed state of the host. PCNSL, however, is generally an aggressive lymphoma. The significant incidence of synchronous cancers in our study may be due to immunosuppression of PCNSL patients if the hypothesis previously proposed with low-grade lymphomas is proven. We are unable to further investigate the mechanisms underlying synchronous PCNSL due to the limited number of cases. Compared with the data of SM in patients with systemic NHL in other studies, our study showed that the prognosis of concomitant PCNSL was extremely poor, with only one patient with synchronous malignancies surviving during the studied period. In addition, patients with PCNSL as a primary cancer seemed to have a better outcome than patients with PCNSL as a second or concomitant cancer. The mortality in this review was 20%, 66.67%, and 87.50%, respectively. This may be partly due to the younger age and better performance scores of the primary group, which have been previously shown to be important prognostic factors.10 Another possible reason is that patients in the primary group are all survivors of PCNSL, with better responses to the treatment, whereas PCNSL is lethal in the subsequent or concomitant group. Compared with second cancer prior or subsequent to PCNSL, clinicians may need to be more alert when a second cancer occurs simultaneously with PCNSL. Furthermore, since synchronous malignancies may be more common in patients with PCNSL, the diagnosis of intracranial metastasis from a primary systemic malignancy other than lymphoma, when the brain mass decreases significantly with steroid treatment, may need further investigation. There was a high incidence of NMSC in the study population. NMSC was observed in 8 cases with PCNSL. Three patients had their NMSC diagnosed prior to PCNSL, one patient was diagnosed simultaneously, and 4 patients were diagnosed subsequently. It is possible that the subsequent NMSC can be attributed to the late effects of treatment for PCNSL. It is unlikely, however, to be the cause in other cases. Previous studies have examined possible links between skin cancers and NHL. A strong association of increased risk for subsequent NHL in patients with skin cancers has been identified. Among those reports from large population-based cancer registries, most reported melanoma, which was absent from our study.32 – 35 Several other studies found an elevated risk of NHL among patients with NMSC.32,36 – 39 Some reported that the risk for NMSC patients was even higher than that for melanoma patients.8,33 In a Danish cohort study, history of NMSC was suggested to be associated with significantly increased mortality of patients diagnosed with NHL before the age of 80 years.40 In addition, an increased risk of NMSC after other malignancies, especially those of hematological origin, has also been reported.8,33 Thus, immunosuppression is suggested to be the common risk factor for both malignancies.8 In summary, this study showed that SM in patients with PCNSL is not uncommon. Clinicians should be alert to the possibility of a synchronous PCNSL versus CNS metastasis when a brain mass is found at the diagnosis of other malignancies. Those doing long-term follow-up of patients with PCNSL should also be aware of the significant incidence of subsequent cancers. Synchronous PCNSL with other systemic malignancies may be a signal for poor prognosis. In addition, the high incidence of subsequent cancer and synchronous cancer, as well as the frequently seen NMSCs, may all highlight the
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cancer ranged from 0.5 years – 7 years. Overall, except for the absence of t-MDS/AML, the sites and latency of SMs in this study are consistent with the late effects of treatment according to previous studies.19 – 23 However, the incidence may be underestimated due to the short follow-up time in this study. The underlying pathophysiology behind development of other cancers may suggest not only a treatment factor but also an intrinsic mechanism, possibly involving immune defects as suggested in indolent lymphomas.24 As with SM studies in patients with solid organ malignancies, studies of SMs associated with lymphoid malignancies have looked for genetic factors, treatment-related effects, and possible immune defects as causes. As a rare brain tumor, primary CNS lymphoma is even more rarely seen as a SM in immunocompetent patients. Until now, there have been only sporadic reports about PCNSL as a second or concomitant malignancy with very limited cases.25 – 27 Deangelis et al reported the largest case series27 of PCNSL as a SM, identified 7 cases, 2 of which had systemic lymphoma as their first malignancy. Four patients were diagnosed with biopsy. The median age was 69 years at the time of PCNSL diagnosis. Another case series presented 4 cases (8%) of PCNSL with prior malignancies.26 According to the previous studies, the median latency between the 2 malignancies was 8 –10 years. The nonhematological sites of original cancers in these studies included breast (4), colon and rectum (3), lung (3), head and neck (2), prostate (2), kidney (1), brain (glioblastoma) (1), uterus (1), and thyroid (1). Only one case of synchronous cancer was observed (prostate). There was no evidence that any late complications of treatment for the primary cancer accounted for their subsequent PCNSL in these patients. In our study, 20 patients (15.50%) had a prior or concomitant malignancy. Except for the synchronous cases, 83.3% (10/12) of patients developed PCNSL 5 years after their first malignancy. The median age at diagnosis of PCNSL was 67 years, and median latency was 8 years, consistent with the previous studies. Sites were similar except for 4 cases of NMSC, which have never been reported before. Interestingly, when combining our data with all of the other case reports, breast, prostate, and colon cancers seemed much more prevalent than other cancers. This may be attributed to the long-term survival of patients with these 3 kinds of tumors. Alternatively, it may suggest some potential connection, rather than coincidence, between PCNSL and these tumors. Similar to the previous studies, no immune disorders were identified in these patients, nor could any late effects of treatment explain the etiology of the PCNSL since surgery was the only treatment for most of them. Possible reasons may be genetic predisposition or acquired susceptibility caused by immunological impairment. We observed 8 synchronous malignancies in these immunocompetent patients in our study. Synchronous malignancies have been well documented in immunocompromised patients; they are unusual, however, in immunocompetent patients. An autopsy study of 1870 cases showed synchronous cancers in only 15 (0.8%) of the 68 patients with multiple primary cancers.28 In our study, the proportion was as high as 6.20% (8/ 129). Most of the synchronous lymphomas in previous reports29 – 31 were low grade and had a good prognosis. Therefore, it was hypothesized that low-grade lymphoma was susceptible to synchronous cancers due to the
Wang et al.: Second Malignancies in PCNSL
immunosuppression state in patients with PCNSL. This singleinstitution study is limited by small sample size and a short mean follow-up of 44.8 months, which may be insufficient to estimate the true risk of second cancer. Moreover, as a descriptive study, it was uncontrolled. Potential bias may exist because the selection and data collection depended mainly on the availability and accuracy of medical records. A multicenter study of SMs in patients with this disease is necessary and should include investigation of NMSC.
primary central nervous system lymphoma. Leukemia. 2011; 25(12):1797 –1807. 11.
Gluckman JL, Crissman JD, Donegan JO. Multicentric squamous-cell carcinoma of the upper aerodigestive tract. Head Neck Surg. 1980;3(2):90– 96.
12.
Travis LB, Curtis RE, Boice JD Jr., et al. Second cancers following non-Hodgkin’s lymphoma. Cancer. 1991;67(7):2002–2009.
13.
Travis LB, Curtis RE, Glimelius B, et al. Second cancers among long-term survivors of non-Hodgkin’s lymphoma. J Natl Cancer Inst. 1993;85(23):1932 –1937.
14.
Brennan P, Coates M, Armstrong B, et al. Second primary neoplasms following non-Hodgkin’s lymphoma in New South Wales, Australia. Br J Cancer. 2000;82(7):1344–1347.
Funding
Acknowledgments Special thanks is given to Dr. Ivana Micallef for critical review of the manuscript.
Conflict of interest Statement: None declared.
References 1.
Dores GM, Cote TR, Travis LB. New malignancies following Hodgkin lymphoma, non-Hodgkin lymphoma and myeloma (NIH Pub. No. 05-5302). In: Curtis RE, Freedman DM, Ron E, eds. New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973-2000. Bethesda, MD: National Cancer Institute; 2006:397 –428.
2.
Mudie NY, Swerdlow AJ, Higgins CD, et al. Risk of second malignancy after non-Hodgkin’s lymphoma: a British Cohort Study. J Clin Oncol. 2006;24(10):1568– 1574.
3.
Pirani M, Marcheselli R, Marcheselli L, et al. Risk for second malignancies in non-Hodgkin’s lymphoma survivors: a meta-analysis. Ann Oncol. 2011;22(8):1845– 1858.
15. Dong C, Hemminki K. Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958 – 1996: a search for common mechanisms. Br J Cancer. 2001;85(7):997– 1005. 16. Sacchi S, Marcheselli L, Bari A, et al. Secondary malignancies after treatment for indolent non-Hodgkin’s lymphoma: a 16-year follow-up study. Haematologica. 2008;93(3):398– 404. 17. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst. 1995;87(7):524– 530. 18.
Ellis M, Lishner M. Second malignancies following treatment in non-Hodgkin’s lymphoma. Leuk Lymphoma. 1993;9(4 – 5): 337– 342.
19. Minn AY, Riedel E, Halpern J, et al. Long-term outcomes after high dose therapy and autologous haematopoietic cell rescue for refractory/relapsed Hodgkin lymphoma. Br J Haematol. 2012; 159(3):329 –339. 20.
Burns LJ. Late effects after autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(1 Suppl): 21 –24.
21. Seshadri T, Pintilie M, Kuruvilla J, et al. Incidence and risk factors for second cancers after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Leuk Lymphoma. 2009;50(3):380 –386. 22. Baker KS, DeFor TE, Burns LJ, et al. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21(16): 1352– 1358.
4.
Sacchi S, Marcheselli L, Bari A, et al. Second malignancies after treatment of diffuse large B-cell non-Hodgkin’s lymphoma: a GISL cohort study. Haematologica. 2008;93(9):1335–1342.
5.
Tward J, Glenn M, Pulsipher M, et al. Incidence, risk factors, and pathogenesis of second malignancies in patients with non-Hodgkin lymphoma. Leuk Lymphoma. 2007;48(8): 1482 –1495.
23.
6.
Tward JD, Wendland MM, Shrieve DC, et al. The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma. Cancer. 2006;107(1):108 –115.
24. Reed JC, Kitada S, Kim Y, et al. Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. Semin Oncol. 2002;29(1 Suppl 2):10– 24.
7.
Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol. 2010;28(33): 4935–4944.
25. Padhi S, Banerjee S, Das S, et al. Primary CNS lymphoma as second malignancy in a case of carcinoma larynx treated with chemoradiation. Eur J Cancer Care (Engl). 2009;18(5):517–520. 26.
8.
Hemminki K, Jiang Y, Steineck G. Skin cancer and non-Hodgkin’s lymphoma as second malignancies. markers of impaired immune function? Eur J Cancer. 2003;39(2):223– 229.
Reni M, Ferreri AJ, Zoldan MC, et al. Primary brain lymphomas in patients with a prior or concomitant malignancy. J Neurooncol. 1997;32(2):135 –142.
27.
9.
Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol. 2007;3(1):24 –35.
DeAngelis LM. Primary central nervous system lymphoma as a secondary malignancy. Cancer. 1991;67(5):1431– 1435.
28.
10.
Deckert M, Engert A, Bruck W, et al. Modern concepts in the biology, diagnosis, differential diagnosis and treatment of
Lee TK, Myers RT, Scharyj M, et al. Multiple primary malignant tumors (MPMT): study of 68 autopsy cases (1963 – 1980). J Am Geriatr Soc. 1982;30(12):744–753.
134
Jantunen E, Itala M, Siitonen T, et al. Late non-relapse mortality among adult autologous stem cell transplant recipients: a nation-wide analysis of 1,482 patients transplanted in 1990 – 2003. Eur J Haematol. 2006;77(2):114– 119.
Downloaded from http://neuro-oncology.oxfordjournals.org/ at New York University on April 30, 2015
Supported in part by Mayo SPORE in Brain Cancer (P50 CA108961), University of Iowa/Mayo SPORE in Lymphoma (P50 CA97274) and an unrestricted grant from Research to Prevent Blindness Inc.
Wang et al.: Second Malignancies in PCNSL
29.
Cuff KE, Dettrick AJ, Chern B. Synchronous breast cancer and lymphoma: a case series and a review of the literature. J Clin Pathol. 2010;63(6):555– 557.
30. Kunthur A, Wiernik PH, Dutcher JP. Renal parenchymal tumors and lymphoma in the same patient: case series and review of the literature. Am J Hematol. 2006;81(4):271–280. 31.
Hu XR, Hu YX, Fu HR, et al. Diffuse large B-cell lymphoma with concurrent gastric adenocarcinoma: case report and literature review. J Int Med Res. 2011;39(5):2051–2058.
35.
McKenna DB, Stockton D, Brewster DH, et al. Evidence for an association between cutaneous malignant melanoma and lymphoid malignancy: a population-based retrospective cohort study in Scotland. Br J Cancer. 2003;88(1):74 –78.
36. Wheless L, Black J, Alberg AJ. Nonmelanoma skin cancer and the risk of second primary cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1686–1695. 37. Frisch M, Melbye M. New primary cancers after squamous cell skin cancer. Am J Epidemiol. 1995;141(10):916– 922.
32.
Hu S, Federman DG, Ma F, et al. Skin cancer and non-Hodgkin’s lymphoma: examining the link. Dermatol Surg. 2005;31(1): 76 –82.
38.
33.
Adami J, Frisch M, Yuen J, et al. Evidence of an association between non-Hodgkin’s lymphoma and skin cancer. BMJ. 1995; 310(6993):1491 –1495.
39. Hemminki K, Dong C. Subsequent cancers after in situ and invasive squamous cell carcinoma of the skin. Arch Dermatol. 2000;136(5): 647–651.
34.
Goggins WB, Finkelstein DM, Tsao H. Evidence for an association between cutaneous melanoma and non-Hodgkin lymphoma. Cancer. 2001;91(4):874 –880.
40. Hjalgrim H, Frisch M, Storm HH, et al. Non-melanoma skin cancer may be a marker of poor prognosis in patients with non-Hodgkin’s lymphoma. Int J Cancer. 2000;85(5):639 –642.
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Levi F, Randimbison L, Te VC, et al. Non-Hodgkin’s lymphomas, chronic lymphocytic leukaemias and skin cancers. Br J Cancer. 1996;74(11):1847 – 1850.
Second malignancies in patients with primary central nervous system lymphoma Jun Wang, Jose S. Pulido, Brian Patrick O’Neill, and Patrick B. Johnston Department of Hematology, First People’s Hospital of Changde, Changde, China (J.W.); Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota (J.S.P.); Department of Neurology, Mayo Clinic, Rochester, Minnesota (B.P.O.); Division of Hematology, Mayo Clinic, Rochester, Minnesota (P.B.J.)
Background. Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma with distinctive biological behaviors. The evolving treatment of PCNSL has greatly improved the outcome for patients with this disease and has stimulated interest in second malignancies (SMs) in patients diagnosed with PCNSL. Methods. The records of 129 cases of PCNSL at Mayo Clinic, diagnosed between January 1, 1988, and November 26, 2012, were reviewed. Data on clinical characteristics, laboratory parameters, treatments, outcomes, and SMs were collected. The mean follow-up time was 44.8 months (range, 0.5 –240 months; median, 28.0 months). Results. Altogether, 28 cases with 30 (23.26%) SMs were identified. Twenty (15.50%) patients had prior or synchronous SM. Ten (7.76%) patients developed a subsequent primary cancer after PCNSL. The most common sites of prior or synchronous SMs were prostate (4/20), skin (4/20), and gastrointestinal (3/20). The most common site of the subsequent SM was skin (4/10). Two cases were identified with both prior SM and subsequent SM. Conclusions. Second malignancies in cases with PCNSL were not uncommon and occurred in nearly a quarter of our cohort. Nonmelanoma skin cancers were frequently seen. Therefore, screening for SMs should also be considered in long-term follow-up of patients with PCNSL. In addition, the high incidence of subsequent cancer, synchronous cancer, and frequently seen nonmelanoma skin cancers may all indicate an immunosuppressed state in patients with PCNSL. Keywords: primary central nervous lymphoma, second malignancies.
Long-term survival has been achieved in many malignancies, including lymphoma, due to substantial progress in therapeutic strategies. Thus, second malignancies (SMs) in these long-term survivors have been extensively studied to investigate the late side effects of treatment and increase understanding of the etiology and biology of different malignancies. According to recent studies, patients with non-Hodgkin lymphoma (NHL) are more likely to develop SMs, with a relative risk from 1.14 – to 1.47 over the general population.1 – 6 Solid tumors, especially lung cancer, brain cancer, renal cancer, bladder cancer, melanoma, Hodgkin lymphoma, and acute myelogenous leukemia (AML), are reported as the most frequent SM.2,6 Moreover, risks for SM vary between different subtypes of NHL. Specifically in the case of HIV-negative diffuse large B-cell lymphoma (DLBCL), the risk of hematological malignancies, especially acute myelogenous leukemia, were significantly increased,
whereas nonhematologic malignancies did not exhibit significant elevation.7 Prior studies have noted an increased risk of developing NHL in patients diagnosed with other malignancies.8 Although mechanisms underlying SM are not fully understood, common predisposing factors, genetic mutation, defect in or suppression of the immune system, and treatment such as chemotherapy, autologous stem cell transplantation (ASCT), and radiation therapy have been implicated as factors in immunocompetent patients.6 Primary central nervous system lymphoma (PCNSL) is an uncommon extranodal NHL variant with an incidence of 0.46 per 100 000 patients per year.9 It refers to lymphomas arising exclusively in the central nervous system (ie, the brain parenchyma, spinal cord, eyes, cranial nerves, and/or meninges). As PCNSL represents 3% of primary brain cancers, its rarity makes it challenging to study. Between the years 1970 and
Received 30 December 2013; accepted 11 May 2014 # The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Corresponding Author: Patrick B. Johnston, MD, PhD, Mayo Clinic, Department of Hematology, 200 First St SW, Rochester, MN 55905. (johnston. [email protected]).
Wang et al.: Second Malignancies in PCNSL
Materials and Methods After obtaining IRB approval, the records of 129 PCNSL cases at Mayo Clinic (Rochester, Minnesota) between January 1, 1988, and November 26, 2012, were reviewed. The diagnoses of PCNSL and SM were confirmed histopathologically in all cases. Bone marrow biopsy and PET-CT and/or CT scans were done in each patient to determine the stage and to exclude systemic lymphoma. HIV was tested as a routine. Data were collected on clinical characteristics, laboratory parameters, treatments, outcomes, and occurrences of SM. Malignancies diagnosed 6 months or more before the diagnosis of PCNSL were considered
to be prior second cancers. Malignancies diagnosed 6 months or more after the diagnosis of PCNSL were considered to be subsequent second cancers. Malignancies diagnosed simultaneously or within a 6-month interval of PCNSL diagnosis were considered to be synchronous second cancers.11 All cases were followed from the diagnosis of lymphoma to death, emigration, or the end of the study, whichever occurred first. The mean follow-up time was 44.8 months (range, 0.5 – 240 months; median, 28.0 months). CNS lymphoma secondary to systemic lymphoma or lymphocytic leukemia was excluded from this study.
Results Of the 129 PCNSL cases, 65 were male, and 64 were female. The mean age at diagnosis of lymphoma was 58.3 years (median, 61.0 y; range, 9 – 87 y). Except for 2 cases of T-cell lymphoma, the remaining (98.45%) cases were all B-cell types, including 2 cases of posttransplantation lymphoproliferative disorders. Large B-cell lymphoma was found in 113 cases (87.60%). HIV was negative in all but one case in the entire group, and that patient was excluded from the SM analysis. At a mean follow-up of 44.8 months, 69 (53.49%) patients died. The characteristics of the cases are summarized in Table 1. In total, 28 cases with 30 (23.26%) SMs were identified. All were HIV negative, and there were no autoimmune disorders detected in this group. Except for one case with mantle cell lymphoma and another with follicular lymphoma involving the CNS only, the remainder of cases identified with SMs had
Table 1. Characteristics of patients Characteristics
Total Sex Male Female Age at diagnosis, years ,30 30– 49 50– 69 70– 79 ≥80 Mean Median Range Follow-up (months) Mean Median Range ,1 years 1 –5 years .5 years Death
130
All Patients
Patients with Second Malignancy
No. of Patients
Percent of Patients
Prior No. of Patients
Subsequent No. of Patients
129
100%
20
10
65 64
50.39 49.61
11 9
7 3
4 29 64 26 6
3.10 22.48 49.61 20.16 4.65
0 0 13 5 2 67.5 67.0 50 –84
0 2 5 3 0 62.5 43–72
58.3 61.0 9 – 87
44.8 28.5 0.5– 240 43 50 36 69
33.33 38.76 27.91 53.49
1 6 13 15(75.00%)
0 2 8 2(20.00%)
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2000, PCNSL comprised mostly patients with AIDS, whereas the incidence of PCNSL has increased significantly in the immunocompetent population over the past decades. Approximately 95% of PCNSLs are mature DLBCLs. PCNSL shares some features in common with systemic DLBCL but has a different profile with regard to biology, histopathology, and pathogenesis that may result in its distinctive clinical response to therapy and its poor prognosis.10 In the past few years, evolving therapies, such as high-dose methotrexate, rituximab, and high-dose chemotherapy followed by ASCT, have greatly improved long-term survival for patients with PCNSL. However, few data have been reported about second cancers in patients with PCNSL except for some sporadic case reports. To address this unmet clinical gap, we reviewed the Mayo Clinic database of all PCNSL cases over a 24-year period.
Wang et al.: Second Malignancies in PCNSL
Table 2. Prior and synchronous cancers Site
Time Between the Diagnosis of 2 Malignancies ,6 m
6 m– 1 y
1 2
5 y–9 y
≥10 y
Total
1 1
2 1
1 1 1 1
4 4 3 2 2 2 1 1 1 20
1 2 2 1
1 1 8
0
Site
1 y –4 y
2
5
5
Abbreviations: ENT, ear-nose-throat; GI, gastrointestinal; m, month; NMSC, non-melanoma skin cancers; y, year.
large B-cell lymphoma. SM was not identified in the 2 cases with a posttransplantation lymphoproliferative disorder. Twenty cases were found with a history of prior or synchronous SM (see Table 2); 11 were males, and 9 were females. The mean age at diagnosis of PCNSL was 67.5 years (median, 67 y; range, 50–84 y). The latency of the 2 cancers was ,6 months in 8 cases, and these were classified as synchronous primary malignancies. Two patients developed PCNSL within the first 4 years of the prior malignancy, followed by 5 more patients during the following 5 years and another 4 patients after 10 years. One patient had a remote history of prior skin cancer without a documented date. The most common sites of the prior or synchronous second cancers in our study were prostate (4/20), skin (4/20), and gastrointestinal (GI; 3/20). The 4 skin cancers were all nonmelanoma skin cancers (NMSCs). Of the 3 GI cancers, 2 were in the colon. We also found 2 cases each of breast, head and neck, and thyroid cancers. Lung, uterine, and kidney cancers were not as common, with one case each (Table 2). Treatment for the prior cancers included surgery in 17 cases and radiation in 2 cases (1 with breast cancer and 1 with tonsillar cancer; Table 3). None of the 20 patients had received any chemotherapy before developing PCNSL, and 15 (75%) had died by the end of the study. In those with synchronous cancers, the mortality was 87.5% (7/8). Altogether, 10 patients developed a subsequent primary cancer after developing PCNSL (see Table 4); 7 of them were males, and 3 were females. Median age at diagnosis of PCNSL was 62.5 years (range 50 – 84 y). Four underwent highdose chemotherapy and autologous stem cell transplant (ASCT). The interval between ASCT and development of subsequent second cancer was a median of 3 years (range 0.5 –7 y). Six patients were diagnosed with subsequent cancers within the first 4 years after development of PCNSL. The numbers of subsequent cancers decreased as time went on, with 4 cases during the 5 –9 year interval and no cases after 10 years. The most common sites of the subsequent cancers in our study were skin cancers (4/10). We also found 2 cases involving the GI tract and one case each in lung, prostate, breast, and AML (Table 3). Eight of the 10 patients had previously received
Neuro-Oncology
Treatment of First Primary Malignancy Surgery Alone
Prostate 4 Skin (NMSC) 4 GI 2 Breast 1 ENT 1 Thyroid 1 Lung 1 Uterine 1 Kidney 1 Total 16
Radiotherapy Chemotherapy* No Treatment
1 1 1 1
2
0
2
Abbreviations: ENT, ear-nose-throat; GI, gastrointestinal; NMSC, non-melanoma skin cancers. *With or without surgery.
Table 4. Subsequent cancers Site
Time Between the Diagnosis of the 2 Malignancies ,1 year
Skin (NMSC) GI Prostate Breast AML Lung Total
1 y –4 y
5 y–9y
≥10 y
Total
0
4 2 1 1 1 1 10
4 2 1 1
0
1 1 6
4
Abbreviations: AML, acute myelogenous leukemia; GI, gastrointestinal; NMSC, non-melanoma skin cancers; y, year.
chemotherapy for PCNSL: 4 had received radiation, and 3 were treated with combined modality. One patient had been treated with rituximab alone. Of the 29 patients treated with ASCT for PCNSL, 4 (13.79%) developed subsequent cancers after autologous transplant. One patient had also received radiation for relapse after transplant. The latency between transplant and second cancer ranged from 0.5 – 7years. The conditioning regimens were non-TBI based. The 4 subsequent cancers were one each: NMSC, breast cancer, lung cancer, and prostate cancer (see Table 5). Two (20%) of the 10 patients had died by the end of the study. Two cases were identified with both prior cancer and subsequent cancer. One case was a male, aged 72 years at the time he was diagnosed with PCNSL. He had a history of histologically confirmed prostate cancer 8 years prior to PCNSL and was treated with surgery only for the prostate cancer. He achieved his first complete remission (CR) for PCNSL with chemotherapy containing methotrexate, rituximab, and temozolomide and was maintained with temozolomide. The lymphoma recurred
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Prostate Skin (NMSC) GI Breast ENT Thyroid Lung Uterine Kidney Total
Table 3. Treatment of the prior or synchronous primary malignancy in patients with primary central nervous system lymphoma
Wang et al.: Second Malignancies in PCNSL
Table 5. Treatment of primary central nervous system lymphoma in patients with subsequent cancers Site
Chemotherapy Alone
Chemotherapy and ASCT
1 1
1
Chemotherapy and Radiotherapy
Radiotherapy Alone
Chemotherapy, ASCT, and Radiotherapy
1
Other
1
1 1 1 1
2
1 3
2
1
1
1
Abbreviations: AML, acute myelogenous leukemia; ASCT, autologous stem cell transplantation; GI, gastrointestinal; NMSC, non-melanoma skin cancers.
2 years later in the testicle. He managed to achieve his second CR after resection and 30 Gy of local radiation in 15 fractions. He was diagnosed with AML 4 years after his lymphoma and died from the disease with no additional therapy. The other case was a female who had PCNSL diagnosed at the age of 65 years. She had been diagnosed with lung cancer 9 years before the PCNSL. Surgery was performed for her lung cancer without any radiation or chemotherapy. She underwent anthracycline-containing chemotherapy combined with radiation for treatment of the PCNSL and achieved a first CR. She was treated with methotrexate, rituximab, and temozolomide for relapse 3 years later but only achieved a partial remission. She developed GI-type 3A hilar cholangiocarcinoma at the age of 69 years and entered hospice care.
Discussion Previous studies have described SMs in patients with NHL. This current study focused on the SMs that developed in 129 patients identified with PCNSL. These are the most data related to SM in patients with PCNSL. In this study, we found that SMs were not uncommon in this population, with a total proportion of 23.26% (30/129). Not only were subsequent malignancies observed (7.75%), as in other studies of the NHL population, but a significant number of prior cancers (9.30%) and synchronous cancers (6.20%) were also identified. Recent studies1,2,6,7,12 – 16 have reported that patients with NHL are at high risk for subsequent malignancy, with an overall rate of 4.2% –8.8%. We cannot compare the standard incidence ratio (SIR) in this study with other studies, nor can we reach a conclusion due to the limited sample size in this study. However, given the high percentage and the relative short follow-up time, these percentages may actually be an underestimation of the true incidence. It is reasonable to suspect that these patients may have had a higher risk of second cancers than non-PCNSL NHL patients. Male sex has been considered a risk factor for SM in NHL patients in some studies,2,16 but other studies have proposed a similar or higher overall risk for females.1,6 In our study, the male:female ratio of the 129 patients with PCNSL was 1.02:1,
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whereas it was 1.50:1 for patients with SM. The ratio was similar (1.56:1) when sex-specific cancer sites were excluded, indicating a possible male preference. The initial purpose of the previous studies in secondary malignancies was to investigate the delayed effects of treatment. In this study, most of the subsequent cancers can be explained as late effects of treatment according to previous reports. Whole brain radiation or chemotherapy is the first-line therapeutic strategy for PCNSL. Chemotherapy is an established risk factor for SM after NHL. AML, bladder cancer, and lung cancer have been reported to be the most frequent SMs in patients treated with chemotherapy, especially those with alkylating agents.7,17 Radiation has been associated with a significantly elevated risk of secondary lung cancer, bladder cancer, thyroid cancer, and female breast cancer.1,2,5,6 As far as non-HIV-related diffuse large B-cell lymphoma is concerned, only the risk of developing AML was significantly elevated.7 Despite the alkylator-based chemotherapy regimen in 8 patients, AML was observed in only one patient 4 years after diagnosis of PCNSL. Bladder cancer was not observed as a SM, which may have been due to the small sample size in this study. NMSC appeared to be a predominant SM in this study. Interestingly, this cancer was excluded from most of the previous registry-based studies of SM in patients with NHL because of the incomplete data entered into the databases.1,2,4 – 7,18 Out of the 10 cases with subsequent cancers, 4 secondary NMSCs were identified. We cannot exclude the late effects of radiation since one patient had been exposed to radiation, and the skin lesions were located in the radiation fields. ASCT has also been introduced recently to achieve durable complete remissions in PCNSL patients. SM is a big concern after stem cell transplantation since it is the most common cause of nonrelapse mortality. T-MDS/AML and solid tumors are the most frequently seen. The incidence of solid tumors following ASCT varies from 0.2% – 4% at 20 years.19 The risk for (therapy-related myelodysplastic syndrome) t-MDS/AML seems to be highest in the first decade after transplantation, whereas the risk for solid tumors persists for at least 20 years.20 In this report, second solid tumors such as lung cancer, prostate cancer, and skin cancer were seen in 13.8% patients (4/29) after ASCT. The latency between transplant and second
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Skin (NMSC) GI Prostate Breast AML Lung Total
Treatment of Primary Central Nervous System Lymphoma
Wang et al.: Second Malignancies in PCNSL
Neuro-Oncology
immunosuppressed state of the host. PCNSL, however, is generally an aggressive lymphoma. The significant incidence of synchronous cancers in our study may be due to immunosuppression of PCNSL patients if the hypothesis previously proposed with low-grade lymphomas is proven. We are unable to further investigate the mechanisms underlying synchronous PCNSL due to the limited number of cases. Compared with the data of SM in patients with systemic NHL in other studies, our study showed that the prognosis of concomitant PCNSL was extremely poor, with only one patient with synchronous malignancies surviving during the studied period. In addition, patients with PCNSL as a primary cancer seemed to have a better outcome than patients with PCNSL as a second or concomitant cancer. The mortality in this review was 20%, 66.67%, and 87.50%, respectively. This may be partly due to the younger age and better performance scores of the primary group, which have been previously shown to be important prognostic factors.10 Another possible reason is that patients in the primary group are all survivors of PCNSL, with better responses to the treatment, whereas PCNSL is lethal in the subsequent or concomitant group. Compared with second cancer prior or subsequent to PCNSL, clinicians may need to be more alert when a second cancer occurs simultaneously with PCNSL. Furthermore, since synchronous malignancies may be more common in patients with PCNSL, the diagnosis of intracranial metastasis from a primary systemic malignancy other than lymphoma, when the brain mass decreases significantly with steroid treatment, may need further investigation. There was a high incidence of NMSC in the study population. NMSC was observed in 8 cases with PCNSL. Three patients had their NMSC diagnosed prior to PCNSL, one patient was diagnosed simultaneously, and 4 patients were diagnosed subsequently. It is possible that the subsequent NMSC can be attributed to the late effects of treatment for PCNSL. It is unlikely, however, to be the cause in other cases. Previous studies have examined possible links between skin cancers and NHL. A strong association of increased risk for subsequent NHL in patients with skin cancers has been identified. Among those reports from large population-based cancer registries, most reported melanoma, which was absent from our study.32 – 35 Several other studies found an elevated risk of NHL among patients with NMSC.32,36 – 39 Some reported that the risk for NMSC patients was even higher than that for melanoma patients.8,33 In a Danish cohort study, history of NMSC was suggested to be associated with significantly increased mortality of patients diagnosed with NHL before the age of 80 years.40 In addition, an increased risk of NMSC after other malignancies, especially those of hematological origin, has also been reported.8,33 Thus, immunosuppression is suggested to be the common risk factor for both malignancies.8 In summary, this study showed that SM in patients with PCNSL is not uncommon. Clinicians should be alert to the possibility of a synchronous PCNSL versus CNS metastasis when a brain mass is found at the diagnosis of other malignancies. Those doing long-term follow-up of patients with PCNSL should also be aware of the significant incidence of subsequent cancers. Synchronous PCNSL with other systemic malignancies may be a signal for poor prognosis. In addition, the high incidence of subsequent cancer and synchronous cancer, as well as the frequently seen NMSCs, may all highlight the
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cancer ranged from 0.5 years – 7 years. Overall, except for the absence of t-MDS/AML, the sites and latency of SMs in this study are consistent with the late effects of treatment according to previous studies.19 – 23 However, the incidence may be underestimated due to the short follow-up time in this study. The underlying pathophysiology behind development of other cancers may suggest not only a treatment factor but also an intrinsic mechanism, possibly involving immune defects as suggested in indolent lymphomas.24 As with SM studies in patients with solid organ malignancies, studies of SMs associated with lymphoid malignancies have looked for genetic factors, treatment-related effects, and possible immune defects as causes. As a rare brain tumor, primary CNS lymphoma is even more rarely seen as a SM in immunocompetent patients. Until now, there have been only sporadic reports about PCNSL as a second or concomitant malignancy with very limited cases.25 – 27 Deangelis et al reported the largest case series27 of PCNSL as a SM, identified 7 cases, 2 of which had systemic lymphoma as their first malignancy. Four patients were diagnosed with biopsy. The median age was 69 years at the time of PCNSL diagnosis. Another case series presented 4 cases (8%) of PCNSL with prior malignancies.26 According to the previous studies, the median latency between the 2 malignancies was 8 –10 years. The nonhematological sites of original cancers in these studies included breast (4), colon and rectum (3), lung (3), head and neck (2), prostate (2), kidney (1), brain (glioblastoma) (1), uterus (1), and thyroid (1). Only one case of synchronous cancer was observed (prostate). There was no evidence that any late complications of treatment for the primary cancer accounted for their subsequent PCNSL in these patients. In our study, 20 patients (15.50%) had a prior or concomitant malignancy. Except for the synchronous cases, 83.3% (10/12) of patients developed PCNSL 5 years after their first malignancy. The median age at diagnosis of PCNSL was 67 years, and median latency was 8 years, consistent with the previous studies. Sites were similar except for 4 cases of NMSC, which have never been reported before. Interestingly, when combining our data with all of the other case reports, breast, prostate, and colon cancers seemed much more prevalent than other cancers. This may be attributed to the long-term survival of patients with these 3 kinds of tumors. Alternatively, it may suggest some potential connection, rather than coincidence, between PCNSL and these tumors. Similar to the previous studies, no immune disorders were identified in these patients, nor could any late effects of treatment explain the etiology of the PCNSL since surgery was the only treatment for most of them. Possible reasons may be genetic predisposition or acquired susceptibility caused by immunological impairment. We observed 8 synchronous malignancies in these immunocompetent patients in our study. Synchronous malignancies have been well documented in immunocompromised patients; they are unusual, however, in immunocompetent patients. An autopsy study of 1870 cases showed synchronous cancers in only 15 (0.8%) of the 68 patients with multiple primary cancers.28 In our study, the proportion was as high as 6.20% (8/ 129). Most of the synchronous lymphomas in previous reports29 – 31 were low grade and had a good prognosis. Therefore, it was hypothesized that low-grade lymphoma was susceptible to synchronous cancers due to the
Wang et al.: Second Malignancies in PCNSL
immunosuppression state in patients with PCNSL. This singleinstitution study is limited by small sample size and a short mean follow-up of 44.8 months, which may be insufficient to estimate the true risk of second cancer. Moreover, as a descriptive study, it was uncontrolled. Potential bias may exist because the selection and data collection depended mainly on the availability and accuracy of medical records. A multicenter study of SMs in patients with this disease is necessary and should include investigation of NMSC.
primary central nervous system lymphoma. Leukemia. 2011; 25(12):1797 –1807. 11.
Gluckman JL, Crissman JD, Donegan JO. Multicentric squamous-cell carcinoma of the upper aerodigestive tract. Head Neck Surg. 1980;3(2):90– 96.
12.
Travis LB, Curtis RE, Boice JD Jr., et al. Second cancers following non-Hodgkin’s lymphoma. Cancer. 1991;67(7):2002–2009.
13.
Travis LB, Curtis RE, Glimelius B, et al. Second cancers among long-term survivors of non-Hodgkin’s lymphoma. J Natl Cancer Inst. 1993;85(23):1932 –1937.
14.
Brennan P, Coates M, Armstrong B, et al. Second primary neoplasms following non-Hodgkin’s lymphoma in New South Wales, Australia. Br J Cancer. 2000;82(7):1344–1347.
Funding
Acknowledgments Special thanks is given to Dr. Ivana Micallef for critical review of the manuscript.
Conflict of interest Statement: None declared.
References 1.
Dores GM, Cote TR, Travis LB. New malignancies following Hodgkin lymphoma, non-Hodgkin lymphoma and myeloma (NIH Pub. No. 05-5302). In: Curtis RE, Freedman DM, Ron E, eds. New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973-2000. Bethesda, MD: National Cancer Institute; 2006:397 –428.
2.
Mudie NY, Swerdlow AJ, Higgins CD, et al. Risk of second malignancy after non-Hodgkin’s lymphoma: a British Cohort Study. J Clin Oncol. 2006;24(10):1568– 1574.
3.
Pirani M, Marcheselli R, Marcheselli L, et al. Risk for second malignancies in non-Hodgkin’s lymphoma survivors: a meta-analysis. Ann Oncol. 2011;22(8):1845– 1858.
15. Dong C, Hemminki K. Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958 – 1996: a search for common mechanisms. Br J Cancer. 2001;85(7):997– 1005. 16. Sacchi S, Marcheselli L, Bari A, et al. Secondary malignancies after treatment for indolent non-Hodgkin’s lymphoma: a 16-year follow-up study. Haematologica. 2008;93(3):398– 404. 17. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst. 1995;87(7):524– 530. 18.
Ellis M, Lishner M. Second malignancies following treatment in non-Hodgkin’s lymphoma. Leuk Lymphoma. 1993;9(4 – 5): 337– 342.
19. Minn AY, Riedel E, Halpern J, et al. Long-term outcomes after high dose therapy and autologous haematopoietic cell rescue for refractory/relapsed Hodgkin lymphoma. Br J Haematol. 2012; 159(3):329 –339. 20.
Burns LJ. Late effects after autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(1 Suppl): 21 –24.
21. Seshadri T, Pintilie M, Kuruvilla J, et al. Incidence and risk factors for second cancers after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Leuk Lymphoma. 2009;50(3):380 –386. 22. Baker KS, DeFor TE, Burns LJ, et al. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21(16): 1352– 1358.
4.
Sacchi S, Marcheselli L, Bari A, et al. Second malignancies after treatment of diffuse large B-cell non-Hodgkin’s lymphoma: a GISL cohort study. Haematologica. 2008;93(9):1335–1342.
5.
Tward J, Glenn M, Pulsipher M, et al. Incidence, risk factors, and pathogenesis of second malignancies in patients with non-Hodgkin lymphoma. Leuk Lymphoma. 2007;48(8): 1482 –1495.
23.
6.
Tward JD, Wendland MM, Shrieve DC, et al. The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma. Cancer. 2006;107(1):108 –115.
24. Reed JC, Kitada S, Kim Y, et al. Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. Semin Oncol. 2002;29(1 Suppl 2):10– 24.
7.
Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol. 2010;28(33): 4935–4944.
25. Padhi S, Banerjee S, Das S, et al. Primary CNS lymphoma as second malignancy in a case of carcinoma larynx treated with chemoradiation. Eur J Cancer Care (Engl). 2009;18(5):517–520. 26.
8.
Hemminki K, Jiang Y, Steineck G. Skin cancer and non-Hodgkin’s lymphoma as second malignancies. markers of impaired immune function? Eur J Cancer. 2003;39(2):223– 229.
Reni M, Ferreri AJ, Zoldan MC, et al. Primary brain lymphomas in patients with a prior or concomitant malignancy. J Neurooncol. 1997;32(2):135 –142.
27.
9.
Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol. 2007;3(1):24 –35.
DeAngelis LM. Primary central nervous system lymphoma as a secondary malignancy. Cancer. 1991;67(5):1431– 1435.
28.
10.
Deckert M, Engert A, Bruck W, et al. Modern concepts in the biology, diagnosis, differential diagnosis and treatment of
Lee TK, Myers RT, Scharyj M, et al. Multiple primary malignant tumors (MPMT): study of 68 autopsy cases (1963 – 1980). J Am Geriatr Soc. 1982;30(12):744–753.
134
Jantunen E, Itala M, Siitonen T, et al. Late non-relapse mortality among adult autologous stem cell transplant recipients: a nation-wide analysis of 1,482 patients transplanted in 1990 – 2003. Eur J Haematol. 2006;77(2):114– 119.
Downloaded from http://neuro-oncology.oxfordjournals.org/ at New York University on April 30, 2015
Supported in part by Mayo SPORE in Brain Cancer (P50 CA108961), University of Iowa/Mayo SPORE in Lymphoma (P50 CA97274) and an unrestricted grant from Research to Prevent Blindness Inc.
Wang et al.: Second Malignancies in PCNSL
29.
Cuff KE, Dettrick AJ, Chern B. Synchronous breast cancer and lymphoma: a case series and a review of the literature. J Clin Pathol. 2010;63(6):555– 557.
30. Kunthur A, Wiernik PH, Dutcher JP. Renal parenchymal tumors and lymphoma in the same patient: case series and review of the literature. Am J Hematol. 2006;81(4):271–280. 31.
Hu XR, Hu YX, Fu HR, et al. Diffuse large B-cell lymphoma with concurrent gastric adenocarcinoma: case report and literature review. J Int Med Res. 2011;39(5):2051–2058.
35.
McKenna DB, Stockton D, Brewster DH, et al. Evidence for an association between cutaneous malignant melanoma and lymphoid malignancy: a population-based retrospective cohort study in Scotland. Br J Cancer. 2003;88(1):74 –78.
36. Wheless L, Black J, Alberg AJ. Nonmelanoma skin cancer and the risk of second primary cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1686–1695. 37. Frisch M, Melbye M. New primary cancers after squamous cell skin cancer. Am J Epidemiol. 1995;141(10):916– 922.
32.
Hu S, Federman DG, Ma F, et al. Skin cancer and non-Hodgkin’s lymphoma: examining the link. Dermatol Surg. 2005;31(1): 76 –82.
38.
33.
Adami J, Frisch M, Yuen J, et al. Evidence of an association between non-Hodgkin’s lymphoma and skin cancer. BMJ. 1995; 310(6993):1491 –1495.
39. Hemminki K, Dong C. Subsequent cancers after in situ and invasive squamous cell carcinoma of the skin. Arch Dermatol. 2000;136(5): 647–651.
34.
Goggins WB, Finkelstein DM, Tsao H. Evidence for an association between cutaneous melanoma and non-Hodgkin lymphoma. Cancer. 2001;91(4):874 –880.
40. Hjalgrim H, Frisch M, Storm HH, et al. Non-melanoma skin cancer may be a marker of poor prognosis in patients with non-Hodgkin’s lymphoma. Int J Cancer. 2000;85(5):639 –642.
135
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Neuro-Oncology
Levi F, Randimbison L, Te VC, et al. Non-Hodgkin’s lymphomas, chronic lymphocytic leukaemias and skin cancers. Br J Cancer. 1996;74(11):1847 – 1850.
