Original Articles
Malignant (Diffuse) Mesothelioma in Patients With Hematologic Malignancies A Clinicopathologic Study of 45 Cases Xin Li, MD; Noel A. Brownlee, MD, PhD; Thomas A. Sporn, MD; Annabelle Mahar, MBBS, FRCPA; Victor L. Roggli, MD
Context.—Ionizing radiation has a role in the development of malignant mesothelioma, in several epidemiologic studies, including patients with hematologic malignancies. Objective.—To study the clinicopathologic characteristics of patients with malignant mesothelioma and hematologic malignancies with and without a history of radiotherapy. Design.—From a database of approximately 3600 patients with malignant mesothelioma, we identified 45 patients (1%) who also had hematologic malignancies. We examined clinicopathologic features and noted whether the patient had received radiotherapy for malignancy, comparing those with and those without such exposure. Results.—Among the 45 cases, 18 (40%) had Hodgkin lymphoma, 15 (33%) had non-Hodgkin lymphoma, 10 (4%) had chronic lymphocytic leukemia, and 2 (22%) had chronic myelogenous leukemia; 20 patients (44%) had a history of radiotherapy, and 23 (51%) did not. Most patients with Hodgkin lymphoma (16 of 18; 90.0%)
received radiation, whereas none of the patients with leukemia (0 of 12) and only 20% (3 of 15) of the patients with non-Hodgkin lymphoma did so. Patients without radiation were older than patients who received radiotherapy (median, 73 versus 54 years, respectively; P , .001), had a shorter interval from diagnosis of hematologic malignancy to that of mesothelioma (median, 2 versus 24 years, respectively; P , .001), and had a shorter survival period (median, 6.0 versus 14.0 months, respectively; P ¼ .02). Epithelial mesotheliomas were proportionately more common in patients with a history of radiotherapy. Conclusions.—Patients with mesothelioma and hematologic malignancies with a history of radiation tended to be younger, had a longer interval from diagnosis of hematologic malignancy to that of mesothelioma, had a longer survival period, and were more likely to have the epithelial variant compared with patients without radiotherapy. (Arch Pathol Lab Med. 2015;139:1129–1136; doi: 10.5858/arpa.2014-0569-OA)
M
to confirm those findings.8–10 Furthermore, epidemiologic studies have generally failed to confirm an increased risk of hematologic malignancies in association with asbestos exposure.11–15 Consequently, asbestos is not regarded as a human lymphoid carcinogen, although asbestos fibers have been reported in lymph nodes and bone marrow.16–18 Although hematologic malignancies have been reported in experimental animals exposed to asbestos via inhalation or inoculation, no statistically increased incidence of those malignancies was detected.19–21 However, at least one study22 suggested that asbestos might interact with ionizing radiation in the process of oncogenic transformation. Ionizing radiation has been linked to malignant mesothelioma both in animals and in humans.23–39 Sanders and Jackson23 reported that 27% of rats treated with plutonium particles developed malignant mesotheliomas and concluded that the pathogenesis of malignant mesotheliomas induced by radioactive particles seemed similar to that of mesothelioma after intracavitary administration of asbestos. Several forms of ionizing radiation have been related to the development of malignant mesothelioma, including administration of Thorotrast (an x-ray contrast medium),24 working at nuclear facilities,25–26 and radiation treatment for first primary malignancies.27–39 Case reports29–33 of patients developing malignant mesothelioma within or
alignant mesothelioma is a universally fatal malignancy with most cases attributable to prior asbestos exposure.1 A number of case reports have suggested a relationship between asbestos exposure and hematologic malignancies, including non-Hodgkin lymphoma, leukemia, and multiple myeloma/plasmacytoma.2–6 Whereas Ross et al7 reported that primary large cell lymphomas of the gastrointestinal tract and oral cavity were related to asbestos exposure in a case-control study, subsequent studies failed Accepted for publication December 30, 2014. Published as an Early Online Release April 6, 2015. From the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Drs Roggli and Sporn); the Department of Pathology, Tianjin Haihe Hospital, Tianjin Institute of Respiratory Diseases, Tianjin, China (Dr Li); the Pathology Associates of Greenville, Greenville, South Carolina (Dr Brownlee); and the Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (Dr Mahar). Dr Roggli has consulted with plaintiff and defense attorneys in asbestos litigation in the United States and abroad. The other authors have no relevant financial interest in the products or companies described in this article. Reprints: Victor L. Roggli, MD, Department of Pathology, Duke University Medical Center, Box 3712, Durham, NC 27710 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 139, September 2015
Mesothelioma and Hematologic Malignancies—Li et al 1129
Table 1.
Characteristics of 45 Patients With Malignant Mesothelioma (MM) and Hematologic Malignancy Age,a y/Sex
Diagnostic Interval, y
Age at MM Diagnosis, y
MM Histology
69/M b /M 69/M 87/M b /M 73/M 64/M 76/M 85/M NA/M 65/M 82/M
2 NA 0 0 NA 2 5 5 0 NA 5 0
71 73 69 87 77 75 69 81 85 87 70 82
Sarcomatoid Epithelial Sarcomatoid Sarcomatoid Epithelial Epithelial Biphasic* Sarcomatoid Epithelial Epithelial Epithelial Biphasic
CML CLL SLL/CLL CLL CLL CLL/SLL CLL CML CLL CLL CLL CLL
Non-Hodgkin lymphoma 13 29/F 14 67/M
16 10
45 77
Epithelial Desmoplastic
Case No. Leukemia 1 2 3 4 5 6 7 8 9 10 11 12
Leukemia/Lymphoma Classification
15 16 17 18 19 20
72/M 67/M 64/F 64/M 63/M 57/M
5 2 11 7 2 8
77 69 75 71 65 65
Sarcomatoid Epithelial Biphasic Desmoplastic Desmoplastic Epithelial
Diffuse large B-cell lymphoma Poorly differentiated lymphocytic lymphoma (parotid gland) MALT lymphoma (stomach) SLL Follicular B-cell type Gastric lymphoma Follicular lymphoma, grade 2 NHL
21 22 23 24 25 26 27
56/M NA/M 26/M 73/M 78/M 9/F 67/M
0 NA 42 0 2 55 6
56 67 68 73 80 64 73
Biphasic Biphasic Sarcomatoid Sarcomatoid Epithelial Epithelial Biphasic
Mantle zone lymphoma NHL; prostate adenocarcinoma Follicular lymphoma, stage IV NHL Diffuse follicular center lymphoma, grade 1 Lymphosarcoma Diffuse large B-cell lymphoma
Hodgkin lymphoma 28 52/M 29 34/M 30 70/M 31 22/F 32 20/F
1 20 0 9 24
53 54 70 31 44
Biphasic Epithelial Epithelial Epithelial Epithelial
33
24/M
11
35
Epithelial*
HL, nodular sclerosis HL, HL, nodular sclerosis HL, nodular sclerosis HL, nodular sclerosis carcinoma HL
type
34 35 36 37 38 39 40 41 42 43 44 45
24/F 10/M 19/M 43/M 29/M 35/M 82/F 22/F 46/M 19/M 15/M 25/M
16 32 37 26 20 23 3 32 24 31 38 39
40 42 56 69 49 58 85 54 70 50 53 64
Biphasic Epithelial Epithelial Epithelial Epithelial* Epithelial Epithelial Epithelial Biphasic Biphasic Epithelial Epithelial
HL, nodular sclerosis type HL HL HL HL HL HL; breast cancer HL HL, nodular lymphocytic predominant type HL HL HL
type type type; papillary thyroid
Abbreviations: þ (plus), presence; (minus), absence; * (asterisk), peritoneal mesothelioma; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MALT, mucosa-associated lymphoid tissue; NA, not available; ND, further data regarding smoking history not available; NHL, non-Hodgkin lymphoma; NP, not performed; NS, nonsmoker; ppd, packs/d; SLL, small lymphocytic lymphoma; wkr, worker; XS, ex-smoker. a Age at time of diagnosis with leukemia or lymphoma. b Many years previously.
adjacent to radiation fields were followed by large-scale retrospective cohort studies, using data from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results program, indicating an increased risk of malignant mesothelioma in patients receiving radiotherapy for primary malignancies. Patients at risk included those treated for Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer, and breast cancer.34–39 1130 Arch Pathol Lab Med—Vol 139, September 2015
The occurrence of both malignant mesothelioma and hematologic malignancy in the same individual is a rare event. We identified 45 such patients in a database including more than 3600 cases of malignant mesothelioma, including 18 (40%) with Hodgkin lymphoma, 15 (33%) with non-Hodgkin lymphoma, and 12 (27%) with leukemia. We identified the clinical and pathologic features of those 45 cases, including demographic and survival data, Mesothelioma and Hematologic Malignancies—Li et al
Table 1. Extended Occupation/y
Asbestos Exposure Duration, y
Pleural Plaques and Asbestosis
Smoking History, ppd (y)/XS, y
Pipefitter Merchant marine; radiologist Boiler maker US Navy/4; power plant wkr/6; chemical plant wkr/31 Merchant marine/5; oil refinery wkr/29 Electrician Insulator (steel mills and power plants) NA Electric power plants, asbestos abatement Electrician Insulator Industrial electrician
50 1 28 41 34 8 42 NA 2–3 31 30 NA
Plaquesþ Asbestosis Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA)
1.5 (52)/2 2 (40)/6 NS NS 1 (27)/32 NS NA (13)/35 XS/ND NA (1)/60þ 1 (11)/57 NS NS
Household contact (husband-auto mechanic) NA
NA NA
Plaques Asbestosis Plaques (NA) Asbestosis (NA)
ND ND
Machinist, US Navy Foundry, power plant wkr Household contact (husband-pier wkr) Construction wkr Power plant wkr Shipyard mechanic/1; steel wkr/4; power plant wkr/32; paper mill wkr-exposed/4 mo Household contact (father-field technician) NA Electrician/construction wkr Chemical Co/4; auto mechanic/25; construction/7 Electrician Office wkr Pipefitter
25 36 30 20 28 37 þ 4 mo
Plaques Asbestosisþ Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA)
XS/ND NS 1–4 (57) XS/ND 1 (25)/18 NS
5 NA 44 36 36 NA NA
Plaques (NA) Asbestosis Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA)
ND ND XS/ND 1 (30)/43 NS 1 (10)/30 NS
Furnace technician Plasterer, optician Auto mechanic, asbestos factory Household contact (father-construction wkr) Household contact (father-field engineer)
NA NA 5 19 20
Plaques Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques Asbestosis Plaques Asbestosis (NA)
2–3 (ND) 3 (4)/35 NS 1 (11)/4 NS
Muffler shop assistant; household contact (stepfather-auto repair) Household contact (father-sheetmetal wkr) Auto mechanic/6; electrician/23 Electrician US navy/4; auto repair/32 Machinist; cabinet maker NA NA Household contact Taconite mine laborer Household contact (father-paper mill) Boiler wkr Airline mechanic
NA
Plaques (NA) Asbestosis (NA)
NS
28 29 14 36 NA NA NA NA 14 mo NA NA NA
Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA)
3–4 (11)/15 NS 1; pipe (10–12)/12 1–1.5 (17)/30 1 (30)/1–2 NS ND ND NS NS NS 5 (4)/20
site and histologic type of mesothelioma, asbestos exposure history, presence or absence of parietal pleural plaques or asbestosis, smoking history, and treatment history, including information available regarding the use of therapeutic radiation. In addition, we compared the clinicopathologic profiles of those cases with and without prior therapeutic radiation. MATERIALS AND METHODS Patient Selection Forty-five patients with a diagnosis of hematologic malignancy were identified in a database of more than 3600 consecutive cases Arch Pathol Lab Med—Vol 139, September 2015
of malignant mesothelioma, which comprised mainly professional and medicolegal consultation cases from 1982 to 2013. Information regarding patient age, sex, occupational history, smoking history, presence or absence of histologic asbestosis or parietal pleural plaques, treatment, and survival were obtained from medical records. The diagnosis of malignant mesothelioma was based on the gross distribution of tumor, histologic appearance, and the results of histochemical and immunohistochemical studies, as previously described.1 Histologic asbestosis40 and parietal pleural plaques41 were identified as present or absent according to published criteria. The diagnosis of lymphoma or leukemia was based on clinical and radiographic features, histologic patterns, and immunohistochemical features. Mesothelioma and Hematologic Malignancies—Li et al 1131
Statistical Analysis Exposure durations were compared with Student t tests. The interval from diagnosis of hematologic malignancy to the diagnosis of mesothelioma and ages were compared using the Kruskal-Wallis test. Other categoric data were compared by the Fisher exact test. Overall survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the statistical differences among groups. For all statistical analyses, a P value of less than .05 was considered statistically significant. Statistical analysis was performed using SAS version 9.4 statistical software (SAS Institute, Cary, North Carolina). Kaplan-Meier survival curves were drawn with SigmaPlot version 12.0 data graphing software (Systat Software, Inc, Chicago, Illinois).
RESULTS Demographic and Pathologic Findings Data for individual patients with both malignant mesothelioma and hematologic malignancy are listed in Table 1. Of the 45 patients, there were 37 men (82.0%) and 8 women (18.0%). The median age at diagnosis of malignant mesothelioma was 69 years (mean, 65 years; range, 31–87 years) and 57 years (mean, 50 years; range, 9–87 years) at diagnosis of hematologic malignancy. Most patients (25 of 45; 56.0%) had epithelial mesotheliomas, 10 patients (22.0%) had biphasic mesotheliomas, and 10 patients (22.0%) had sarcomatoid mesotheliomas (3 patients had desmoplastic mesotheliomas). Forty-two cases (93%) arose in the pleura and 3 (7%) in the peritoneum. The types of hematologic malignancy included 12 cases (27%) with leukemia, 15 cases (33%) with non-Hodgkin lymphoma, and 18 cases (40%) with Hodgkin lymphoma (Table 1; Figure 1, A through F). Among the 12 cases with leukemia, 8 (67%) were diagnosed with chronic lymphocytic leukemia (CLL), 2 (16%) with CLL/small lymphocytic lymphoma, and 2 (16%) with chronic myelogenous leukemia (Table 1). Three of 45 patients (7%) had 3 primary malignancies; in addition to mesothelioma and Hodgkin lymphoma, 1 patient had breast cancer, and another had papillary thyroid carcinoma (Table 1; cases 32 and 40). An additional patient with mesothelioma and non-Hodgkin lymphoma also had adenocarcinoma of the prostate (Table 1; case 22). The median interval from the diagnosis of a hematologic malignancy to the diagnosis of malignant mesothelioma was 8.0 years (mean, 13.9 years; range, 0–55 years). Eight cases (18%) with hematologic malignancy and malignant mesothelioma were diagnosed within 1 year of each other (Hodgkin lymphoma, 2 of 8 cases [25%]; non-Hodgkin lymphoma, 2 cases [25%]; CLL, 3 cases [38%]; CLL/small lymphocytic lymphoma, 1 case [13%]). Twenty-two patients (49%) were smokers or ex-smokers and 17 patients (38%) were nonsmokers. The remaining cases (n ¼ 6; 13%) were uninformative for smoking. Parietal pleural plaques were identified in 13 patients (29%) and were absent in 9 patients (20%) (the other cases [n ¼ 23; 51%] were uninformative for plaques). Histologic asbestosis was confirmed in 1 patient (2%) and absent in 11 (24%) (the remaining cases [n ¼ 33; 73%] were uninformative for asbestosis). Occupational Data Information regarding occupational exposure history was available in 39 of the 45 cases (87.0%), including 16 of 39 cases (41%) with prior therapeutic radiation and 21 cases 1132 Arch Pathol Lab Med—Vol 139, September 2015
(54%) without (Table 1). Several individuals worked in more than one exposure category. The largest exposure categories were household contact of an asbestos worker (9 of 39 cases; 23%) and boiler or power plant worker (9 of 39 cases; 23%). Information on duration of asbestos exposure was available for 8 patients with a history of radiotherapy, 19 patients without a history of radiotherapy, and 28 patients in total. The duration of exposure to asbestos was a mean (SD) of 23.9 (13.3) years for patients with a history of radiotherapy, 25.8 (14.8) years for patients without a history of radiotherapy (radiotherapy group versus nonradiotherapy group; P ¼ .76), and 25.6 (14.0) years for all cases with available information. No information was available regarding intensity of exposure for individual patients. Characteristics of Patients With or Without Past Radiation Therapy History Nineteen patients received radiation therapy for underlying malignancy 9 or more years before the diagnosis of malignant mesothelioma (Table 2). Twenty-three patients had no history of radiation therapy. One patient received radiation therapy for Hodgkin lymphoma 1.5 years before the diagnosis of mesothelioma. One patient with chronic myelogenous leukemia worked in a nuclear power plant for 20 years. For 2 additional cases, no information was available regarding treatment with radiation therapy. Men predominated in both of the 2 groups (group 1 [radiated], 12 of 19, 63.0%; group 2 [no radiation], 22 of 23, 96.0%), with women more common in the radiated group (P ¼ .01; Table 3). The age at the diagnosis of hematologic malignancy and malignant mesothelioma for group 1 was younger than it was for group 2 (P , .001). The duration from diagnosis of hematologic malignancy to the diagnosis of malignant mesothelioma in group 1 was longer than it was in group 2 (P , .001). Nearly all patients with Hodgkin lymphoma were treated with radiation therapy 9 years or more before the diagnosis (16 of 18; 89.0%). In contrast, none of the patients with leukemia and few patients with non-Hodgkin lymphoma (3 of 15; 20%) received radiotherapy. Most malignant mesotheliomas in the radiated group were epithelial (15 of 19; 79.0%); in the nonradiated group, 9 of 23 patients (39.0%) had sarcomatoid mesotheliomas, 9 of 23 (39.0%) had epithelial mesotheliomas, and 5 of 23 (22.0%) had biphasic mesotheliomas. Asbestosis (P . .99), plaques (P ¼ .16), and smoking history (P . .99) were not significantly different between the 2 groups (Table 3). Follow-up and Survival Analysis The median follow up time using censored data was 9.0 months (mean, 14.5 months; 95% confidence interval, 7.5– 21.4 months). Patients with a history of radiation had a significantly longer survival period than did those without a history of radiotherapy (median survival, 14.0 versus 6.0 months, respectively; P ¼ .02; Figure 2, A). Survival time in patients with epithelial mesotheliomas was not significantly different between groups (median survival, 18.0 versus 9.0 months, respectively; P ¼ .24; Figure 2, B). COMMENT We report a series of patients with malignant mesothelioma and hematologic malignancy and describe their clinicopathologic characteristics. This combination is an Mesothelioma and Hematologic Malignancies—Li et al
Figure 1. Case 30, a 70-year-old man with synchronous diagnosis of malignant pleural mesothelioma, epithelial variant, and the nodular sclerosis variant of Hodgkin lymphoma. A, Low-power view showing epithelial mesothelioma (right) and nodular sclerosis Hodgkin lymphoma (left). B, Same field as shown in A showing strong staining of the mesothelioma for calretinin (right). C, Higher-power magnification showing the detail of epithelial mesothelioma. D, Higher-power magnification showing strong nuclear staining of tumor cells for calretinin. E, Higher-power magnification of Hodgkin lymphoma showing detail of Reed-Sternberg cells. F, Positive membranous staining of Reed-Sternberg cells for CD15 (hematoxylin-eosin, original magnifications 34 [A], 320 [C], and 340 [E]; original magnifications 34 [B], 320 [D], and 340 [F]).
uncommon event, as we have observed 45 such cases in a series of more than 3600 mesotheliomas (approximately 1% of our cases). We categorized the cases into 3 groups: chronic leukemia (12 cases; 27%); non-Hodgkin lymphoma (15 cases; 33%); and Hodgkin lymphoma (18 cases; 40%). Arch Pathol Lab Med—Vol 139, September 2015
Most cases occurred in men, and most mesotheliomas were of the epithelial type. All but 3 cases arose in the pleura. Although asbestos exposure is considered the main cause of malignant mesothelioma, other factors have been implicated, including ionizing radiation.1 Patients treated Mesothelioma and Hematologic Malignancies—Li et al 1133
Table 2.
Characteristics of Patients With a History of Radiotherapy
Case No. Age, y/Sex MM Histology 13 23 26 29 31 32
45/F 68/M 64/F 54/M 31/F 44/F
Epithelial Sarcomatoid Epithelial Epithelial Epithelial Epithelial
33 34 35 36 37 38 39 40 41 42 43 44 45
35/M 40/F 42/M 56/M 69/M 49/M 58/M 85/F 54/F 70/M 50/M 53/M 64/M
Epithelial Biphasic Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Biphasic Biphasic Epithelial Epithelial
Lymphoma Classification Diffuse large B-cell lymphoma Follicular lymphoma, stage IV Lymphosarcoma HL HL, nodular sclerosis type HL, nodular sclerosis type; papillary thyroid carcinoma HL HL, nodular sclerosis type HL HL HL HL HL HL; breast cancer HL HL, nodular lymphocytic predominant type HL HL HL
Radiation PTD, y Survival, mo Survival Status 16 42 55 20 9 24
24 14 21 3 7 18
DOD DOD DOD DOD DOD DWD
11 16 32 37 26 20 23 27 32 24 30 35 35
10 4 99 17þ 3 25 NA NA 10 16 13 26þ 8
DOD DOD DOD AWD DOD DOD NA NA DOD DOD DOD AWD DOD
Abbreviations: AWD, alive with disease; DOD, dead of disease; DWD, dead with disease; HL, Hodgkin lymphoma; MM, malignant mesothelioma; NA, not available; PTD, years before the diagnosis of mesothelioma.
Table 3.
Demographic and Histologic Characteristics of 42 Patientsa With Mesothelioma and Hematologic Malignancy With and Without Prior Radiation Therapy
Demographic and Histologic Characteristics
Prior Radiation, n ¼ 19
No Prior Radiation, n ¼ 23
Sex, No. (%) F M
7 (37) 12 (63)
1 (4) 22 (96)
Age, y Mean (SD) Median Range
54.3 (13.6) 54 31–85
73.8 (7.4) 73 56–87
Age at lymphoma/leukemia diagnosis,b y Mean (SD) Median Range
28.1 (16.2) 24 9–82
69.5 (8.2) 68 56–87
Diagnostic interval,b y Mean (SD) Median Range
26.2 (12.8) 24 3–55
3.5 (3.6) 2 0–11
Histology of malignant mesothelioma, No. (%) Epithelial Biphasic Sarcomatoid
15 (79) 3 (16) 1 (84)
9 (39) 5 (39) 9 (39)
Histology of lymphoma or leukemia, No. (%) Hodgkin lymphoma Non-Hodgkin lymphoma Leukemia
16 (84) 3 (16) 0 (0)
1 (4) 10 (43) 12 (52)
Smoking history,c No. (%) Smokers or ex-smokers Nonsmokers
9 (47) 7 (37)
12 (52) 9 (39)
Histologic asbestosis,d No. (%) Presence Absence
0 (0) 5 (26)
1 (4) 5 (22)
Parietal pleural plaques,e No. (%) Presence Absence
3 (16) 5 (26)
10 (43) 3 (13)
P .01
,.001
,.001
,.001
.003
.01
..99
..99
.16
a
No information was available regarding treatment with radiation therapy in 2 cases, and 1 patient receiving radiotherapy 18 mo before the diagnosis of mesothelioma was excluded. Information was unavailable in 3 cases. c Information was unavailable in 5 cases. d No data were available in 31 cases. e Information was unavailable in 21 cases. b
1134 Arch Pathol Lab Med—Vol 139, September 2015
Mesothelioma and Hematologic Malignancies—Li et al
Figure 2. A, Kaplan-Meier survival curves for patients with malignant mesothelioma and hematologic malignancy, with and without prior radiation treatment for the hematologic malignancy. Survival was measured from the time of diagnosis of mesothelioma. Those undergoing prior radiation had better survival (P ¼ .02). B, Kaplan-Meier survival curves for patients with the epithelial variant of malignant mesothelioma and hematologic malignancy, with and without prior radiation treatment for the hematologic malignancy. There is a trend toward better survival in the group receiving radiation therapy, but the difference is not statistically significant (P ¼ .24).
with radiation for Hodgkin lymphoma have been reported to develop second primary malignancies (including mesothelioma) since the 1970s.27,28 Therefore, we decided to examine the clinicopathologic features of our cases treated with radiation, compared with those who did not receive radiotherapy. We previously reported patients with postradiation mesotheliomas having a latency interval of 7 to more than 50 years.42 Using these criteria, we found that there were 19 cases treated with radiation more than 7 years before the diagnosis of mesothelioma, and 23 patients who did not receive radiation. Of the 19 patients with prior radiation, 16 (84%) had Hodgkin lymphoma and 3 (16%) had non-Hodgkin lymphoma (Tables 1 and 2). The median interval from radiation treatment to the diagnosis of mesothelioma was 26 years (range, 9–42 years). The predominant histologic type in patients receiving prior radiotherapy was epithelial mesothelioma (15 of 19 cases; 79%). This finding is similar to the histologic types of postradiation mesotheliomas reported by Chirieac et al.43 Two of the 22 cases (9%) in that series were pleomorphic epithelial mesotheliomas, a histologic pattern typically having a poor prognosis.43 One of our cases (case 44; Tables 1 and 2) was the pleomorphic variant, and, as was the case in the Chirieac et al43 series, that patient had a longer than expected survival period. Indeed, our patients with postradiation mesothelioma had significantly longer survival periods than did the patients without radiation (Figure 2, A). However, when we controlled for histologic type, the survival difference was no longer significant (Figure 2, B). This is likely due to the known poor survival in sarcomatoid mesotheliomas,44 which were more common in the nonirradiated group. Nonetheless, there was still a trend toward longer survival in the postradiation group, and the lack of statistical significance may have been due to the few cases. Several of our postradiation cases had parietal pleural plaques (cases 36, 37, and 43; Table 1). In one additional case (case 23; Table 1), a fiber analysis of lung tissue demonstrated an elevated level of amosite asbestos fibers. These cases satisfy published criteria for a diagnosis of asbestos-related mesothelioma.45 Experimental studies22 have reported an interaction between ionizing radiation and asbestos in the process of malignant transformation. Further studies will be necessary to determine whether the interaction is additive, synergistic, or something in between. Arch Pathol Lab Med—Vol 139, September 2015
Two of our postradiation cases were peritoneal mesotheliomas (cases 33 and 38; Table 1). Individuals radiated for Hodgkin lymphoma may, therefore, be at increased risk for peritoneal, in addition to pleural, mesothelioma.29,31–33 One additional patient (case 40; Table 1) was diagnosed with Hodgkin lymphoma only 3 years before the diagnosis of mesothelioma but had received radiation for breast cancer 27 years before the diagnosis of mesothelioma. Patients receiving radiation therapy for breast cancer have an increased risk for subsequent development of mesothelioma.38 Hodgkin lymphoma has similarly been reported following radiation treatment.46,47 For many of our cases, the occurrence of mesothelioma and hematologic malignancy may have been a matter of chance. This is particularly true for cases of CLL because this is a fairly common disorder among elderly individuals, and mesothelioma also tends to occur among the elderly. The median age for patients with CLL and mesothelioma was 76 years (range, 69–87 years). A similar argument could be applied to the 12 patients with non-Hodgkin lymphoma who had not undergone radiotherapy before the diagnosis of mesothelioma. However, it should be noted that BAP1 (BRCA1 associated protein 1), which is mutated in many malignant mesotheliomas, has been reported to have a role in the regulation of hematopoietic stem cell function.48–50 Further studies will be needed to clarify whether this or other molecular pathways have a role in the simultaneous occurrence of mesothelioma and hematologic malignancies. There are a number of limitations in the present study, including lack of information regarding radiation dose and intensity of asbestos exposure. Furthermore, for many cases, information was unavailable regarding the presence or absence of asbestosis or parietal pleural plaques. Such information would be useful to explore the potential interaction between radiation and asbestos in the pathogenesis of mesothelioma. In conclusion, patients with malignant mesothelioma and a prior history of ionizing radiation for hematologic malignancies have some noted differences from patients with mesothelioma and hematologic malignancy without prior radiation. These include younger age at the diagnosis of hematologic malignancy and malignant mesothelioma, longer duration from diagnosis of hematologic malignancy to diagnosis of mesothelioma, and longer survival times. In addition, the hematologic malignancy in the former group is more likely to be Hodgkin disease, and the histologic type of mesothelioma is more likely to be epithelial. Mesothelioma and Hematologic Malignancies—Li et al 1135
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27. Brody RS, Schottenfeld D, Reid A. Multiple primary cancer risk after therapy for Hodgkin’s disease. Cancer. 1977;40(4)(suppl):1917–1926. 28. Tester WJ, Kinsella TJ, Waller B, et al. Second malignant neoplasms complicating Hodgkin’s disease: the National Cancer Institute experience. J Clin Oncol. 1984;2(7):762–769. 29. Babcock TL, Powell DH, Bothwell RS. Radiation-induced peritoneal mesothelioma. J Surg Oncol. 1976;8(5):369–372. 30. Austin MB, Fechner RE, Roggli VL. Pleural malignant mesothelioma following Wilms’ tumor. Am J Clin Pathol. 1986;86(2):227–230. 31. Tassile D, Roth AD, Kurt AM, Rohner A, Morel P. Colon cancers and peritoneal mesothelioma occurring 29 years after abdominal radiation for testicular seminoma: a case report and review of the literature. Oncology. 1998;55(4):289–292. 32. Sato F, Yamazaki H, Ataka K, et al. Malignant peritoneal mesothelioma associated with deep vein thrombosis following radiotherapy for seminoma of the testis. Intern Med. 2000;39(11):920–924. 33. Amin AM, Mason C, Rowe P. Diffuse malignant mesothelioma of the peritoneum following abdominal radiotherapy. Eur J Surg Oncol. 2001;27(2): 214–215. 34. Cavazza A, Travis LB, Travis WD, et al. Post-irradiation malignant mesothelioma. Cancer. 1996;77(7):1379–1385. 35. Travis LB, Foss˚a SD, Schonfeld SJ, et al. Second cancers among 40 576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005; 97(18):1354–1365. 36. Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK. The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma. Cancer. 2006;107(1):108–115. 37. Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5- year survivors of Hodgkin’s lymphoma. J Clin Oncol. 2007;25(12): 1489–1497. 38. Deutsch M, Land SR, Begovic M, Cecchini R, Wolmark N. An association between postoperative radiotherapy for primary breast cancer in 11 National Surgical Adjuvant Breast and Bowel Project (NASBP) studies and the subsequent appearance of pleural mesothelioma. Am J Clin Oncol. 2007;30(3):294–296. 39. De Bruin ML, Burgers JA, Baas P, et al. Malignant mesothelioma after radiation treatment for Hodgkin lymphoma. Blood. 2009;113(16):3679–3681. 40. Roggli VL, Gibbs AR, Attanoos R, et al. Pathology of asbestosis—an update of the diagnostic criteria: report of the Asbestosis Committee of the College of American Pathologists and Pulmonary Pathology Society. Arch Pathol Lab Med. 2010;134(3):462–480. 41. Oury TD. Benign asbestos-related pleural disease. In: Roggli VL, Oury TD, Sporn TA, eds. Pathology of Asbestos-Associated Diseases. 2nd ed. New York, NY: Springer; 2004:169–192. 42. Roggli VL, Oury TD, Moffatt EJ. Malignant mesothelioma in women. Anat Pathol. 1997;2:147–163. 43. Chirieac LR, Barletta JA, Yeap BY, et al. Clinicopathologic characteristics of malignant mesothelioma arising in patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. J Clin Oncol. 2013;31(36):4544–4549. 44. Klebe S, Brownlee NA, Mahar A, et al. Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases. Mod Pathol. 2010;23(3):470–479. 45. Henderson DW, Rantanen J, Barnhart S, et al. Asbestos, asbestosis, and cancer: the Helsinki criteria for diagnosis and attribution. Scand J Work Environ Health. 1997;23(4):311–316. 46. Zarate-Osorno A, Medeiros LJ, Kingma DW, Longo DL, Jaffe ES. Hodgkin’s disease following non-Hodgkin’s lymphoma: a clinicopathologic and immunophenotypic study of nine cases. Am J Surg Pathol. 1993;17(2):123–132. 47. Travis LB, Gonzalez CL, Hankey BF, Jaffe ES. Hodgkin’s disease following non-Hodgkin’s lymphoma. Cancer. 1992;69(9):2337–2342. 48. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022–1025. 49. Dey A, Seshasayee D, Noubade R, et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science. 2012;337(6101):1541–1546. 50. Abdel-Wahab O, Dey A. The ASXL-BAP1 axis: new factors in myelopoiesis, cancer and epigenetics. Leukemia. 2013;27(1):10–15.
Mesothelioma and Hematologic Malignancies—Li et al
Malignant (Diffuse) Mesothelioma in Patients With Hematologic Malignancies A Clinicopathologic Study of 45 Cases Xin Li, MD; Noel A. Brownlee, MD, PhD; Thomas A. Sporn, MD; Annabelle Mahar, MBBS, FRCPA; Victor L. Roggli, MD
Context.—Ionizing radiation has a role in the development of malignant mesothelioma, in several epidemiologic studies, including patients with hematologic malignancies. Objective.—To study the clinicopathologic characteristics of patients with malignant mesothelioma and hematologic malignancies with and without a history of radiotherapy. Design.—From a database of approximately 3600 patients with malignant mesothelioma, we identified 45 patients (1%) who also had hematologic malignancies. We examined clinicopathologic features and noted whether the patient had received radiotherapy for malignancy, comparing those with and those without such exposure. Results.—Among the 45 cases, 18 (40%) had Hodgkin lymphoma, 15 (33%) had non-Hodgkin lymphoma, 10 (4%) had chronic lymphocytic leukemia, and 2 (22%) had chronic myelogenous leukemia; 20 patients (44%) had a history of radiotherapy, and 23 (51%) did not. Most patients with Hodgkin lymphoma (16 of 18; 90.0%)
received radiation, whereas none of the patients with leukemia (0 of 12) and only 20% (3 of 15) of the patients with non-Hodgkin lymphoma did so. Patients without radiation were older than patients who received radiotherapy (median, 73 versus 54 years, respectively; P , .001), had a shorter interval from diagnosis of hematologic malignancy to that of mesothelioma (median, 2 versus 24 years, respectively; P , .001), and had a shorter survival period (median, 6.0 versus 14.0 months, respectively; P ¼ .02). Epithelial mesotheliomas were proportionately more common in patients with a history of radiotherapy. Conclusions.—Patients with mesothelioma and hematologic malignancies with a history of radiation tended to be younger, had a longer interval from diagnosis of hematologic malignancy to that of mesothelioma, had a longer survival period, and were more likely to have the epithelial variant compared with patients without radiotherapy. (Arch Pathol Lab Med. 2015;139:1129–1136; doi: 10.5858/arpa.2014-0569-OA)
M
to confirm those findings.8–10 Furthermore, epidemiologic studies have generally failed to confirm an increased risk of hematologic malignancies in association with asbestos exposure.11–15 Consequently, asbestos is not regarded as a human lymphoid carcinogen, although asbestos fibers have been reported in lymph nodes and bone marrow.16–18 Although hematologic malignancies have been reported in experimental animals exposed to asbestos via inhalation or inoculation, no statistically increased incidence of those malignancies was detected.19–21 However, at least one study22 suggested that asbestos might interact with ionizing radiation in the process of oncogenic transformation. Ionizing radiation has been linked to malignant mesothelioma both in animals and in humans.23–39 Sanders and Jackson23 reported that 27% of rats treated with plutonium particles developed malignant mesotheliomas and concluded that the pathogenesis of malignant mesotheliomas induced by radioactive particles seemed similar to that of mesothelioma after intracavitary administration of asbestos. Several forms of ionizing radiation have been related to the development of malignant mesothelioma, including administration of Thorotrast (an x-ray contrast medium),24 working at nuclear facilities,25–26 and radiation treatment for first primary malignancies.27–39 Case reports29–33 of patients developing malignant mesothelioma within or
alignant mesothelioma is a universally fatal malignancy with most cases attributable to prior asbestos exposure.1 A number of case reports have suggested a relationship between asbestos exposure and hematologic malignancies, including non-Hodgkin lymphoma, leukemia, and multiple myeloma/plasmacytoma.2–6 Whereas Ross et al7 reported that primary large cell lymphomas of the gastrointestinal tract and oral cavity were related to asbestos exposure in a case-control study, subsequent studies failed Accepted for publication December 30, 2014. Published as an Early Online Release April 6, 2015. From the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Drs Roggli and Sporn); the Department of Pathology, Tianjin Haihe Hospital, Tianjin Institute of Respiratory Diseases, Tianjin, China (Dr Li); the Pathology Associates of Greenville, Greenville, South Carolina (Dr Brownlee); and the Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (Dr Mahar). Dr Roggli has consulted with plaintiff and defense attorneys in asbestos litigation in the United States and abroad. The other authors have no relevant financial interest in the products or companies described in this article. Reprints: Victor L. Roggli, MD, Department of Pathology, Duke University Medical Center, Box 3712, Durham, NC 27710 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 139, September 2015
Mesothelioma and Hematologic Malignancies—Li et al 1129
Table 1.
Characteristics of 45 Patients With Malignant Mesothelioma (MM) and Hematologic Malignancy Age,a y/Sex
Diagnostic Interval, y
Age at MM Diagnosis, y
MM Histology
69/M b /M 69/M 87/M b /M 73/M 64/M 76/M 85/M NA/M 65/M 82/M
2 NA 0 0 NA 2 5 5 0 NA 5 0
71 73 69 87 77 75 69 81 85 87 70 82
Sarcomatoid Epithelial Sarcomatoid Sarcomatoid Epithelial Epithelial Biphasic* Sarcomatoid Epithelial Epithelial Epithelial Biphasic
CML CLL SLL/CLL CLL CLL CLL/SLL CLL CML CLL CLL CLL CLL
Non-Hodgkin lymphoma 13 29/F 14 67/M
16 10
45 77
Epithelial Desmoplastic
Case No. Leukemia 1 2 3 4 5 6 7 8 9 10 11 12
Leukemia/Lymphoma Classification
15 16 17 18 19 20
72/M 67/M 64/F 64/M 63/M 57/M
5 2 11 7 2 8
77 69 75 71 65 65
Sarcomatoid Epithelial Biphasic Desmoplastic Desmoplastic Epithelial
Diffuse large B-cell lymphoma Poorly differentiated lymphocytic lymphoma (parotid gland) MALT lymphoma (stomach) SLL Follicular B-cell type Gastric lymphoma Follicular lymphoma, grade 2 NHL
21 22 23 24 25 26 27
56/M NA/M 26/M 73/M 78/M 9/F 67/M
0 NA 42 0 2 55 6
56 67 68 73 80 64 73
Biphasic Biphasic Sarcomatoid Sarcomatoid Epithelial Epithelial Biphasic
Mantle zone lymphoma NHL; prostate adenocarcinoma Follicular lymphoma, stage IV NHL Diffuse follicular center lymphoma, grade 1 Lymphosarcoma Diffuse large B-cell lymphoma
Hodgkin lymphoma 28 52/M 29 34/M 30 70/M 31 22/F 32 20/F
1 20 0 9 24
53 54 70 31 44
Biphasic Epithelial Epithelial Epithelial Epithelial
33
24/M
11
35
Epithelial*
HL, nodular sclerosis HL, HL, nodular sclerosis HL, nodular sclerosis HL, nodular sclerosis carcinoma HL
type
34 35 36 37 38 39 40 41 42 43 44 45
24/F 10/M 19/M 43/M 29/M 35/M 82/F 22/F 46/M 19/M 15/M 25/M
16 32 37 26 20 23 3 32 24 31 38 39
40 42 56 69 49 58 85 54 70 50 53 64
Biphasic Epithelial Epithelial Epithelial Epithelial* Epithelial Epithelial Epithelial Biphasic Biphasic Epithelial Epithelial
HL, nodular sclerosis type HL HL HL HL HL HL; breast cancer HL HL, nodular lymphocytic predominant type HL HL HL
type type type; papillary thyroid
Abbreviations: þ (plus), presence; (minus), absence; * (asterisk), peritoneal mesothelioma; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MALT, mucosa-associated lymphoid tissue; NA, not available; ND, further data regarding smoking history not available; NHL, non-Hodgkin lymphoma; NP, not performed; NS, nonsmoker; ppd, packs/d; SLL, small lymphocytic lymphoma; wkr, worker; XS, ex-smoker. a Age at time of diagnosis with leukemia or lymphoma. b Many years previously.
adjacent to radiation fields were followed by large-scale retrospective cohort studies, using data from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results program, indicating an increased risk of malignant mesothelioma in patients receiving radiotherapy for primary malignancies. Patients at risk included those treated for Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer, and breast cancer.34–39 1130 Arch Pathol Lab Med—Vol 139, September 2015
The occurrence of both malignant mesothelioma and hematologic malignancy in the same individual is a rare event. We identified 45 such patients in a database including more than 3600 cases of malignant mesothelioma, including 18 (40%) with Hodgkin lymphoma, 15 (33%) with non-Hodgkin lymphoma, and 12 (27%) with leukemia. We identified the clinical and pathologic features of those 45 cases, including demographic and survival data, Mesothelioma and Hematologic Malignancies—Li et al
Table 1. Extended Occupation/y
Asbestos Exposure Duration, y
Pleural Plaques and Asbestosis
Smoking History, ppd (y)/XS, y
Pipefitter Merchant marine; radiologist Boiler maker US Navy/4; power plant wkr/6; chemical plant wkr/31 Merchant marine/5; oil refinery wkr/29 Electrician Insulator (steel mills and power plants) NA Electric power plants, asbestos abatement Electrician Insulator Industrial electrician
50 1 28 41 34 8 42 NA 2–3 31 30 NA
Plaquesþ Asbestosis Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA)
1.5 (52)/2 2 (40)/6 NS NS 1 (27)/32 NS NA (13)/35 XS/ND NA (1)/60þ 1 (11)/57 NS NS
Household contact (husband-auto mechanic) NA
NA NA
Plaques Asbestosis Plaques (NA) Asbestosis (NA)
ND ND
Machinist, US Navy Foundry, power plant wkr Household contact (husband-pier wkr) Construction wkr Power plant wkr Shipyard mechanic/1; steel wkr/4; power plant wkr/32; paper mill wkr-exposed/4 mo Household contact (father-field technician) NA Electrician/construction wkr Chemical Co/4; auto mechanic/25; construction/7 Electrician Office wkr Pipefitter
25 36 30 20 28 37 þ 4 mo
Plaques Asbestosisþ Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA)
XS/ND NS 1–4 (57) XS/ND 1 (25)/18 NS
5 NA 44 36 36 NA NA
Plaques (NA) Asbestosis Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA)
ND ND XS/ND 1 (30)/43 NS 1 (10)/30 NS
Furnace technician Plasterer, optician Auto mechanic, asbestos factory Household contact (father-construction wkr) Household contact (father-field engineer)
NA NA 5 19 20
Plaques Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques Asbestosis Plaques Asbestosis (NA)
2–3 (ND) 3 (4)/35 NS 1 (11)/4 NS
Muffler shop assistant; household contact (stepfather-auto repair) Household contact (father-sheetmetal wkr) Auto mechanic/6; electrician/23 Electrician US navy/4; auto repair/32 Machinist; cabinet maker NA NA Household contact Taconite mine laborer Household contact (father-paper mill) Boiler wkr Airline mechanic
NA
Plaques (NA) Asbestosis (NA)
NS
28 29 14 36 NA NA NA NA 14 mo NA NA NA
Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaquesþ Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA) Plaques Asbestosis Plaques (NA) Asbestosis (NA) Plaquesþ Asbestosis Plaques (NA) Asbestosis (NA) Plaques (NA) Asbestosis (NA)
3–4 (11)/15 NS 1; pipe (10–12)/12 1–1.5 (17)/30 1 (30)/1–2 NS ND ND NS NS NS 5 (4)/20
site and histologic type of mesothelioma, asbestos exposure history, presence or absence of parietal pleural plaques or asbestosis, smoking history, and treatment history, including information available regarding the use of therapeutic radiation. In addition, we compared the clinicopathologic profiles of those cases with and without prior therapeutic radiation. MATERIALS AND METHODS Patient Selection Forty-five patients with a diagnosis of hematologic malignancy were identified in a database of more than 3600 consecutive cases Arch Pathol Lab Med—Vol 139, September 2015
of malignant mesothelioma, which comprised mainly professional and medicolegal consultation cases from 1982 to 2013. Information regarding patient age, sex, occupational history, smoking history, presence or absence of histologic asbestosis or parietal pleural plaques, treatment, and survival were obtained from medical records. The diagnosis of malignant mesothelioma was based on the gross distribution of tumor, histologic appearance, and the results of histochemical and immunohistochemical studies, as previously described.1 Histologic asbestosis40 and parietal pleural plaques41 were identified as present or absent according to published criteria. The diagnosis of lymphoma or leukemia was based on clinical and radiographic features, histologic patterns, and immunohistochemical features. Mesothelioma and Hematologic Malignancies—Li et al 1131
Statistical Analysis Exposure durations were compared with Student t tests. The interval from diagnosis of hematologic malignancy to the diagnosis of mesothelioma and ages were compared using the Kruskal-Wallis test. Other categoric data were compared by the Fisher exact test. Overall survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the statistical differences among groups. For all statistical analyses, a P value of less than .05 was considered statistically significant. Statistical analysis was performed using SAS version 9.4 statistical software (SAS Institute, Cary, North Carolina). Kaplan-Meier survival curves were drawn with SigmaPlot version 12.0 data graphing software (Systat Software, Inc, Chicago, Illinois).
RESULTS Demographic and Pathologic Findings Data for individual patients with both malignant mesothelioma and hematologic malignancy are listed in Table 1. Of the 45 patients, there were 37 men (82.0%) and 8 women (18.0%). The median age at diagnosis of malignant mesothelioma was 69 years (mean, 65 years; range, 31–87 years) and 57 years (mean, 50 years; range, 9–87 years) at diagnosis of hematologic malignancy. Most patients (25 of 45; 56.0%) had epithelial mesotheliomas, 10 patients (22.0%) had biphasic mesotheliomas, and 10 patients (22.0%) had sarcomatoid mesotheliomas (3 patients had desmoplastic mesotheliomas). Forty-two cases (93%) arose in the pleura and 3 (7%) in the peritoneum. The types of hematologic malignancy included 12 cases (27%) with leukemia, 15 cases (33%) with non-Hodgkin lymphoma, and 18 cases (40%) with Hodgkin lymphoma (Table 1; Figure 1, A through F). Among the 12 cases with leukemia, 8 (67%) were diagnosed with chronic lymphocytic leukemia (CLL), 2 (16%) with CLL/small lymphocytic lymphoma, and 2 (16%) with chronic myelogenous leukemia (Table 1). Three of 45 patients (7%) had 3 primary malignancies; in addition to mesothelioma and Hodgkin lymphoma, 1 patient had breast cancer, and another had papillary thyroid carcinoma (Table 1; cases 32 and 40). An additional patient with mesothelioma and non-Hodgkin lymphoma also had adenocarcinoma of the prostate (Table 1; case 22). The median interval from the diagnosis of a hematologic malignancy to the diagnosis of malignant mesothelioma was 8.0 years (mean, 13.9 years; range, 0–55 years). Eight cases (18%) with hematologic malignancy and malignant mesothelioma were diagnosed within 1 year of each other (Hodgkin lymphoma, 2 of 8 cases [25%]; non-Hodgkin lymphoma, 2 cases [25%]; CLL, 3 cases [38%]; CLL/small lymphocytic lymphoma, 1 case [13%]). Twenty-two patients (49%) were smokers or ex-smokers and 17 patients (38%) were nonsmokers. The remaining cases (n ¼ 6; 13%) were uninformative for smoking. Parietal pleural plaques were identified in 13 patients (29%) and were absent in 9 patients (20%) (the other cases [n ¼ 23; 51%] were uninformative for plaques). Histologic asbestosis was confirmed in 1 patient (2%) and absent in 11 (24%) (the remaining cases [n ¼ 33; 73%] were uninformative for asbestosis). Occupational Data Information regarding occupational exposure history was available in 39 of the 45 cases (87.0%), including 16 of 39 cases (41%) with prior therapeutic radiation and 21 cases 1132 Arch Pathol Lab Med—Vol 139, September 2015
(54%) without (Table 1). Several individuals worked in more than one exposure category. The largest exposure categories were household contact of an asbestos worker (9 of 39 cases; 23%) and boiler or power plant worker (9 of 39 cases; 23%). Information on duration of asbestos exposure was available for 8 patients with a history of radiotherapy, 19 patients without a history of radiotherapy, and 28 patients in total. The duration of exposure to asbestos was a mean (SD) of 23.9 (13.3) years for patients with a history of radiotherapy, 25.8 (14.8) years for patients without a history of radiotherapy (radiotherapy group versus nonradiotherapy group; P ¼ .76), and 25.6 (14.0) years for all cases with available information. No information was available regarding intensity of exposure for individual patients. Characteristics of Patients With or Without Past Radiation Therapy History Nineteen patients received radiation therapy for underlying malignancy 9 or more years before the diagnosis of malignant mesothelioma (Table 2). Twenty-three patients had no history of radiation therapy. One patient received radiation therapy for Hodgkin lymphoma 1.5 years before the diagnosis of mesothelioma. One patient with chronic myelogenous leukemia worked in a nuclear power plant for 20 years. For 2 additional cases, no information was available regarding treatment with radiation therapy. Men predominated in both of the 2 groups (group 1 [radiated], 12 of 19, 63.0%; group 2 [no radiation], 22 of 23, 96.0%), with women more common in the radiated group (P ¼ .01; Table 3). The age at the diagnosis of hematologic malignancy and malignant mesothelioma for group 1 was younger than it was for group 2 (P , .001). The duration from diagnosis of hematologic malignancy to the diagnosis of malignant mesothelioma in group 1 was longer than it was in group 2 (P , .001). Nearly all patients with Hodgkin lymphoma were treated with radiation therapy 9 years or more before the diagnosis (16 of 18; 89.0%). In contrast, none of the patients with leukemia and few patients with non-Hodgkin lymphoma (3 of 15; 20%) received radiotherapy. Most malignant mesotheliomas in the radiated group were epithelial (15 of 19; 79.0%); in the nonradiated group, 9 of 23 patients (39.0%) had sarcomatoid mesotheliomas, 9 of 23 (39.0%) had epithelial mesotheliomas, and 5 of 23 (22.0%) had biphasic mesotheliomas. Asbestosis (P . .99), plaques (P ¼ .16), and smoking history (P . .99) were not significantly different between the 2 groups (Table 3). Follow-up and Survival Analysis The median follow up time using censored data was 9.0 months (mean, 14.5 months; 95% confidence interval, 7.5– 21.4 months). Patients with a history of radiation had a significantly longer survival period than did those without a history of radiotherapy (median survival, 14.0 versus 6.0 months, respectively; P ¼ .02; Figure 2, A). Survival time in patients with epithelial mesotheliomas was not significantly different between groups (median survival, 18.0 versus 9.0 months, respectively; P ¼ .24; Figure 2, B). COMMENT We report a series of patients with malignant mesothelioma and hematologic malignancy and describe their clinicopathologic characteristics. This combination is an Mesothelioma and Hematologic Malignancies—Li et al
Figure 1. Case 30, a 70-year-old man with synchronous diagnosis of malignant pleural mesothelioma, epithelial variant, and the nodular sclerosis variant of Hodgkin lymphoma. A, Low-power view showing epithelial mesothelioma (right) and nodular sclerosis Hodgkin lymphoma (left). B, Same field as shown in A showing strong staining of the mesothelioma for calretinin (right). C, Higher-power magnification showing the detail of epithelial mesothelioma. D, Higher-power magnification showing strong nuclear staining of tumor cells for calretinin. E, Higher-power magnification of Hodgkin lymphoma showing detail of Reed-Sternberg cells. F, Positive membranous staining of Reed-Sternberg cells for CD15 (hematoxylin-eosin, original magnifications 34 [A], 320 [C], and 340 [E]; original magnifications 34 [B], 320 [D], and 340 [F]).
uncommon event, as we have observed 45 such cases in a series of more than 3600 mesotheliomas (approximately 1% of our cases). We categorized the cases into 3 groups: chronic leukemia (12 cases; 27%); non-Hodgkin lymphoma (15 cases; 33%); and Hodgkin lymphoma (18 cases; 40%). Arch Pathol Lab Med—Vol 139, September 2015
Most cases occurred in men, and most mesotheliomas were of the epithelial type. All but 3 cases arose in the pleura. Although asbestos exposure is considered the main cause of malignant mesothelioma, other factors have been implicated, including ionizing radiation.1 Patients treated Mesothelioma and Hematologic Malignancies—Li et al 1133
Table 2.
Characteristics of Patients With a History of Radiotherapy
Case No. Age, y/Sex MM Histology 13 23 26 29 31 32
45/F 68/M 64/F 54/M 31/F 44/F
Epithelial Sarcomatoid Epithelial Epithelial Epithelial Epithelial
33 34 35 36 37 38 39 40 41 42 43 44 45
35/M 40/F 42/M 56/M 69/M 49/M 58/M 85/F 54/F 70/M 50/M 53/M 64/M
Epithelial Biphasic Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Biphasic Biphasic Epithelial Epithelial
Lymphoma Classification Diffuse large B-cell lymphoma Follicular lymphoma, stage IV Lymphosarcoma HL HL, nodular sclerosis type HL, nodular sclerosis type; papillary thyroid carcinoma HL HL, nodular sclerosis type HL HL HL HL HL HL; breast cancer HL HL, nodular lymphocytic predominant type HL HL HL
Radiation PTD, y Survival, mo Survival Status 16 42 55 20 9 24
24 14 21 3 7 18
DOD DOD DOD DOD DOD DWD
11 16 32 37 26 20 23 27 32 24 30 35 35
10 4 99 17þ 3 25 NA NA 10 16 13 26þ 8
DOD DOD DOD AWD DOD DOD NA NA DOD DOD DOD AWD DOD
Abbreviations: AWD, alive with disease; DOD, dead of disease; DWD, dead with disease; HL, Hodgkin lymphoma; MM, malignant mesothelioma; NA, not available; PTD, years before the diagnosis of mesothelioma.
Table 3.
Demographic and Histologic Characteristics of 42 Patientsa With Mesothelioma and Hematologic Malignancy With and Without Prior Radiation Therapy
Demographic and Histologic Characteristics
Prior Radiation, n ¼ 19
No Prior Radiation, n ¼ 23
Sex, No. (%) F M
7 (37) 12 (63)
1 (4) 22 (96)
Age, y Mean (SD) Median Range
54.3 (13.6) 54 31–85
73.8 (7.4) 73 56–87
Age at lymphoma/leukemia diagnosis,b y Mean (SD) Median Range
28.1 (16.2) 24 9–82
69.5 (8.2) 68 56–87
Diagnostic interval,b y Mean (SD) Median Range
26.2 (12.8) 24 3–55
3.5 (3.6) 2 0–11
Histology of malignant mesothelioma, No. (%) Epithelial Biphasic Sarcomatoid
15 (79) 3 (16) 1 (84)
9 (39) 5 (39) 9 (39)
Histology of lymphoma or leukemia, No. (%) Hodgkin lymphoma Non-Hodgkin lymphoma Leukemia
16 (84) 3 (16) 0 (0)
1 (4) 10 (43) 12 (52)
Smoking history,c No. (%) Smokers or ex-smokers Nonsmokers
9 (47) 7 (37)
12 (52) 9 (39)
Histologic asbestosis,d No. (%) Presence Absence
0 (0) 5 (26)
1 (4) 5 (22)
Parietal pleural plaques,e No. (%) Presence Absence
3 (16) 5 (26)
10 (43) 3 (13)
P .01
,.001
,.001
,.001
.003
.01
..99
..99
.16
a
No information was available regarding treatment with radiation therapy in 2 cases, and 1 patient receiving radiotherapy 18 mo before the diagnosis of mesothelioma was excluded. Information was unavailable in 3 cases. c Information was unavailable in 5 cases. d No data were available in 31 cases. e Information was unavailable in 21 cases. b
1134 Arch Pathol Lab Med—Vol 139, September 2015
Mesothelioma and Hematologic Malignancies—Li et al
Figure 2. A, Kaplan-Meier survival curves for patients with malignant mesothelioma and hematologic malignancy, with and without prior radiation treatment for the hematologic malignancy. Survival was measured from the time of diagnosis of mesothelioma. Those undergoing prior radiation had better survival (P ¼ .02). B, Kaplan-Meier survival curves for patients with the epithelial variant of malignant mesothelioma and hematologic malignancy, with and without prior radiation treatment for the hematologic malignancy. There is a trend toward better survival in the group receiving radiation therapy, but the difference is not statistically significant (P ¼ .24).
with radiation for Hodgkin lymphoma have been reported to develop second primary malignancies (including mesothelioma) since the 1970s.27,28 Therefore, we decided to examine the clinicopathologic features of our cases treated with radiation, compared with those who did not receive radiotherapy. We previously reported patients with postradiation mesotheliomas having a latency interval of 7 to more than 50 years.42 Using these criteria, we found that there were 19 cases treated with radiation more than 7 years before the diagnosis of mesothelioma, and 23 patients who did not receive radiation. Of the 19 patients with prior radiation, 16 (84%) had Hodgkin lymphoma and 3 (16%) had non-Hodgkin lymphoma (Tables 1 and 2). The median interval from radiation treatment to the diagnosis of mesothelioma was 26 years (range, 9–42 years). The predominant histologic type in patients receiving prior radiotherapy was epithelial mesothelioma (15 of 19 cases; 79%). This finding is similar to the histologic types of postradiation mesotheliomas reported by Chirieac et al.43 Two of the 22 cases (9%) in that series were pleomorphic epithelial mesotheliomas, a histologic pattern typically having a poor prognosis.43 One of our cases (case 44; Tables 1 and 2) was the pleomorphic variant, and, as was the case in the Chirieac et al43 series, that patient had a longer than expected survival period. Indeed, our patients with postradiation mesothelioma had significantly longer survival periods than did the patients without radiation (Figure 2, A). However, when we controlled for histologic type, the survival difference was no longer significant (Figure 2, B). This is likely due to the known poor survival in sarcomatoid mesotheliomas,44 which were more common in the nonirradiated group. Nonetheless, there was still a trend toward longer survival in the postradiation group, and the lack of statistical significance may have been due to the few cases. Several of our postradiation cases had parietal pleural plaques (cases 36, 37, and 43; Table 1). In one additional case (case 23; Table 1), a fiber analysis of lung tissue demonstrated an elevated level of amosite asbestos fibers. These cases satisfy published criteria for a diagnosis of asbestos-related mesothelioma.45 Experimental studies22 have reported an interaction between ionizing radiation and asbestos in the process of malignant transformation. Further studies will be necessary to determine whether the interaction is additive, synergistic, or something in between. Arch Pathol Lab Med—Vol 139, September 2015
Two of our postradiation cases were peritoneal mesotheliomas (cases 33 and 38; Table 1). Individuals radiated for Hodgkin lymphoma may, therefore, be at increased risk for peritoneal, in addition to pleural, mesothelioma.29,31–33 One additional patient (case 40; Table 1) was diagnosed with Hodgkin lymphoma only 3 years before the diagnosis of mesothelioma but had received radiation for breast cancer 27 years before the diagnosis of mesothelioma. Patients receiving radiation therapy for breast cancer have an increased risk for subsequent development of mesothelioma.38 Hodgkin lymphoma has similarly been reported following radiation treatment.46,47 For many of our cases, the occurrence of mesothelioma and hematologic malignancy may have been a matter of chance. This is particularly true for cases of CLL because this is a fairly common disorder among elderly individuals, and mesothelioma also tends to occur among the elderly. The median age for patients with CLL and mesothelioma was 76 years (range, 69–87 years). A similar argument could be applied to the 12 patients with non-Hodgkin lymphoma who had not undergone radiotherapy before the diagnosis of mesothelioma. However, it should be noted that BAP1 (BRCA1 associated protein 1), which is mutated in many malignant mesotheliomas, has been reported to have a role in the regulation of hematopoietic stem cell function.48–50 Further studies will be needed to clarify whether this or other molecular pathways have a role in the simultaneous occurrence of mesothelioma and hematologic malignancies. There are a number of limitations in the present study, including lack of information regarding radiation dose and intensity of asbestos exposure. Furthermore, for many cases, information was unavailable regarding the presence or absence of asbestosis or parietal pleural plaques. Such information would be useful to explore the potential interaction between radiation and asbestos in the pathogenesis of mesothelioma. In conclusion, patients with malignant mesothelioma and a prior history of ionizing radiation for hematologic malignancies have some noted differences from patients with mesothelioma and hematologic malignancy without prior radiation. These include younger age at the diagnosis of hematologic malignancy and malignant mesothelioma, longer duration from diagnosis of hematologic malignancy to diagnosis of mesothelioma, and longer survival times. In addition, the hematologic malignancy in the former group is more likely to be Hodgkin disease, and the histologic type of mesothelioma is more likely to be epithelial. Mesothelioma and Hematologic Malignancies—Li et al 1135
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