Incidental non-Hodgkin’s lymphoma in patients with localized prostate cancer

ADULT UROLOGY

INCIDENTAL NON-HODGKIN’S LYMPHOMA IN PATIENTS WITH LOCALIZED PROSTATE CANCER CLAUS F. EISENBERGER, PATRICK C. WALSH, MARIO A. EISENBERGER, NAN-HAW CHOW, ALAN W. PARTIN, JACEK L. MOSTWIN, FRAY F. MARSHALL, JONATHAN I. EPSTEIN, AND MARK SCHOENBERG

ABSTRACT Objectives. To determine the outcome of patients with clinically organ-confined prostate cancer undergoing radical retropubic prostatectomy for cure and incidentally discovered concurrent low-grade non-Hodgkin’s lymphoma at time of surgery. Methods. From September 1986 to September 1997, 4319 patients underwent radical retropubic prostatectomy at our institution. The records of 10 patients incidentally diagnosed to have low-grade nonHodgkin’s lymphoma at the time of radical prostatectomy were retrospectively reviewed. Results. Of 4319 patients requiring radical prostatectomy, 10 (0.2%) were found to have low-grade non-Hodgkin’s lymphoma. All 10 men had an uneventful postoperative course. Two patients subsequently developed progression of lymphoma, one of whom required treatment. One patient died of sepsis associated with his lymphoma and 1 patient died of an unrelated malignancy (lung cancer), both 7 years following surgery. Two patients developed biochemical prostate-specific antigen recurrence. The remainder of men were free of prostate cancer recurrence and experienced no progression of lymphoma at an average of 45 months (range 12 to 142). Conclusions. Patients with organ-confined prostate cancer, who are candidates for radical prostatectomy, experience long-term prostate cancer-free survival in the face of incidentally diagnosed low-grade lymphoma. Because the management of most incidentally discovered low-grade lymphomas is expectant, patients discovered at surgery to have this clinical entity should not be denied radical prostatectomy. UROLOGY 53: 175–179, 1999. © 1999, Elsevier Science Inc. All rights reserved.

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ncidence of prostate cancer is rising among American men, which may result in a higher frequency of second malignancies in these patients.1 Radical retropubic prostatectomy (RRP) and external beam radiation therapy represent the most commonly used forms of intervention in the management of localized prostate cancer. Radical prostatectomy has been found to produce excellent

C.F.E. is supported by the Deutsche Forschungsgemeinschaft. M.P.S. is the recipient of American Cancer Society Oncology Career Development Award 97-86. From The James Buchanan Brady Urological Institute and The Johns Hopkins Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland Reprint requests: Mark P. Schoenberg, M.D., James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, 145 Marburg Building, 600 North Wolfe Street, Baltimore, MD 21287-2101 Submitted: April 22, 1998, accepted (with revisions): July 8, 1998 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

long-term disease-free survival.2–5 The pathologic stage following radical prostatectomy can be estimated on the basis of the patient’s presenting prostate-specific antigen (PSA) level, the prostate biopsy Gleason sum, and clinical assessment of stage based on digital rectal examination.6 Axial imaging (computed tomography [CT] and magnetic resonance imaging) of the abdomen and pelvis typically fails to augment the preoperative clinical evaluation of patients considering radical prostatectomy. Many patients come to surgery with no additional diagnostic imaging except bone scan.6,7 Although complete history and physical examination usually identify significant comorbidity, some clinical entities can elude detection. One such entity is low-grade non-Hodgkin’s lymphoma. Low-grade lymphoma is a disease of the elderly. Fifty percent of patients with low-grade non-Hodgkin’s lymphoma are 60 years of age or older.8 –10 Many patients experience no symptoms 0090-4295/99/$19.00 PII S0090-4295(98)00422-1 175

TABLE I. Patient

Age (yr)

Patient characteristics

Prostate

1

64

Adenocarcinoma/NED Gleason 3 1 3 Adenocarcinoma/NED Gleason 3 1 4 Adenocarcinoma/NED Gleason 3 1 4; distal margin positive Adenocarcinoma Gleason 3 1 4; apex positive Adenocarcinoma/NED Gleason 3 1 4 Adenocarcinoma/NED Gleason 3 1 3 Adenocarcinoma Gleason 3 1 4 Adenocarcinoma Gleason 3 1 3

2

69

3

62

4

64

5

67

6

67

7

59

8

56

9

68

Adenocarcinoma Gleason 3 1 4 involving apex and soft tissue

10

57

Adenocarcinoma/NED Gleason 3 1 3

Lymphoma

Follow-up (mo)

Mixed cell follicular lymphoma Small cell lymphocytic lymphoma Well-differentiated lymphocytic lymphoma Small cell lymphocytic lymphoma Small cell lymphocytic lymphoma Well-differentiated lymphocytic lymphoma Small cell lymphocytic lymphoma DOD (sepsis) Small cell lymphocytic lymphoma treated for persistent lymphocytosis Small cell lymphocytic lymphoma

Follicular small cell lymphoma

12 No detectable PSA 12 No detectable PSA 102 No detectable PSA 40 PSA 0.4/no therapy 34 months after surgery 24 No detectable PSA 15 No detectable PSA 82 No detectable PSA 142 No detectable PSA 83 Died of lung cancer PSA 0.7/radiation 7 months after surgery 8 No detectable PSA

KEY: NED 5 no evidence of disease; PSA 5 prostate-specific antigen; DOD 5 dead of disease.

of disease at time of diagnosis.10 Common presentations of the disease include painless lymph node enlargement, fever, night sweats, and weight loss. The actuarial survival of patients with untreated, low-grade, non-Hodgkin’s lymphoma is 83% and 73% at 5 and 10 years, respectively. Approximately 80% of patients require treatment after 10 years.11,12 The incidental discovery of non-Hodgkin’s lymphoma during pelvic lymphadenectomy for localized prostate cancer raises the following question: should radical prostatectomy be performed in patients with both malignancies? To address this, we reviewed our experience with this clinical scenario. MATERIAL AND METHODS The clinical records of 10 men (mean age 63 years; range 56 to 69) with coincident low-grade non-Hodgkin’s lymphoma, detected at the time of lymphadenectomy, and clinically localized prostate cancer undergoing RRP at Johns Hopkins Hospital between 1986 and 1997 were reviewed. Patient demographics are summarized in Table I. Particular attention focused on whether patients experienced comorbidity perioperatively, which might have distinguished them from patients without lymphoma. In addition, long-term cancer-specific survival was 176

assessed in the group. RRP with pelvic lymph node dissection was performed in all patients. Histopathologic diagnosis of lymphoma was made, and surgical pathology reports were reviewed for this study.

RESULTS Between 1986 and 1997, of the 4319 men who underwent RRP for clinically localized prostate cancer, we encountered 10 individuals (5 tumors had Gleason 6 and 5 tumors had Gleason 7 prostate cancer; 10 of 4319 [0.2%]) who had coincident low-grade non-Hodgkin’s lymphoma. Eight patients had well-differentiated lymphocytic lymphoma, and 2 patients had follicular lymphoma. In 9 of 10 patients, the diagnosis of lymphoma was not suspected prior to surgery. In 1 patient, the diagnosis of indolent, asymptomatic lymphoma with mild lymphadenopathy was known prior to surgery. All patients were found to have gross pelvic lymphadenopathy at surgery. None of the patients had elevated lymphocyte counts on peripheral blood examination prior to surgery. None of the patients had prostatic involvement by the hematopoetic malignancy. Pelvic lymph node dissection and frozen sections were UROLOGY 53 (1), 1999

due to soft tissue tumor infiltration. Of these, 1 patient, who died of lung cancer 83 months following surgery, had a rising PSA level (0.7 ng/mL 7 months after surgery) requiring local radiation therapy; another patient had a rising PSA level (0.4 ng/mL) 34 months after surgery with no therapy instituted at time of this report (40 months), and 1 patient had no evidence of recurrent prostate cancer 102 months after surgery. Only 1 other patient required treatment (single-agent chemotherapy) because of persistent lymphocytosis due to lymphoma 2 years after surgery. No patient died of prostate cancer during follow-up. The mean follow-up period was 52 months (range 8 to 142). FIGURE 1. Malignant lymphoma, small cleaved type, follicular pattern: replacement of node by small neoplastic follicles (H & E stain).

FIGURE 2. Higher magnification of the germinal center, showing infiltration of small lymphocytic cells with cleaved nuclei and barely visible cytoplasm (H & E stain).

performed to determine the nature of the lymphadenopathy at the time of surgery (Figs. 1 and 2). No metastatic prostate cancer was identified in any specimen. None of the patients had a preoperative CT scan. All patients were subsequently referred to Medical Oncology for follow-up evaluations, staging, and further therapy for lymphoma postoperatively. No surgical or infectious complications associated with the diagnosis of non-Hodgkin’s lymphoma were identified in this group. One patient in the cohort died of sepsis due to progressive non-Hodgkin’s lymphoma 82 months after surgery. Three patients had positive surgical margins UROLOGY 53 (1), 1999

COMMENT The overall incidence of low-grade lymphoma of 0.2% (10 of 4319 patients) in our series is relatively low compared with that described by Donohue13 (3 of 225) and Terris et al.14 (13 of 1092 patients), who both reported an incidence of 1.2%. No substantive demographic characteristics distinguish the group of patients studied for this report from those evaluated by other groups. Although involvement of the prostate with suspicious lymphocytic infiltrate was detected in 69.2% of the patients studied by Terris et al., we did not find such involvement in any of our patients. Few patients with low-grade non-Hodgkin’s lymphoma can be cured, but long-term survival without therapy is common (83% at 5 and 73% at 10 years).12 Given the indolent nature of this disease, the need for therapy prior to the onset of symptoms has been questioned. Patients who are asymptomatic at the time of diagnosis are followed closely by an oncologist to identify and treat early sites of disease progression that can lead to serious and avoidable complications.12 The treatment options include radiotherapy in localized nonHodgkin’s lymphoma, single-agent chemotherapy (alklating agents and glucocorticoids), and intensive combination-chemotherapy (ie, CHOP [cyclophosphamide, doxorubicin, Oncovin (vincristine), prednisone] regimen) with/without radiotherapy.10,11,15–17 Complete remissions can be achieved in symptomatic patients (patients with significant lymphadenopathy, lymphocytosis, or infectious complications) and can last for an extended time. Patients treated with aggressive chemotherapy tend to have remissions that do not last longer than those achieved more slowly with single-agent chemotherapy. No difference in overall survival was found in comparing an intensive combination-chemotherapy regimen and no initial therapy, with the same chemotherapy regimen administered at the 177

onset of progressive, systemic disease.11 In some patients with low-grade non-Hodgkin’s lymphoma, treatment may not be needed for months or years, so unpleasant side effects of chemotherapy and radiation can be avoided in asymptomatic patients. A substantial proportion of patients have spontaneous remissions (up to 23%).12,18 –21 The median survival for patients with low-grade lymphoma is 8 to 10 years13 and may even be similar to age and sex-matched control patients.22,23 Patients with more aggressive grades of lymphoma may fare less well than the population examined for this report but may be detected prior to surgery because of earlier onset of symptoms. The discovery of substantial lymphadenopathy at the time of pelvic exploration for radical prostatectomy can prompt termination of the surgical procedure. Although in the past, the distinction of malignant lymphoma from reactive lymphoid lesions often required fresh frozen tissue, currently most markers can be performed on routinely paraffinembedded tissue. These include common lymphocyte markers, B- and T-cell markers, stains that react with Reed-Sternberg cells in Hodgkin’s lymphoma, kappa and lambda stains for light chain expression, B-cell markers to distinguish reactive from neoplastic follicles, proliferation markers to add in the distinction of low- versus high-grade lymphomas, as well as other less commonly used markers. For intraoperative fresh frozen section the common hematoxylin-eosin (H & E) stain is the method of choice, but above mentioned stains need to be performed to distinguish the different kinds of lymphoma. The clinical importance of low-grade lymphoma within the context of curable prostate cancer must be understood. Follow-up in this study is too short to draw conclusions about the impact of the diagnosis of lymphoma on patients with potentially curable prostate cancer. Nonetheless, this report and the observations of investigators at other centers suggest that the incidental discovery of lowgrade lymphoma at the time of radical prostatectomy need not de facto result in the termination of the surgical procedure. Further clinical follow-up of this unusual patient subgroup will be required before definitive observations about disease-specific survival can be made.

CONCLUSIONS Patients with coincidental low-grade lymphoma and clinically organ-confined prostate cancer are candidates for radical prostatectomy. These patients can enjoy good short-term re178

sponses to surgery for the prostate malignancy, although long-term follow-up will be required to ascertain the impact of the lymphoma on the survival of patients with potentially curable prostate cancer.

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