SEARCH

SEARCH BY CITATION

Keywords:

  • non-Hodgkin lymphoma;
  • primary breast lymphoma;
  • diffuse large B cell lymphoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Primary lymphoma of the breast has been reported to have a high local and central nervous system recurrence (CNS) rate, suggesting the need for consolidation radiotherapy and CNS prophylaxis. A retrospective study was done to evaluate the institutional experience in this patient population.

METHODS.

In all, 37 patients with lymphoma involving the breast at initial diagnosis and managed at Stanford University from 1981–2005 were included. Diagnostic tissue biopsies were obtained either from the breast mass or an involved lymph node. Treatment and response data, patterns of recurrence, and outcomes were reviewed.

RESULTS.

Diffuse large B cell lymphoma (DLBCL) was the most common histologic subtype seen in 18 of 37 (49%) patients. Follicular and marginal zone subtypes were seen in 38%. Most patients presented with an incidental breast mass in stage IE or IIE. Four (11%) patients presented with bilateral breast involvement, with only 1 patient presenting with CNS disease. DLBCL patients received doxorubicin-based chemotherapy, with 70% receiving involved field radiotherapy and a single patient receiving intrathecal therapy. No recurrences occurred in the involved breast and a single parenchymal CNS recurrence was recorded. Among the DLBCL patients, the 5-year progression-free survival (PFS) was 61%, with a median follow-up of 3.8 years (range, 5 months to 19 years) and the 5-year overall survival (OS) was estimated at 82%. Patients with indolent lymphoma had an estimated 5-year PFS of 76% and an OS of 92%.

CONCLUSIONS.

DLBCL of the breast was successfully treated with doxorubicin-based chemotherapy alone or with involved field radiotherapy in an estimated 61% of patients at 5 years. A single CNS recurrence was observed in our series of patients, most of whom presented with limited disease. Cancer 2007. © 2007 American Cancer Society.

The prognosis and treatment of patients with non-Hodgkin lymphomas (NHLs) depends on the histologic subtype as categorized in the WHO classification.1 Diffuse large B cell lymphoma (DLBCL) is the most common subtype and prognosis correlates with the International Prognostic Index score (IPI).2 Only 1% of patients presenting with extranodal disease have involvement of the breast3 and only 0.1% of breast cancers are lymphomas.4 DLBCL is the most common histologic subtype in most series. Systemic chemotherapy with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently the standard of care in patients with DLBCL.5–7 The 5-year survival rate in the larger series is 46% to 61%, which largely antedated rituximab therapy.4, 8 Patient with stage IE disease, as expected, have the most favorable outcome.8 Some series have suggested a high recurrence rate both locally in the breast and in the central nervous system (CNS).8–12 Published series have not reliably clarified if the CNS recurrences were leptomeningeal or parenchymal in nature. This is a single institution retrospective study to evaluate the outcome of patients with primary breast lymphoma (PBL).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The Stanford lymphoma database was searched for patients with documented lymphoma involving the breast between 1981 and 2005. Fifty-one patients were identified out of 10,125 in the database. Ten patients with lymphoma of the breast at the time of recurrence were excluded. An additional 4 patients were excluded due to lack of adequate treatment history. Thus, 37 patients with involvement of the breast at the time of diagnosis were included in this analysis. These patients all had a breast mass with or without distant disease. Patients were included if they had involvement of the breast by any NHL at initial diagnosis of any NHL. This was confirmed by a biopsy of the mammary tissue or local lymph node. Patients with all stages were included. The clinical charts were reviewed after approval by the Institutional Review Board.

Initial evaluation in all patients included a history and physical examination, complete blood counts, and chemistries. Computed tomography (CT) of the chest, abdomen, and pelvis and bone marrow biopsy were done. More recently, positron emission tomography (PET) scans were performed in patients with aggressive histologies. Diagnostic tissue biopsies were obtained either from the breast mass (n = 31) by a core needle biopsy, excisional biopsy, mastectomy, or an involved lymph node (n = 6). The diagnoses of 31 patients were reconfirmed by Stanford pathologists and classified based on the Working Formulation13 for cases before 1997 and by the WHO classification thereafter.1 Immunohistochemical staining performed at the time of diagnosis was collected and analyzed. Immunostains for CD20 were performed in all cases of DLBCL.

Treatment of patients was based on histology, stage, and era of practice. Patients with aggressive histologies were treated with systemic chemotherapy with or without radiation therapy. Rituximab was administered with chemotherapy in a majority of patients with aggressive lymphomas after 2001. Indolent lymphoma patients were treated variably.

Statistical Considerations

Progression-free survival (PFS) was calculated from the date of diagnosis to the date of first recurrence, progression, change in therapy, or death from any cause. Overall survival (OS) was calculated from the date of diagnosis to the date of last follow-up or death from any cause. The Kaplan-Meier method was used to estimate PFS and OS distributions. Prognostic factors for OS in DLBCL were evaluated using the log-rank test. Prognostic factors considered in the univariate analysis included age, performance status, lactate dehydrogenase (LDH), number of extranodal sites, and stage. Statistical significance is represented by a 2-tailed P value <0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Thirty-seven patients (36 females, 1 male) with PBL were included. The patient characteristics are listed in Table 1. Four patients presented with bilateral breast involvement. The most common presenting feature was a breast mass occurring in 24 patients. In 9 patients an abnormal screening mammogram led to the diagnosis. Thirty-six patients had documented radiographic staging with CT scans of the chest, abdomen, and pelvis. Bone marrow biopsies were performed on 28 patients plus a sternal bone marrow aspirate in 1 patient with T lymphoblastic lymphoma. Diagnosis was established with a core needle or an excisional biopsy of the breast mass in 28 patients, fine-needle aspirate in 1, mastectomy in 2, and lymph node biopsy in 6.

Table 1. Patient Characteristics (N = 37)
 No.(%)
  • LDH indicates lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma; SLL, small lymphocytic lymphoma; MZL, marginal zone lymphoma.

  • *

    The nature of the mammogram abnormality could not be retrieved.

  • Diffuse lymphadenopathy, CNS symptoms, shortness of breath, skin nodules.

  • Breast (37), bone marrow (4), brain (1), lung/pleura (5), bone (2), skin (2), liver (2), orbit (1).

  • §

    31 patients had breast biopsies and 6 had lymph node biopsies.

  • NHL-NOS (1), T lymphoblastic lymphoma (1), small noncleaved non-Burkitt (1), mantle cell lymphoma (1).

Age
 Median 53 y  
 Range 19–91 y  
Presenting features
 Abnormal screening mammogram*9(24)
 Breast mass24(65)
 Other4(11)
B symptoms
 Present3(8)
 Absent34(92)
LDH, n=26
 High9(35)
 Normal17(65)
ECOG
 034(92)
 11(3)
 22(5)
Extranodal sites
 125(68)
 29(24)
 ≥33(8)
Pathology§
 DLBCL18(49)
 FL7(19)
 MZL7(19)
 SLL1(3)
 Other4(10)
Stage
 I13(35)
 II11(30)
 III2(5)
 IV11(30)

The pathologic features of the DLBCL were described as poorly circumscribed masses, infiltrating into stroma, surrounding breast lobules, and ducts. Immunoperoxidase stains were performed on an automated immunostainer using diaminobenzidine as a chromogen. Diffuse sheets of large pleomorphic cells staining positively for CD20 was seen in all the cases. Eight of 18 cases were stained for Ki-67 and all of these showed an intermediate to high proliferative activity (70%–95%).

DLBCL was the most common histologic subtype diagnosed in 18 out of 37 patients with a median age of 55 years (range, 30–76 years). One patient had bilateral breast involvement and 4 had other extranodal sites involved by lymphoma. One patient presented with parenchymal CNS disease. Three patients had bulky disease (>10 cm) and only 1 patient presented with B symptoms. Seventeen patients were treated with doxorubicin-based chemotherapy, and 1 had no further treatment after a total mastectomy for stage I disease (Table 2). This patient died without lymphoma progression 7 years after diagnosis. Twelve of 17 patients had consolidative radiotherapy with doses between 3600 and 5040 cGy. The radiation field was variable but generally included the breast with or without the axilla and the supraclavicular area. Fifteen of 17 patients responded to treatment. Among 4 patients with recurrence, 2 have no evidence of disease (NED) after salvage therapy. One patient with stage IE disease recurred with parenchymal brain lesions and died of disease. Thirteen of 18 patients are alive without disease with a median follow-up of 3.8 years (range, 5 months to 19 years) with an estimated 5-year OS of 82% (Fig. 1) and an estimated PFS of 61%.

thumbnail image

Figure 1. Overall survival and progression-free survival in diffuse large B cell lymphoma (DLBCL) patients.

Download figure to PowerPoint

Table 2. DLBCL Treatment (N = 18)
 Stage IE, IIE n = 13Stage IIIE, IV n = 5
  • DLBCL indicates diffuse large B cell lymphoma IPI, International Prognostic Index; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; RCHOP, rituximab plus CHOP; mBACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; RESHAP, rituximab, etoposide, cisplatin, cytarabine, methylprednisolone; BCEPP, bleomycin, cyclophosphamide, etoposie, procarbazine, prednisone.

  • *

    Six early stage patients had 6–8 cycles of chemotherapy while 6 had 3–4 cycles.

IPI (0,1)131
IPI (2,3)03
IPI (4,5)01
Chemotherapy*
 CHOP73
 RCHOP42
 mBACOD10
Radiation
Ipsilateral breast102
Intrathecal chemotherapy01
Progression02
Recurrence (sites)40
 Contralateral breast30
 Central nervous system10
Salvage treatment
 RESHAP/zevalin10
 Radiation to brain10
 Stem cell transplant20
 Gemcitabine/navelbine10
 BCEPP01

The effects of the prognostic variables on OS were evaluated. An elevated LDH (n = 9) and an Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (n = 2) adversely affected the OS in patients with DLBCL (P < .0579 and P < .0001, respectively). However, there are only 3 deaths in this subset so these results must be viewed accordingly.

Fifteen of 37 patients had indolent lymphoma (7 follicular lymphoma [FL], 7 marginal zone lymphoma [MZL], 1 small lymphocytic lymphoma [SLL]) with a mean age of 49 years (range, 34–91 years) (Table 3). None of these patients had constitutional symptoms at the time of diagnosis and all patients had an ECOG performance status of zero. One patient with FL and 2 with MZL presented with bilateral breast involvement. Five out of 15 had more than 1 extranodal site, with 1 FL patient presenting with 5 extranodal sites. This patient had chemotherapy-refractory disease and died of secondary acute leukemia 26 months after diagnosis. Five patients (1 FL, 4 MZL) with early-stage disease received between 3600–5040 cGy of radiotherapy to the affected sites and 4 out of 5 remain NED with a median follow-up of 5.8 years (range, 2.3–13 years). The radiation fields were variable but generally included the breast and the axilla with or without the supraclavicular area. The 5-year OS for patients with indolent lymphoma is 92%, with a predicted 10-year OS of 70% (Fig. 2). The OS for all 37 patients is shown in Figure 3.

thumbnail image

Figure 2. Overall survival and progression-free survival in indolent patients.

Download figure to PowerPoint

thumbnail image

Figure 3. Overall survival for all patients.

Download figure to PowerPoint

Table 3. Indolent Treatment (N = 15)
 IE, IIEIIIE, IV
  1. FL indicates follicular lymphoma; SLL, small lymphocytic lymphoma; MZL, marginal zone lymphoma.

FL16
MZL61
SLL10
Radiotherapy
 FL11
 MZL40
Rituximab
 FL01
 MZL00
CHOP/CVP
 FL03
 MZL00

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Approximately one-third of patients with NHL present with extranodal disease.14–16 The most common extranodal site in DLBCL is the gastrointestinal tract, with only 1% of patients presenting with a breast primary.3 The PBL patients mostly present with a breast lump. In our study the most common presenting features were a breast mass (65%) or an abnormal screening mammogram (24%). The remaining 4 patients presenting features were either respiratory, lymphadenopathy, B symptoms, or CNS disease. Four (11%) patients presented with bilateral breast involvement. Ten patients had other extranodal sites involved with lymphoma, with bone marrow the most common site involved.

DLBCL is the most common histology in PBL.8, 11, 12 These lymphomas have been shown to be of nongerminal center B cell phenotype17 with a high proliferation index and thought to be associated with a poor outcome. In our study, 4 of the 5 cases for which CD10 data were available were consistent with a CD10-negative nongerminal center cell phenotype. In addition, Ki-67 revealed a high proliferative fraction in 8 cases on which ki-67 stain was performed.

The prognosis of patients with DLBCL is dependent on the IPI score and the individual prognostic factors.2 The Mayo Clinic has found the stage to be the only significant prognostic factor for PBL patients, with a 5-year OS of 83% for stage I compared with 20% for stage II.8 However, this analysis was for all histological subtypes including indolent disease. IPI, LDH, and performance status predicted OS in another report of patients with PBL.18 In our study we analyzed the individual prognostic factors as well as the IPI score in the 18 DLBCL patients and found LDH and the ECOG performance status to be correlated with OS.

The treatment of PBL patients is related to the lymphoma subtype. Chemotherapy with RCHOP is the current standard of care for patients with DLBCL. In our series, 6 of 18 patients were treated with RCHOP, 10 of 18 with CHOP, and 1 with mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone). The number of chemotherapy cycles depended on the stage of disease. Some series report local recurrences and suggest radiotherapy to the affected breast.8, 18 Twelve of 18 patients in our series were consolidated with radiotherapy, with 3 of 10 early-stage patients experiencing systemic recurrence. There were no local recurrences regardless of radiotherapy. CNS recurrence in DLBCL of the breast has been reported by multiple authors,8–12, 19 leading to recommendations for CNS prophylaxis. The incidence of CNS recurrence has varied from 5% to 29%, with the inclusion of high-grade lymphomas in some reports.8, 11, 12 The literature has not always clearly defined whether such recurrences were primarily parenchymal or meningeal. Au et al.20 described cranial nerve palsies, mental confusion, and headache in their patients. The 3 CNS recurrences in the Mayo clinic study occurred in the brain, similar to our experience with 1 parenchymal brain metastases at presentation and a second at recurrence.8 CNS recurrences in primary testicular lymphoma, as opposed to primary nodal lymphoma, occur primarily in the brain parenchyma rather than the meninges.21 The extent to which this is true in PBL, another extranodal site, remains to be clarified but has obvious implications for prophylaxis and evaluation of neurologic signs and symptoms.

Indolent PBL should be treated based on the stage of the disease and the need for therapy. Some series support the use of radiation therapy alone for localized disease.8 In our study, 5 patients received radiation therapy for localized disease and 4 out of 5 are still in remission. Patients with systemic disease and symptoms should be treated with therapy geared toward indolent lymphoma.

In conclusion, DLBCL of the breast was the most common histologic subtype in our series and was successfully treated with doxorubicin-containing regimens. The role of consolidative local radiotherapy could not be definitively addressed by our experience. The question remains whether prophylactic CNS therapy would be beneficial in PBL and what treatment is likely to be most effective and well tolerated. Based on our experience, we do not recommend routine prophylaxis. Further study of the biology of extranodal DLBCL is needed to elucidate patterns of spread and therapeutic outcome.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES