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Non-Hodgkin's Lymphoma of the Breast: A Report of 19 Cases and a Review of the Literature
Original Contribution Non-Hodgkin’s Lymphoma of the Breast: A Report of 19 Cases and a Review of the Literature Stéphan Vignot, Véronique Ledoussal, Philippe Nodiot, Alain Bourguignat, Maud Janvier, Nicolas Mounier, Philippe Chérel, Jean-Louis Floiras, François Turpin
Abstract PURPOSE: Non-Hodgkin’s lymphoma of the breast represents 0.04%-0.50% of malignant lesions of the mammary gland. In this article, we report a single institution’s experience with this rare disease. MATERIALS AND METHODS: Between 1982 and 1997, 19 patients with breast lymphoma were diagnosed, treated, and followed at this institution. RESULTS: There were 18 female patients and 1 male patient. All but one were cases of aggressive B-cell lymphoma. Ann Arbor stages were IE (n = 5), IIE (n = 9), IIIE (n = 2), and IV (n = 3). International Prognosis Index scores were 0 (n = 2), 1 (n = 8), 2 (n = 7), and 3 (n = 2). According to the Wiseman and Liao classification established in 1972, 11 cases were primary lymphomas of the breast, and 8 cases were secondary involvement of the breast. Median survival time was 21.5 months (range, 5.1-114.7 months). The 5-year overall survival was 29%. Median event-free survival time was 8.3 months. The clinical, radiologic, and histologic patterns of presentation match previously published data, even if the response rates and the survival times seem disappointing, probably because of the initial treatment by tumorectomy or mastectomy for some patients. CONCLUSIONS: Systemic chemotherapy should be the mainstay of treatment. Based on our experience and a review of the literature, the use of Wiseman and Liao’s classification is questionable. In fact, it fails to detect whether some lymphomas of the breast present a specific natural history and therefore require specific management. New clinical and histologic criteria are to be identified.
Clinical Lymphoma, Vol. 6, No. 1, 37-42, 2005 Key words: Anthracyclines, B-cell lymphoma, Biopsy, Chemotherapy, Fludarabine, Prognosis, Surgery
Introduction
Patients and Methods
Non-Hodgkin’s lymphoma (NHL) of the breast is a rare disease, representing 0.04-0.50% of malignant lesions of the mammary gland. It comprises 2.2% of extranodal NHLs and 0.38% of all NHLs.1-5 In 1972, Wiseman and Liao proposed a classification system for primary and nonprimary lymphomas of the breast.6 Since then, many cases have been reported in the literature, but the series are small, no prospective studies have been done because of the rarity of this disease, and the treatments vary. It is therefore very difficult to determine the prognosis and an adequate therapeutic approach. The aim of this study is to review all cases of lymphoma of the breast observed at the René Huguenin Cancer Center between 1982 and 1997 in order to determine the pattern of presentation, the type of therapy, and the outcome of the disease. We discuss the pertinence of the Wiseman and Liao classification system based on our experience.
All patients presenting lymphoma with breast involvement between 1982 and 1997 were reviewed. They had to meet the following criteria to be included in the study: breast involvement as the initial presenting clinical feature and availability of detailed clinical data, especially staging information. Primary lymphomas of the breast were distinguished from nonprimary lymphomas according to criteria proposed by Wiseman and Liao and commonly used: (1) adequate pathologic specimen; (2) close association of mammary tissue and lymphomatous infiltrate; (3) no other lymphomatous localization at the time of diagnosis, except the presence of ipsilateral axillary nodes if they occurred concomitantly with the primary breast lesion; and (4) no preceding extramammary lymphoma.6 All patients had a pathologic diagnosis established by excisional or needle biopsy, or a tumorectomy or mastectomy specimen. Previously classified with the Kiel system, all cases were reviewed and stratified using the Revised European American Lymphoma (REAL) classification system.7 A series of immunohistochemical stains was performed (CD45RA, CD45RO, CD3, CD20, CD30, and antihuman anaplastic lymphoma kinase protein).
Centre de Lutte Contre le Cancer René Huguenin, St Cloud, France Submitted: Jan 16, 2004; Revised: Mar 10, 2004; Accepted: Jun 7, 2004 Address for correspondence: F. Turpin, MD, Centre de Lutte Contre le Cancer René Huguenin, 35 rue Dailly, 92211 St Cloud, France Fax: 33-01-4711-1629; e-mail: [email protected]
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Clinical Lymphoma June 2005 • 37
Non-Hodgkin’s Lymphoma of the Breast Pretreatment evaluation consisted of a physical examination; a complete blood count; blood chemistry profile (with lactate dehydrogenase); and imaging of chest, abdomen, and pelvis (by radiograph, ultrasonograph, and/or computed tomography scan). Neurologic investigations were done when clinically indicated. Mammograms had to be performed at diagnosis, and mammary ultrasonography was not systematic. A bone marrow biopsy or aspiration was also obtained in every patient. Ann Arbor stage and International Prognostic Index (IPI) and ageadjusted International Prognostic Index (aa-IPI) scores, when relevant, were determined.8 The treatment strategies were chosen after multidisciplinary discussion. Event-free survival (EFS) was measured from the date of diagnosis to disease progression, relapse, or death from any cause, or the stopping date. Overall survival (OS) was measured from the date of diagnosis to death from any cause or the stopping date. The survival functions were estimated by the Kaplan-Meier method and were compared by log-rank test.9 Tests for comparison were regarded as significant if 2-sided with P < 0.05. All statistical analyses were performed using SAS 8 and Splus 2000 software.
Results Patient Characteristics Between 1982 and 1997, 19 patients having lymphoma of the breast were diagnosed, treated, and followed (Table 1). There were 18 female patients and 1 male patient. Mean age was 68 years (range, 35-86 years; median, 69 years). All patients consulted for a mass in the breast, and 1 had inflammatory breast disease. Nine tumors involved the right breast, and 10 involved the left breast; there were no bilateral lesions. Tumors were unique in 15 cases, and 4 patients presented with bifocal lesions. Clinical sizes were < 2 cm (n = 1), 2-5 cm (n = 8), > 5 cm (n = 9), and > 10 cm (n = 5). Five patients had no involved peripheral lymph node areas, 8 patients had 1 area involved (homolateral axillary nodes), and 6 had > 1 area involved. The number of extranodal localizations was 1 (n = 1), 2 (n = 1), and 3 (n = 1). Bone marrow was involved in 2 cases. Ann Arbor stages were IE (n = 5), IIE (n = 9), IIIE (n = 2), and IV (n = 3). There were no B symptoms (eg, weight loss and fever). Lactate dehydrogenase (LDH) levels were normal in 15 patients and elevated in 4. All but 1 patient had a performance status of 0. International Prognosis Index scores were 0 (n = 2), 1 (n = 8), 2 (n =7), and 3 (n = 2). For the 4 patients < 60 years of age, ageadjusted IPI scores were 0 (n = 2), 1 (n = 1), and 2 (n = 1). According to the Wiseman and Liao classification, 11 cases were primary lymphoma of the breast, and 8 cases were to be considered secondary involvement of the breast. Mammograms were performed for the 18 female patients and mammary ultrasonography for 9 patients. At diagnosis, mammogram was normal in 1 patient, presented a unique unilateral lesion in 14 patients and a bifocal unilateral lesion in 3 patients, for a total of 20 lesions. Those lesions were nodular opacities in 16 cases, with sizes ranging from 15 mm to 120 mm (mean, 42 mm; median, 38 mm). The concordance between physical examination and mammogram was good, with radiologic size being slightly inferior to the clinical size (not
38 • Clinical Lymphoma June 2005
significantly). In 3 cases, the density of the mammary gland was enhanced with skin thickening and hypodermic densification. No microcalcification was seen. Eleven lesions were explored by mammary ultrasonography in 9 patients (2 patients with bifocal unilateral lesions). There were nodular lesions with regular outlines in 3 patients and irregular outlines in 8 patients, and the structure was homogeneous in 5 patients and heterogeneous in 6 patients. The nodules were slightly hypoechogenous in 7 patients or very hypoechogenous in 4 patients, with a posterior enhancement in 6 patients, without a posterior enhancement in 5 patients. Histologic diagnosis was made 10 times by biopsy alone, 7 times by tumorectomy with low axillary dissection, and 2 times by mastectomy with axillary dissection. All cases met the histologic criteria for lymphomatous involvement of the breast: technically adequate specimens and mammary tissue and lymphoma infiltration in close association. All cases had B-cell origins. According to the REAL classification, 16 cases were diffuse large B-cell lymphomas, 1 was a diffuse large T-cell rich B-cell lymphoma, 1 was a Burkittlike lymphoma, and 1 was a grade 3 follicular lymphoma with diffuse areas. Treatment and Follow-up Treatment began with surgery for 11 patients, 7 with tumorectomy and 4 with mastectomy (Table 2). Six patients received adjuvant chemotherapy, and 10 received radiation therapy, which was the exclusive adjuvant treatment for 4 patients. For the remaining 8 patients, chemotherapy was started after biopsy and was given with radiation therapy for 4 patients. Overall, 14 patients received chemotherapy, 13 with anthracyclines and 1 with fludarabine. After initial treatment, 14 patients exhibited a complete remission, and 3 exhibited a partial remission. Two patients progressed before the end of the induction treatment, and the second-line treatments were also unsuccessful. During followup, all but 2 patients relapsed. Mean survival time was 36.7 months, and median survival time was 21.5 months (range, 5.1-114.7 months). The 5-year OS was 29%, and EFS was 8.3 months (Figures 1 and 2). After stratification according to the Wiseman and Liao system, there were no statistical differences in OS (mean, 39.4 months for primary lymphoma vs. 48.2 months for nonprimary lymphoma; P = 0.7) or in EFS (mean, 23 months for primary lymphoma vs. 23.3 for nonprimary lymphoma; P = 0.56). No statistical differences were observed according to IPI score: mean OS was 36 months for patients with an IPI score of 0-2 versus 60.7 months for patients with an IPI score of > 2 (P = 0.46), and mean EFS was 21.4 months for patients with an IPI score of 0-2 versus 27.0 for patients with an IPI score of > 2 (P = 0.86).
Discussion Breast lymphoma remains a rare pathology considering the very few cases reported in our center, which specializes in breast diseases. However, we must not forget that the incidence may be reduced by the type of recruitment at our center. Indeed, we see
Stéphan Vignot et al Table 1
Patient Characteristics at Diagnosis
Patient Number
Age (Years)
Wiseman/ Liao Classification
Side
Regional Nodes
Other Nodes
Other Visceral Involvement
Ann Arbor Stage
LDH Level Elevated
Performance Status > 2
IPI
AgeAdjusted IPI
1
69
Primary
Left
Yes
No
No
IIE
No
No
1
–
2
66
Primary
Left
No
No
No
IE
No
No
1
–
3
56
Primary
Right
Yes
No
No
IIE
No
No
0
0
4
70
Primary
Right
Yes
No
No
IIE
Yes
No
2
–
5
72
Primary
Left
Yes
No
No
IIE
No
Yes
2
–
6
81
Primary
Left
No
No
No
IE
No
No
1
–
7
84
Primary
Right
No
No
No
IE
No
No
1
–
8
63
Primary
Right
No
No
No
IE
No
No
1
–
9
58
Primary
Left
No
No
No
IE
No
No
0
0
10
77
Primary
Left
Yes
No
No
IIE
No
No
1
–
11
69
Primary
Right
Yes
No
No
IIE
Yes
No
2
–
12
81
Nonprimary
Right
No
Yes
No
IIE
No
No
1
–
13
71
Nonprimary
Left
Yes
No
Liver, lung
IV
No
No
3
–
14
83
Nonprimary
Left
No
Yes
No
IIE
Yes
No
2
–
15
44
Nonprimary
Right
Yes
No
Bone marrow, brain, uterus
IV
No
No
2
1
16
63
Nonprimary
Right
No
Yes
No
IIIE
No
No
2
–
17
35
Nonprimary
Left
No
Yes
No
IIIE
Yes
No
2
2
18
69
Nonprimary
Left
Yes
Yes
Bone marrow
IV
No
No
2
–
19
86
Nonprimary
Right
Yes
Yes
No
IIE
No
No
1
–
All patients were women with the exception of patient number 16. Histologic classification for all patients was large B-cell lymphoma, with the exception of patient number 8, whose disease classification was diffuse large T-cell–rich B-cell lymphoma; patient 15, whose disease was Burkitt-like lymphoma; and patient 18, whose disease was grade 3 follicular lymphoma.
only the patients initially presenting with a mass in the breast, whereas patients with lymphomas where breast involvement is not the most important symptom, such as patients with severe B symptoms or with diffuse peripheral node involvement, are followed in hematologic centers. We are unable to evaluate the incidence of breast involvement in those cases; it could be much more frequent than what we see. For our patients who are consulting for a mass in the breast, the diagnosis of lymphoma before biopsy is difficult and often missed, the usual preoperative diagnosis being carcinoma. However, some of the clinical features suggest lymphoma.2 These features are a short history and rapidly growing breast mass (breast lymphoma tending to be larger at the time of diagnosis than carcinoma),10 absence of nipple discharge or retraction, multiple lesions, violaceous skin color over the lesion, and softer axillary lymph nodes as compared with metastatic lymph nodes from breast carcinoma. B symptoms are
distinctly unusual in breast lymphoma.11-16 In fact, these clinical features are often missing and are not specific at all. In practice, they do not help with making a diagnosis. The mammographic aspect is not specific but could give clues to suspect a lymphomatous lesion. As observed in our series, nodular opacity seems to be the most frequent presentation.17-21 The concordance between clinical and radiologic sizes is usually good, which can be helpful in discriminating lymphoma from breast carcinoma.17 Some authors observed microcalcifications21 or marginal spiculated appearance;18,21 however, those 2 elements were not observed in our series. The mammogram can be normal, and the mammary ultrasonograph is helpful in those cases,17 because this later examination usually reveals a hypoechogenous nodular lesion. Typically, no posterior attenuation is described.17,20,22 It is important to notice that, in term of the radiologic evaluation, the aspect of the lesion can be less alarming than the
Clinical Lymphoma June 2005 • 39
Non-Hodgkin’s Lymphoma of the Breast Table 2 Patient Number
Treatment and Follow-up Initial Surgery
Other Treatments
Initial Response
Relapse
1
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
2
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 4 and radiation therapy
CR
Yes
3
Mastectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
4
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 2 and radiation therapy
PR
Yes
5
Mastectomy
Radiation therapy
CR
No
6
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Prednisone × 4 and radiation therapy
CR
Yes
7
Mastectomy, axillary dissection
Radiation therapy
CR
Yes
8
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 4 and radiation therapy
CR
Yes
9
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
10
Tumorectomy
Radiation therapy
CR
No
11
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 8
PR
Yes
12
Mastectomy, axillary dissection
Radiation therapy
CR
Yes
13
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 4
CR
Yes
14
Tru-Cut needle biopsy
Radiation therapy and Cyclophosphamide/Epirubicin/Vincristine/Prednisone × 6
PR
Yes
15
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Prednisone; Cyclophosphamide/Doxorubicin/ Vincristine/Prednisone/Methotrexate; Cytarabine/Etoposide
PD
Yes
16
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
17
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone; Doxorubicin/Etoposide/Ifosfamide
PD
Yes
18
Tru-Cut needle biopsy
Fludarabine
CR
Yes
19
Tumorectomy, axillary dissection
Radiation therapy
CR
Yes
Abbreviation: PD = progressive disease
clinical presentation.17,23,24 Other diagnoses can be made: phyllode tumor, adenofibroma, colloide carcinoma, or medullary carcinoma. The hypothesis of invasive adenocarcinoma cannot be excluded. Therefore, a histologic analysis is necessary. During the initial diagnosis, the histologic analysis on frozen sections cannot differentiate a carcinoma from a lymphoma, especially large-cell lymphoma.4,25 The problem is likely to continue, as pathologists are asked to make initial diagnoses on smaller biopsy specimens. There is a risk of performing unnecessary mastectomies. Afterward, the immunohistochemical studies are very important for a precise diagnosis. Are our data consistent with the previously reported series in the literature? The mean age at diagnosis was 68 years, which fits the range usually observed.10,14,15,26-29 There is no difference if we consider primary and nonprimary breast lymphomas in our series (69 and 66 years, respectively). No difference is observed according to the IPI score, but the statistical study of this series is hazardous considering the small number of cases observed in our center. There was no predominance between right and left lesion and no bilateral involvement. Many series initially report a right
40 • Clinical Lymphoma June 2005
predominance,1,5,6,11,16,27,28,30-34 but this conclusion is open to criticism because of the small size of those series and the fact that recent series do not find a preferential side.25,35 The breast lymphomas observed in our center are high-grade lymphomas, which were also reported by previous studies: > 80% of breast lymphomas are high grade, and diffuse large-cell lymphoma is the most frequent histologic type.3,36 We have to admit that the response and survival rates observed in our study are disappointing, considering some previously reported results.2,10,25,27,35,37,38 The explanation could be the high rate of initial surgical treatments, mostly because this is the usual way to treat breast lesions in our center, and the difficulty of the histologic analysis on frozen sections, as previously discussed. Retrospectively, this pattern is not convenient. The increasing cooperation between physician, radiologist, surgeon, and pathologist helps us to improve the management of those patients. Breast lymphoma must be considered a systemic disease at diagnosis, and systemic chemotherapy should be the mainstay of the treatment. This statement seems to be obvious for nonprimary lymphomas of
Stéphan Vignot et al Figure 2 Event-Free Survival Survival Distribution Function (%)
Survival Distribution Function (%)
Figure 1 Overall Survival
100 75 50 25
0
20
40
80
100
120
100 75 50 25
0
10
30
40
50
60
70
80
Months
Months
the breast, which are already systemic disease at diagnosis, but should also be applied to primary breast lymphoma because of the tendency of the disease to disseminate rapidly.13,39 In fact, mastectomy and tumorectomy are not indicated, because they cause a delay in chemotherapy. Since the article by Wiseman and Liao was published in 1972, the tendency is to consider primary breast lymphoma differently in the literature. If their classification is used, in our series there do not seem to be pertinent differences between primary and nonprimary breast lymphomas in terms of clinical or histologic presentation, or indication of treatment or prognosis, with the reservation already mentioned concerning the small size of the population. Does Wiseman and Liao’s classification bring something to the management of our patients? First of all, the possibility of a breast lymphoma that arises primarily in the breast but has disseminated elsewhere before diagnosis is not considered a primary breast lymphoma, whereas lymphomatous involvement of the breast that could disseminate elsewhere in its natural history (as we see in the evolution of some of our patients) but is diagnosed early is considered primary. In this latter case, Wiseman and Liao’s criteria fail to detect the specificity of lymphomatous involvement limited to the breast. In fact, the reality of a true primary breast lymphoma, which could be considered a lesion specially linked to the mammary tissue, has been discussed.26,40 A histologic classification may be more pertinent than Wiseman and Liao’s criteria. For example, the reports of lymphoma of the breast developed from mucosaassociated lymphoid tissue (MALT), with clinical behavior of low-grade lymphoma, could be an answer,28,29,41,42 but they are also very controversial. In fact, the great majority of breast lymphomas are not MALT-type lymphomas,5,26,36,40 but it remains important to notice that, in those case, the prognosis is excellent. Those cases are not identified by the Wiseman and Liao criteria, the diagnosis of MALT-type lymphoma being based on histologic analysis. In our study, we find no MALT lymphomas. Some lymphomas of the breast seem also to present a different pattern. Some authors report data on the possible hormone sensitivity of this disease. Narasimhan described a
20
good response obtained with tamoxifen,43 but no conclusion could be reasonably drawn from this experience. In 16 patients presenting primary and nonprimary breast lymphoma, Ariad et al failed to detect estrogen receptor protein in lymphoid cells of the breast by immunohistochemical investigation.44 Breast lymphomas of young women are a stronger argument to assert that there is a specific pattern for some lymphomatous involvement of the mammary tissues. Breast lymphomas in women of childbearing age are more aggressive, diffuse, associated with a rapidly fatal course corresponding to Burkitt’s lymphoma (such as our patient number 15), and often bilateral. Previous studies notice that the disease appears frequently during and after pregnancy.5,26,36,41,45 In those cases, breast lymphomas seem to have a specific history. In the future, molecular study (eg, of DNA chips) of lymphoma involving the breast could provide information to individualize specific patterns of the disease. At this time, no data have been published.
Conclusion Some lymphomas of the breast act differently than other extranodal lymphomas (lymphomatous involvement associated with MALT or aggressive breast lymphoma in young women), but the data extracted from the literature, especially the Wiseman and Liao classification system, are unable to detect these differences. The hypothesis that some lymphomas of the breast act differently than other extranodal lymphomas cannot strictly be ruled out, and there remains value in reviewing single-institution experience in an attempt to compile enough data, especially molecular data, to make meaningful conclusions for our patients in this rare and finally heterogeneous disease. Without more precise molecular characteristics, we should treat breast lymphoma as we would treat NHL of similar stage and histology at other sites of the body. The use of the IPI has already been validated and should be relevant in this context. Diagnostic surgery followed by chemotherapy and possibly radiation therapy in addition should be the standard approach. Radical and mutilating surgery should be avoided and should be used for excision only if chemotherapy and radiation therapy fail
Clinical Lymphoma June 2005 • 41
Non-Hodgkin’s Lymphoma of the Breast to control the disease. Therefore, the cooperation between physician, radiologist, surgeon, and pathologist is very important in reaching the correct diagnosis before or during the first analysis on frozen sections.
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Abstract PURPOSE: Non-Hodgkin’s lymphoma of the breast represents 0.04%-0.50% of malignant lesions of the mammary gland. In this article, we report a single institution’s experience with this rare disease. MATERIALS AND METHODS: Between 1982 and 1997, 19 patients with breast lymphoma were diagnosed, treated, and followed at this institution. RESULTS: There were 18 female patients and 1 male patient. All but one were cases of aggressive B-cell lymphoma. Ann Arbor stages were IE (n = 5), IIE (n = 9), IIIE (n = 2), and IV (n = 3). International Prognosis Index scores were 0 (n = 2), 1 (n = 8), 2 (n = 7), and 3 (n = 2). According to the Wiseman and Liao classification established in 1972, 11 cases were primary lymphomas of the breast, and 8 cases were secondary involvement of the breast. Median survival time was 21.5 months (range, 5.1-114.7 months). The 5-year overall survival was 29%. Median event-free survival time was 8.3 months. The clinical, radiologic, and histologic patterns of presentation match previously published data, even if the response rates and the survival times seem disappointing, probably because of the initial treatment by tumorectomy or mastectomy for some patients. CONCLUSIONS: Systemic chemotherapy should be the mainstay of treatment. Based on our experience and a review of the literature, the use of Wiseman and Liao’s classification is questionable. In fact, it fails to detect whether some lymphomas of the breast present a specific natural history and therefore require specific management. New clinical and histologic criteria are to be identified.
Clinical Lymphoma, Vol. 6, No. 1, 37-42, 2005 Key words: Anthracyclines, B-cell lymphoma, Biopsy, Chemotherapy, Fludarabine, Prognosis, Surgery
Introduction
Patients and Methods
Non-Hodgkin’s lymphoma (NHL) of the breast is a rare disease, representing 0.04-0.50% of malignant lesions of the mammary gland. It comprises 2.2% of extranodal NHLs and 0.38% of all NHLs.1-5 In 1972, Wiseman and Liao proposed a classification system for primary and nonprimary lymphomas of the breast.6 Since then, many cases have been reported in the literature, but the series are small, no prospective studies have been done because of the rarity of this disease, and the treatments vary. It is therefore very difficult to determine the prognosis and an adequate therapeutic approach. The aim of this study is to review all cases of lymphoma of the breast observed at the René Huguenin Cancer Center between 1982 and 1997 in order to determine the pattern of presentation, the type of therapy, and the outcome of the disease. We discuss the pertinence of the Wiseman and Liao classification system based on our experience.
All patients presenting lymphoma with breast involvement between 1982 and 1997 were reviewed. They had to meet the following criteria to be included in the study: breast involvement as the initial presenting clinical feature and availability of detailed clinical data, especially staging information. Primary lymphomas of the breast were distinguished from nonprimary lymphomas according to criteria proposed by Wiseman and Liao and commonly used: (1) adequate pathologic specimen; (2) close association of mammary tissue and lymphomatous infiltrate; (3) no other lymphomatous localization at the time of diagnosis, except the presence of ipsilateral axillary nodes if they occurred concomitantly with the primary breast lesion; and (4) no preceding extramammary lymphoma.6 All patients had a pathologic diagnosis established by excisional or needle biopsy, or a tumorectomy or mastectomy specimen. Previously classified with the Kiel system, all cases were reviewed and stratified using the Revised European American Lymphoma (REAL) classification system.7 A series of immunohistochemical stains was performed (CD45RA, CD45RO, CD3, CD20, CD30, and antihuman anaplastic lymphoma kinase protein).
Centre de Lutte Contre le Cancer René Huguenin, St Cloud, France Submitted: Jan 16, 2004; Revised: Mar 10, 2004; Accepted: Jun 7, 2004 Address for correspondence: F. Turpin, MD, Centre de Lutte Contre le Cancer René Huguenin, 35 rue Dailly, 92211 St Cloud, France Fax: 33-01-4711-1629; e-mail: [email protected]
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Clinical Lymphoma June 2005 • 37
Non-Hodgkin’s Lymphoma of the Breast Pretreatment evaluation consisted of a physical examination; a complete blood count; blood chemistry profile (with lactate dehydrogenase); and imaging of chest, abdomen, and pelvis (by radiograph, ultrasonograph, and/or computed tomography scan). Neurologic investigations were done when clinically indicated. Mammograms had to be performed at diagnosis, and mammary ultrasonography was not systematic. A bone marrow biopsy or aspiration was also obtained in every patient. Ann Arbor stage and International Prognostic Index (IPI) and ageadjusted International Prognostic Index (aa-IPI) scores, when relevant, were determined.8 The treatment strategies were chosen after multidisciplinary discussion. Event-free survival (EFS) was measured from the date of diagnosis to disease progression, relapse, or death from any cause, or the stopping date. Overall survival (OS) was measured from the date of diagnosis to death from any cause or the stopping date. The survival functions were estimated by the Kaplan-Meier method and were compared by log-rank test.9 Tests for comparison were regarded as significant if 2-sided with P < 0.05. All statistical analyses were performed using SAS 8 and Splus 2000 software.
Results Patient Characteristics Between 1982 and 1997, 19 patients having lymphoma of the breast were diagnosed, treated, and followed (Table 1). There were 18 female patients and 1 male patient. Mean age was 68 years (range, 35-86 years; median, 69 years). All patients consulted for a mass in the breast, and 1 had inflammatory breast disease. Nine tumors involved the right breast, and 10 involved the left breast; there were no bilateral lesions. Tumors were unique in 15 cases, and 4 patients presented with bifocal lesions. Clinical sizes were < 2 cm (n = 1), 2-5 cm (n = 8), > 5 cm (n = 9), and > 10 cm (n = 5). Five patients had no involved peripheral lymph node areas, 8 patients had 1 area involved (homolateral axillary nodes), and 6 had > 1 area involved. The number of extranodal localizations was 1 (n = 1), 2 (n = 1), and 3 (n = 1). Bone marrow was involved in 2 cases. Ann Arbor stages were IE (n = 5), IIE (n = 9), IIIE (n = 2), and IV (n = 3). There were no B symptoms (eg, weight loss and fever). Lactate dehydrogenase (LDH) levels were normal in 15 patients and elevated in 4. All but 1 patient had a performance status of 0. International Prognosis Index scores were 0 (n = 2), 1 (n = 8), 2 (n =7), and 3 (n = 2). For the 4 patients < 60 years of age, ageadjusted IPI scores were 0 (n = 2), 1 (n = 1), and 2 (n = 1). According to the Wiseman and Liao classification, 11 cases were primary lymphoma of the breast, and 8 cases were to be considered secondary involvement of the breast. Mammograms were performed for the 18 female patients and mammary ultrasonography for 9 patients. At diagnosis, mammogram was normal in 1 patient, presented a unique unilateral lesion in 14 patients and a bifocal unilateral lesion in 3 patients, for a total of 20 lesions. Those lesions were nodular opacities in 16 cases, with sizes ranging from 15 mm to 120 mm (mean, 42 mm; median, 38 mm). The concordance between physical examination and mammogram was good, with radiologic size being slightly inferior to the clinical size (not
38 • Clinical Lymphoma June 2005
significantly). In 3 cases, the density of the mammary gland was enhanced with skin thickening and hypodermic densification. No microcalcification was seen. Eleven lesions were explored by mammary ultrasonography in 9 patients (2 patients with bifocal unilateral lesions). There were nodular lesions with regular outlines in 3 patients and irregular outlines in 8 patients, and the structure was homogeneous in 5 patients and heterogeneous in 6 patients. The nodules were slightly hypoechogenous in 7 patients or very hypoechogenous in 4 patients, with a posterior enhancement in 6 patients, without a posterior enhancement in 5 patients. Histologic diagnosis was made 10 times by biopsy alone, 7 times by tumorectomy with low axillary dissection, and 2 times by mastectomy with axillary dissection. All cases met the histologic criteria for lymphomatous involvement of the breast: technically adequate specimens and mammary tissue and lymphoma infiltration in close association. All cases had B-cell origins. According to the REAL classification, 16 cases were diffuse large B-cell lymphomas, 1 was a diffuse large T-cell rich B-cell lymphoma, 1 was a Burkittlike lymphoma, and 1 was a grade 3 follicular lymphoma with diffuse areas. Treatment and Follow-up Treatment began with surgery for 11 patients, 7 with tumorectomy and 4 with mastectomy (Table 2). Six patients received adjuvant chemotherapy, and 10 received radiation therapy, which was the exclusive adjuvant treatment for 4 patients. For the remaining 8 patients, chemotherapy was started after biopsy and was given with radiation therapy for 4 patients. Overall, 14 patients received chemotherapy, 13 with anthracyclines and 1 with fludarabine. After initial treatment, 14 patients exhibited a complete remission, and 3 exhibited a partial remission. Two patients progressed before the end of the induction treatment, and the second-line treatments were also unsuccessful. During followup, all but 2 patients relapsed. Mean survival time was 36.7 months, and median survival time was 21.5 months (range, 5.1-114.7 months). The 5-year OS was 29%, and EFS was 8.3 months (Figures 1 and 2). After stratification according to the Wiseman and Liao system, there were no statistical differences in OS (mean, 39.4 months for primary lymphoma vs. 48.2 months for nonprimary lymphoma; P = 0.7) or in EFS (mean, 23 months for primary lymphoma vs. 23.3 for nonprimary lymphoma; P = 0.56). No statistical differences were observed according to IPI score: mean OS was 36 months for patients with an IPI score of 0-2 versus 60.7 months for patients with an IPI score of > 2 (P = 0.46), and mean EFS was 21.4 months for patients with an IPI score of 0-2 versus 27.0 for patients with an IPI score of > 2 (P = 0.86).
Discussion Breast lymphoma remains a rare pathology considering the very few cases reported in our center, which specializes in breast diseases. However, we must not forget that the incidence may be reduced by the type of recruitment at our center. Indeed, we see
Stéphan Vignot et al Table 1
Patient Characteristics at Diagnosis
Patient Number
Age (Years)
Wiseman/ Liao Classification
Side
Regional Nodes
Other Nodes
Other Visceral Involvement
Ann Arbor Stage
LDH Level Elevated
Performance Status > 2
IPI
AgeAdjusted IPI
1
69
Primary
Left
Yes
No
No
IIE
No
No
1
–
2
66
Primary
Left
No
No
No
IE
No
No
1
–
3
56
Primary
Right
Yes
No
No
IIE
No
No
0
0
4
70
Primary
Right
Yes
No
No
IIE
Yes
No
2
–
5
72
Primary
Left
Yes
No
No
IIE
No
Yes
2
–
6
81
Primary
Left
No
No
No
IE
No
No
1
–
7
84
Primary
Right
No
No
No
IE
No
No
1
–
8
63
Primary
Right
No
No
No
IE
No
No
1
–
9
58
Primary
Left
No
No
No
IE
No
No
0
0
10
77
Primary
Left
Yes
No
No
IIE
No
No
1
–
11
69
Primary
Right
Yes
No
No
IIE
Yes
No
2
–
12
81
Nonprimary
Right
No
Yes
No
IIE
No
No
1
–
13
71
Nonprimary
Left
Yes
No
Liver, lung
IV
No
No
3
–
14
83
Nonprimary
Left
No
Yes
No
IIE
Yes
No
2
–
15
44
Nonprimary
Right
Yes
No
Bone marrow, brain, uterus
IV
No
No
2
1
16
63
Nonprimary
Right
No
Yes
No
IIIE
No
No
2
–
17
35
Nonprimary
Left
No
Yes
No
IIIE
Yes
No
2
2
18
69
Nonprimary
Left
Yes
Yes
Bone marrow
IV
No
No
2
–
19
86
Nonprimary
Right
Yes
Yes
No
IIE
No
No
1
–
All patients were women with the exception of patient number 16. Histologic classification for all patients was large B-cell lymphoma, with the exception of patient number 8, whose disease classification was diffuse large T-cell–rich B-cell lymphoma; patient 15, whose disease was Burkitt-like lymphoma; and patient 18, whose disease was grade 3 follicular lymphoma.
only the patients initially presenting with a mass in the breast, whereas patients with lymphomas where breast involvement is not the most important symptom, such as patients with severe B symptoms or with diffuse peripheral node involvement, are followed in hematologic centers. We are unable to evaluate the incidence of breast involvement in those cases; it could be much more frequent than what we see. For our patients who are consulting for a mass in the breast, the diagnosis of lymphoma before biopsy is difficult and often missed, the usual preoperative diagnosis being carcinoma. However, some of the clinical features suggest lymphoma.2 These features are a short history and rapidly growing breast mass (breast lymphoma tending to be larger at the time of diagnosis than carcinoma),10 absence of nipple discharge or retraction, multiple lesions, violaceous skin color over the lesion, and softer axillary lymph nodes as compared with metastatic lymph nodes from breast carcinoma. B symptoms are
distinctly unusual in breast lymphoma.11-16 In fact, these clinical features are often missing and are not specific at all. In practice, they do not help with making a diagnosis. The mammographic aspect is not specific but could give clues to suspect a lymphomatous lesion. As observed in our series, nodular opacity seems to be the most frequent presentation.17-21 The concordance between clinical and radiologic sizes is usually good, which can be helpful in discriminating lymphoma from breast carcinoma.17 Some authors observed microcalcifications21 or marginal spiculated appearance;18,21 however, those 2 elements were not observed in our series. The mammogram can be normal, and the mammary ultrasonograph is helpful in those cases,17 because this later examination usually reveals a hypoechogenous nodular lesion. Typically, no posterior attenuation is described.17,20,22 It is important to notice that, in term of the radiologic evaluation, the aspect of the lesion can be less alarming than the
Clinical Lymphoma June 2005 • 39
Non-Hodgkin’s Lymphoma of the Breast Table 2 Patient Number
Treatment and Follow-up Initial Surgery
Other Treatments
Initial Response
Relapse
1
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
2
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 4 and radiation therapy
CR
Yes
3
Mastectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
4
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 2 and radiation therapy
PR
Yes
5
Mastectomy
Radiation therapy
CR
No
6
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Prednisone × 4 and radiation therapy
CR
Yes
7
Mastectomy, axillary dissection
Radiation therapy
CR
Yes
8
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 4 and radiation therapy
CR
Yes
9
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
10
Tumorectomy
Radiation therapy
CR
No
11
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 8
PR
Yes
12
Mastectomy, axillary dissection
Radiation therapy
CR
Yes
13
Tumorectomy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 4
CR
Yes
14
Tru-Cut needle biopsy
Radiation therapy and Cyclophosphamide/Epirubicin/Vincristine/Prednisone × 6
PR
Yes
15
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Prednisone; Cyclophosphamide/Doxorubicin/ Vincristine/Prednisone/Methotrexate; Cytarabine/Etoposide
PD
Yes
16
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone × 6 and radiation therapy
CR
Yes
17
Tru-Cut needle biopsy
Cyclophosphamide/Doxorubicin/Vincristine/Prednisone; Doxorubicin/Etoposide/Ifosfamide
PD
Yes
18
Tru-Cut needle biopsy
Fludarabine
CR
Yes
19
Tumorectomy, axillary dissection
Radiation therapy
CR
Yes
Abbreviation: PD = progressive disease
clinical presentation.17,23,24 Other diagnoses can be made: phyllode tumor, adenofibroma, colloide carcinoma, or medullary carcinoma. The hypothesis of invasive adenocarcinoma cannot be excluded. Therefore, a histologic analysis is necessary. During the initial diagnosis, the histologic analysis on frozen sections cannot differentiate a carcinoma from a lymphoma, especially large-cell lymphoma.4,25 The problem is likely to continue, as pathologists are asked to make initial diagnoses on smaller biopsy specimens. There is a risk of performing unnecessary mastectomies. Afterward, the immunohistochemical studies are very important for a precise diagnosis. Are our data consistent with the previously reported series in the literature? The mean age at diagnosis was 68 years, which fits the range usually observed.10,14,15,26-29 There is no difference if we consider primary and nonprimary breast lymphomas in our series (69 and 66 years, respectively). No difference is observed according to the IPI score, but the statistical study of this series is hazardous considering the small number of cases observed in our center. There was no predominance between right and left lesion and no bilateral involvement. Many series initially report a right
40 • Clinical Lymphoma June 2005
predominance,1,5,6,11,16,27,28,30-34 but this conclusion is open to criticism because of the small size of those series and the fact that recent series do not find a preferential side.25,35 The breast lymphomas observed in our center are high-grade lymphomas, which were also reported by previous studies: > 80% of breast lymphomas are high grade, and diffuse large-cell lymphoma is the most frequent histologic type.3,36 We have to admit that the response and survival rates observed in our study are disappointing, considering some previously reported results.2,10,25,27,35,37,38 The explanation could be the high rate of initial surgical treatments, mostly because this is the usual way to treat breast lesions in our center, and the difficulty of the histologic analysis on frozen sections, as previously discussed. Retrospectively, this pattern is not convenient. The increasing cooperation between physician, radiologist, surgeon, and pathologist helps us to improve the management of those patients. Breast lymphoma must be considered a systemic disease at diagnosis, and systemic chemotherapy should be the mainstay of the treatment. This statement seems to be obvious for nonprimary lymphomas of
Stéphan Vignot et al Figure 2 Event-Free Survival Survival Distribution Function (%)
Survival Distribution Function (%)
Figure 1 Overall Survival
100 75 50 25
0
20
40
80
100
120
100 75 50 25
0
10
30
40
50
60
70
80
Months
Months
the breast, which are already systemic disease at diagnosis, but should also be applied to primary breast lymphoma because of the tendency of the disease to disseminate rapidly.13,39 In fact, mastectomy and tumorectomy are not indicated, because they cause a delay in chemotherapy. Since the article by Wiseman and Liao was published in 1972, the tendency is to consider primary breast lymphoma differently in the literature. If their classification is used, in our series there do not seem to be pertinent differences between primary and nonprimary breast lymphomas in terms of clinical or histologic presentation, or indication of treatment or prognosis, with the reservation already mentioned concerning the small size of the population. Does Wiseman and Liao’s classification bring something to the management of our patients? First of all, the possibility of a breast lymphoma that arises primarily in the breast but has disseminated elsewhere before diagnosis is not considered a primary breast lymphoma, whereas lymphomatous involvement of the breast that could disseminate elsewhere in its natural history (as we see in the evolution of some of our patients) but is diagnosed early is considered primary. In this latter case, Wiseman and Liao’s criteria fail to detect the specificity of lymphomatous involvement limited to the breast. In fact, the reality of a true primary breast lymphoma, which could be considered a lesion specially linked to the mammary tissue, has been discussed.26,40 A histologic classification may be more pertinent than Wiseman and Liao’s criteria. For example, the reports of lymphoma of the breast developed from mucosaassociated lymphoid tissue (MALT), with clinical behavior of low-grade lymphoma, could be an answer,28,29,41,42 but they are also very controversial. In fact, the great majority of breast lymphomas are not MALT-type lymphomas,5,26,36,40 but it remains important to notice that, in those case, the prognosis is excellent. Those cases are not identified by the Wiseman and Liao criteria, the diagnosis of MALT-type lymphoma being based on histologic analysis. In our study, we find no MALT lymphomas. Some lymphomas of the breast seem also to present a different pattern. Some authors report data on the possible hormone sensitivity of this disease. Narasimhan described a
20
good response obtained with tamoxifen,43 but no conclusion could be reasonably drawn from this experience. In 16 patients presenting primary and nonprimary breast lymphoma, Ariad et al failed to detect estrogen receptor protein in lymphoid cells of the breast by immunohistochemical investigation.44 Breast lymphomas of young women are a stronger argument to assert that there is a specific pattern for some lymphomatous involvement of the mammary tissues. Breast lymphomas in women of childbearing age are more aggressive, diffuse, associated with a rapidly fatal course corresponding to Burkitt’s lymphoma (such as our patient number 15), and often bilateral. Previous studies notice that the disease appears frequently during and after pregnancy.5,26,36,41,45 In those cases, breast lymphomas seem to have a specific history. In the future, molecular study (eg, of DNA chips) of lymphoma involving the breast could provide information to individualize specific patterns of the disease. At this time, no data have been published.
Conclusion Some lymphomas of the breast act differently than other extranodal lymphomas (lymphomatous involvement associated with MALT or aggressive breast lymphoma in young women), but the data extracted from the literature, especially the Wiseman and Liao classification system, are unable to detect these differences. The hypothesis that some lymphomas of the breast act differently than other extranodal lymphomas cannot strictly be ruled out, and there remains value in reviewing single-institution experience in an attempt to compile enough data, especially molecular data, to make meaningful conclusions for our patients in this rare and finally heterogeneous disease. Without more precise molecular characteristics, we should treat breast lymphoma as we would treat NHL of similar stage and histology at other sites of the body. The use of the IPI has already been validated and should be relevant in this context. Diagnostic surgery followed by chemotherapy and possibly radiation therapy in addition should be the standard approach. Radical and mutilating surgery should be avoided and should be used for excision only if chemotherapy and radiation therapy fail
Clinical Lymphoma June 2005 • 41
Non-Hodgkin’s Lymphoma of the Breast to control the disease. Therefore, the cooperation between physician, radiologist, surgeon, and pathologist is very important in reaching the correct diagnosis before or during the first analysis on frozen sections.
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