APMIS ZOO: 1089-1096, 1992
Primary non-Hodgkin’s lymphoma of the breast (PLB): a clinicopathological study of seven cases TOM GIEDSING HANSEN, GYDA LOLK OTTESEN, NIELS TINGGAARD PEDERSEN and JOHAN A. ANDERSEN Department of Pathology, Odense University Hospital, Odense, Denmark
Giedsing Hansen, T., Lolk Ottesen, G . , Tinggaard Pedersen, N. & Andersen, J. A. Primary nonHodgkin’s lymphoma of the breast (PLB): a clinicopathological study of seven cases. APMIS 100; 1089-1096, 1992. Seven cases of PLB in females were reviewed. Six cases involved the breast alone (stage 1 E), whereas one case also involved the ipsilateral lymph nodes (stage 2E). None had B symptoms. The age range was 37-70 years (mean 52 years). The clinical course was indistinguishable from that of breast carcinomas, though the tumors were relatively large and the duration of symptoms was relatively short. Histologically, all cases were non-Hodgkin’s B-cell lymphomas, comprising five cases of diffuse centroblastic type, one case of diffuse centroblastic-centrocytoid type and one case of follicular centroblastic-centrocytic type, according to the updated Kiel classification, corresponding to six cases of the diffuse large cell type and one case of the follicular mixed, small cleaved and large cell type, according to the modified International Working Formulation (IWF). None of the cases was a lymphoma of mucosa-associated lymphoid tissue (MALT). The mammary glandular tissue outside the tumor showed ductectasia in four cases. Changes resembling fibrous disease of the breast were seen in four cases, too. The inflammatory infiltration in all these cases was mainly composed of T cells. At the time of diagnosis, all patients were receiving cytoreductive treatment. The mean followup time was 34 months (range 5-79 months). At present, six of the patients are alive and well. Key words: Breast; non-Hodgkin’s B-cell lymphoma; inflammation; immunohistochemistry; prognosis. T. Giedsing Hansen, Dr. Olgas Vej 29, DK-5000 Odense C, Denmark.
Primary malignant lymphoma of the breast (PLB) is a rare condition with less than 300 cases reported in the literature (4,7, 17, 23, 31, 35). PLB has been reported to be present in 0.04-0.53% of all malignant breast tumors (4, 19, 36, 38). The differential diagnosis between PBL and breast carcinoma is often difficult and misdiagnosed cases are not infrequent (7, 20, 36). Clinicopathological criteria for PLB diagnosis were proposed by Wisemun & Liuo (38) in 1972: a) the lymphomatous infiltration must be closely associated with mammary glandular tissue,
Received May 4, 1992. Accepted October 5 , 1992.
b) the tumor must be confined to one breast (though presence of ipsilateral axillary lymphadenopathy is acceptable), and c) no evidence of disseminated lymphoma must exist at the time of diagnosis. Whilst cases of Hodgkin’s disease localized to the breast have been described (7, 23, 29), the most common histology is non-Hodgkin’s lymphoma (4,7, 35, 38), predominantly of diffuse large cell type, in the latest published series (7, 17, 26, 31). In this review we focus on the clinical features and histopathological subtypes of seven PLB cases. In addition, we examine the mammary glandular tissue outside the different tumors, especially concerning the presence of local chronic inflammatory changes, in an attempt to contribute to an understanding of 1089
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their histogenesis, making a comparison with lymphomas of mucosa-associated lymphoid tissue (MALT).
low and anti-high molecular weight keratins. In addition, the mammary glandular tissue surrounding the tumor was examined especially for inflammatory changes with increased numbers of lymphocytes.
MATERIALS AND METHODS
RESULTS
During an eight-year period (1983 to 1991), seven patients fulfilling the criteria for PLB were registered at the Department of Pathology, Odense University Hospital. At diagnosis, all cases underwent a thorough clinical staging procedure, including careful history taking and physical examination, with particular attention to all lymphoid regions, ear, nose and throat examination, chest radiography, lymphangiography, bone marrow aspiration and biopsy (Islam needle), 99m Tc scintigraphy of the spleen and liver, and mammography. In addition, an abdominal CT scan was performed in case 4. A blood count and a biochemistry profile including s-calcium, s-copper, s-urate and liver function tests were also performed. All the histological material was reviewed and classified according to the updated Kiel classification, and translated to the modified International Working Formulation (IWF) (16, 18). In case 2, the amount of tissue was confined to a needle biopsy (Tru-cut), while excisional biopsies were available in the remaining six cases. The routine formalin-fixed and paraffin-embedded slides were stained with H&E, Giemsa, PAS and reticulin. Apart from case 2, all the cases were stained with NAS-D chloroacetate esterase. Immunohistochemistry (three layer immunoperoxidase techniques) was performed, including the following monoclonal antibodies: leukocyte common antigen, LCA (CD45, Dako), the B-lymphocyte marker L-26 (CD20, Dako), the T-lymphocyte marker UCHL- 1 (CD-45R0, Dako), anti-immunoglobulins with both light (polyclonal kappa and lambda, Dako) and heavy (polyclonal IgA, IgG and IgM, Dako) chains, and the epithelial antibodies LMW (Dako) and HMW (Dako) against low and high molecular weight keratins, respectively. In the search for interdigitating reticulum cells, case 5 was investigated with anti-S-100 protein (Dako). In five cases, unfixed frozen tumor tissue was available too, and, dependent on the amount of tissue, immunohistochemically (three-layer immunoperoxidase techniques upon acetone-fixed cryostat sections) investigated for the pan-B lymphocyte markers leu12 (CD19, Becton & Dickinson), B-1 (CD20, Coulter), leu14 (CD22, Becton & Dickinson), and the pan-T lymphocyte markers leu9 (CD7, Dako) and T-11 (CD2, Coulter), light chain immunoglobulins (polyclonal kappa and lambda, Dako), the proliferationassociated nuclear antigen, Ki-67 (Dako), and anti-
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Clinical data Patient characteristics, treatment regimens and outcome are summarized in Table 1. The material was collected retrospectively. All seven patients fulfilling the criteria for PLB were females. They all presented with a progressively enlarging breast tumor. Case seven had ipsilatera1 axillary lymphadenopathy and skin involvement. Constitutional symptoms were not seen. In three of the seven cases (nos. 1, 6 & 7) the mammogram gave a suspicion of malignancy, but n o features suggestive of PLB. Two patients (cases nos. 1 & 6 ) had a longstanding history of severe rheumatoid arthritis. Case seven had 18 months previously received local radiation therapy for a basal cell carcinoma of the nose.
All patients had normal blood count and biochemical parameters; chest radiography, liver / spleen scintigraphy (Tc-99m) and lymphangiography were also normal. The abdominal CT scan in case 4 was normal as well. Initially, case 3 was misdiagnosed a s medullary carcinoma and a mastectomy was carried out. The lymphoma diagnosis was not made
until 3.5 years later after a biopsy was taken from the site of a local relapse. Shortly afterwards the patient died from disseminated
lymphoma. The remaining six patients attained complete remission. At present they are all alive and well. Pathological data The histopathological results are summarized
in Tables 2 and 3.
Tumor tissue. Case 1 showed a follicular nonHodgkin’s lymphoma of centroblastic-centrocytic type (Kiel) or a follicular mixed small cleaved and large cell type (IWF) composed of large, sometimes confluent, areas of germ center cells, mostly centrocytes surrounded by a thin inhomogeneous mantle zone of small lymphocytes. We were not able to identify remains of lymph node
NON-HODGKIN’S LYMPHOMA OF THE BREAST
TABLE 1. Patient characteristics, treatment reaimens and outcome Case no. I 2 3 4 Age (years) 46 54 52 50 Post -menopausal no Yes Yes Yes Previous pregnancies no no Yes Yes Sided’ L R R R Size of tumor (cm)b’ 3 6 6 5 Duration of symptoms before 3 4 5 4 diagnosis (weeks) Stage IE IE IE IE Type of surgery‘) eb nb mast eb Cytoreductive treatmentd’ CT CT + RT CT + RT CT+RT Outcomee) CR CR DEAD CR Follow-UD(months) 79 22 42 18 d l R =right, L=left b’ largest diameter eb = excisional biopsy; nb = needle biopsy (Tru-cut); mast =mastectomy CT=chemotherapy; RT= radiotherapy e , CR =complete remission.
structure (Fig. l a x ) . This patient had for many years suffered from rheumatoid arthritis. The remaining tumors were classified as highgrade malignant non-Hodgkin’s B lymphomas, showing a diffuse growth pattern with densely packed large cells (Fig. 2). In one case (case 2) the tumor was composed of centroblasts of centrocytoid type, while the remaining five cases were all classified as centroblastic, two of these of the polymorphic type, in accordance with the updated Kiel classification (1 8). According to the modified International Working Formulation (IWF) these six cases were all of the diffuse large cell subtype (16).
5 37 no Yes L 2 6
6 70 Yes Yes R 3 3
L 4 4
IE eb RT CR 70
IE eb CT CR 10
IIE eb CT CR 7
7 58 no Yes
All tumors were poorly circumscribed, with the lymphoma cells diffusely infiltrating the breast tissue. Only focally, mostly in the periphery at the advancing edge of the lymphomas, were there a few remaining mammary ducts and acini, in most cases completely intact, although compressed and atrophic (Fig. lc). In two cases, the glandular elements were partly destroyed and invaded by large centroblastic lymphoma cells, lying intraepithelially. The tumors were relatively homogeneous, without transition to areas of lower malignancy. In particular, we did not find either lymphoepithelial lesions containing centrocyte-like cells, other areas consisting
TABLE 2.Histopathological results. including classification according to the updated Kiel classification and the modified International Working Formulation ( I W F ) HistoDathological data Case Final diagnosis Reactive changes no. Kiel IWF Ductectasia Resembling fibrous disease of the breast 1. Follicular CB/CC Mixed small cleaved + & large cell 2. Diffuse CB of CC type Diffuse large cell ? ? 3. Diffuse CB Diffuse large cell 4. Diffuse CB Diffuse large cell Diffuse large cell 5 . * ) Diffuse CB 6. Diffuse CB Diffuse large cell 7. Diffuse CB Diffuse large cell + + Abbreviations: CB =centroblastic; CB/CC=centroblastic-centrocytic; CB of CC =centroblasts of centrocytoid type ?: the needle biposy (Tru-cut) consisted only of tumor tissue *) presumably originating from a lymph node.
+ +
+ + +
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TABLE 3. Results of the immunohistochemimcal analysis Immunohistochemical results Case LCA L26 UCHL-1 Pan-B Pan-T Ki-67 LMWiHMW no. CD45 CD20 CD45RO CD19 CD2 n.d. n.d. n.d. 1. n.d. 50% 2. 50% 3. (+) 4. (+I n.d. 50% 5. n.d. n.d. 6. n.d. n.d. 7. (+I n.d. n.d. n.d. n.d. Abbreviations: LCA (CD45, Dako) =leukocyte marker; L26 (CD20)= pan-B marker; UCHL-1 (CD45R0, Dako) = pan-T marker; CD-19 (leu-12, Becton & Dickinson)= pan-B marker; CD-2 (T-11, Coulter)= pan-T marker; Ki-67 (Dako) =the proliferation-associated nuclear antigen; CD =cluster of differentiation; LMW / HMW = low and high molecular weight antikeratins (Dako), n.d. =not done.
+ + + + +
+ + + + + +
of small centrocyte-like cells, or components of monoclonal plasma cells. In case 5, we were able to recognize the remains of a lymph node structure with a cell population of small mature lymphocytes, including dispersed (anti-S-100 protein-positive, Dako) interdigitating reticulum cells, surrounded by a thin fibrous capsule, suggesting that the lymphoma originated from an intramammarian lymph node. In several cases we found a weak-to-moderate infiltration of mature lymphocytes at the tumor margin. Immunohistochemistry on formalin-fixed paraffin-embedded tissue demonstrated the following: only case 2 showed no staining with L26 (CD20, Dako), two cases (case nos. 4 & 6) were LCA (CD45, Dako) negative, and three cases also showed positive reaction to the T-cell marker UCHL- 1 (CD-45R0, Dako). However, occasionally weak cytoplasmic staining for this marker is seen in cases of diffuse centroblastic lymphomas (1 1). Staining reactions to immunoglobulins (light and heavy chains) were inconclusive. In case 2 the material was too scanty and in cases 1 and 4 the results were ambiguous.
+ + + + +
Immunohistochemistry performed on unfixed frozen tumor tissue mainly confirmed the results described above. Case 2, however, showed positive reactions to the pan-B markers B-1 (CD20, Coulter) and leu12 (CD19, Becton & Dickinson). Interestingly, case 4 turned out to be LCA (CD45, Dako) positive on frozen sections. Three cases were tested for the proliferation-associated nuclear antigen Ki-67 (Dako) with staining of more than 50% of the nuclei, suggesting the lymphomas to be high-grade malignancies ( 12). The lymphoid infiltration at the margin of the tumor mostly stained positive with UCHL- 1 (CD45R0, Dako), indicating that the cells are normal T cells. Mammary glandular tissue outside the tumor. The mammary glandular tissue outside the tumor was examined in six cases, as case 2 consisted only of tumor tissue. In case 5 the glandular tissue did not show any pathological changes. In four cases we found varying degrees of ductectasia, with a slight-to-moderate periductal inflammatory infiltration, composed of small mature lymphocytes and relatively few dispersed polyclonal plasma cells. The number of intraepithelially located lymphocytes was increased;
Fig. la. Follicular low-grade malignant B lymphoma of centroblastic-centrocytic type (Kiel) or mixed small cleaved and large cell (IWF) (case 1). L-26 x 32. Fig. Ih. Same case stained with reticulin to show the follicular structure more clearly. Reticulin x 20. Fig. 1c. Same case. The lymphoma cells do not affect the glandular tissue and do not form lymphoepithelial
lesions. L-26 x 200. Fig. 2. High-grade malignant B lymphoma of diffuse centroblastic (Kiel) or large cell (IWF) type. HE x 320.
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GIEDSING HANSEN et a/.
cases were all negative. No cases had bone marrow involvement. DISCUSSION
Fig. 3. Two atrophic mammary lobules with welldemarcated dense lymphocytic infiltrations. HE x 80.
they were lying single or in small clusters, having the appearance of “clear cells”. In addition, a remarkable inflammatory reaction was seen in four cases with rather welldemarcated and dense infiltration of small mature lymphocytes, located around ducts and vascular structures and around and within lobules. The lobules showed varying degrees of atrophia and fibrosis (Fig. 3). Germinal centers were not found. All these changes were found in the mammary parenchyma without continuity to either the tumor or the weak-to-moderate lymphoid infiltration at the margin of the tumor. Most of the lymphocytes located periductally, lobularly, vascularly and intraepithelially stained negative with L-26 (CD20, Dako) and positive with UCHL-1 (CD-45R0, Dako), and are thus assumed to represent normal T cells. There were only a few scattered L-26 (CD-20, Dako)-positive B lymphocytes, and very few polyclonal plasma cells. The six NAS-D chloroacetate esterase-stained 1094
Clinically PLBs are indistinguishable from breast carcinomas (4, 17, 19, 27, 29, 31, 36), although they usually present as relatively large breast tumors with rapid onset and growth (4, 7, 17, 20, 31, 32, 35, 38). PLBs are most frequently seen among the elderly (4, 7 , 17, 27, 35, 38). They are practically unknown among prepuberal females, but may be encountered among younger women (4, 7, 29, 31, 35). A few cases have been described which have presented as nipple edema without a concomitant breast tumor (5, 21). Postpartal cases of PLB, imitating postpartum mastitis, have been described, suggesting that endocrinological factors may be pathogenetically important (24, 30). The role of mammography as a diagnostic tool in PLB is questionable (19, 21, 22, 27, 39). In the present study mammography gave a suspicion of malignancy in only three of seven cases. The mammary glandular tissue is considered to be part of an integrated secretory immune system, where antigen-stimulated lymphocytes are distributed from gut-associated lymphoid tissue to exocrine glandular sites all over the body (2, 3, 9, 13, 14, 15). PLB might therefore belong to the low grade B lymphoma of the mucosa-associated lymphoid tissue (MALT) as described by Zsaacson et al. (6, 8, 13, 14, 15, 34). Today these lymphomas constitute a histopathological entity with several characteristic features, such as lymphoepithelial lesions, ability to overgrow germinal centers, and very low grade malignancy with tendency to “homing”, and the cell type is a centrocyte-like marginal zone lymphocyte with a distinct phenotype. These lymphomas are found particularly in the gastrointestinal tract and salivary glands (6, 8, 13, 14, 15, 34), though it has been claimed that some PLBs may represent lymphomas of the MALT (17, 25). None of the seven PLB cases possessed any of the above-mentioned characteristics, and we were not able to identify a component of monoclonal plasma cells. The only low-grade
NON-HODGKIN’S LYMPHOMA OF THE BREAST
lymphoma was of follicular centroblastic-centrocytic type (Kiel), composed of follicle center cells (FCC), correspondling to the follicular mixed small cleaved and large cell type (IWF) found in a patient with a long-standing autoimmune disease (rheumatoid arthritis). The development of many lymphomas of the MALT is believed to be preceded by a chronic inflammatory disease, resulting in an increase in the local amount of lymphoid tissue, as many of these sites lack the innate lymphoid tissue which develops during fetal life and is present at birth (8, 13, 14). In four of the seven cases the mammary glandular tissue showed ductectasia, with the characteristic inflammatory infiltration, mainly of T lymphocytes, located around the ectatic ducts and intraepithelially. Furthermore, in four cases we found numerous dense and well-demarcated groups of mature T lymphocytes located around otherwise normal ducts as well as around and within lobules, with fibrous obliteration of the epithelial structures. We have no explanation for these findings, which resemble the changes seen in so-called fibrous disease of the breast, a clinicopathological entity of unknown etiology, though there are elements which point to an immune-related disease (10). We do not know whether the inflammatory reaction here is primary or secondary to the lymphoma. Hence, even if the local amount of lymphoid tissue is increased, it is mainly composed of T lymphocytes, without significant hyperplasia of the B lymphocytes. If the malignant mutation takes place in acquired lymphoid tissue within the mammary gland, it is remarkable that we have not found any T lymphomas among our cases. The mutation possibly arises in the bone marrow, in a pre-B lymphoblast, which subsequently migrates to the breast (28). Histologically, five of the seven cases were of the diffuse centroblastic type (Kiel) or diffuse large cell type (IWF). Among several other extranodal lymphomas (localized to the testis and central nervous system) this subtype is also predominant (1, 33). Many PLBs have been histopathologically confused with anaplastic or medullary carcinomas, and thus erroneous mastectomies have been performed (4, 7, 17, 27, 29, 31, 36, 38). This also happened in case 3. The prognosis in the present series seems to
correspond to the reported prognosis of other localized high-grade large cell lymphomas, i.e. a five-year survival rate of approximately 70% in the latest series (4, 7, 26, 27, 31, 34, 37). In order to reach a histopathological diagnosis it is essential to include immunohistochemical analysis. When possible the biopsy should be excisional, thus providing the pathologist with more representative material.
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Primary non-Hodgkin’s lymphoma of the breast (PLB): a clinicopathological study of seven cases TOM GIEDSING HANSEN, GYDA LOLK OTTESEN, NIELS TINGGAARD PEDERSEN and JOHAN A. ANDERSEN Department of Pathology, Odense University Hospital, Odense, Denmark
Giedsing Hansen, T., Lolk Ottesen, G . , Tinggaard Pedersen, N. & Andersen, J. A. Primary nonHodgkin’s lymphoma of the breast (PLB): a clinicopathological study of seven cases. APMIS 100; 1089-1096, 1992. Seven cases of PLB in females were reviewed. Six cases involved the breast alone (stage 1 E), whereas one case also involved the ipsilateral lymph nodes (stage 2E). None had B symptoms. The age range was 37-70 years (mean 52 years). The clinical course was indistinguishable from that of breast carcinomas, though the tumors were relatively large and the duration of symptoms was relatively short. Histologically, all cases were non-Hodgkin’s B-cell lymphomas, comprising five cases of diffuse centroblastic type, one case of diffuse centroblastic-centrocytoid type and one case of follicular centroblastic-centrocytic type, according to the updated Kiel classification, corresponding to six cases of the diffuse large cell type and one case of the follicular mixed, small cleaved and large cell type, according to the modified International Working Formulation (IWF). None of the cases was a lymphoma of mucosa-associated lymphoid tissue (MALT). The mammary glandular tissue outside the tumor showed ductectasia in four cases. Changes resembling fibrous disease of the breast were seen in four cases, too. The inflammatory infiltration in all these cases was mainly composed of T cells. At the time of diagnosis, all patients were receiving cytoreductive treatment. The mean followup time was 34 months (range 5-79 months). At present, six of the patients are alive and well. Key words: Breast; non-Hodgkin’s B-cell lymphoma; inflammation; immunohistochemistry; prognosis. T. Giedsing Hansen, Dr. Olgas Vej 29, DK-5000 Odense C, Denmark.
Primary malignant lymphoma of the breast (PLB) is a rare condition with less than 300 cases reported in the literature (4,7, 17, 23, 31, 35). PLB has been reported to be present in 0.04-0.53% of all malignant breast tumors (4, 19, 36, 38). The differential diagnosis between PBL and breast carcinoma is often difficult and misdiagnosed cases are not infrequent (7, 20, 36). Clinicopathological criteria for PLB diagnosis were proposed by Wisemun & Liuo (38) in 1972: a) the lymphomatous infiltration must be closely associated with mammary glandular tissue,
Received May 4, 1992. Accepted October 5 , 1992.
b) the tumor must be confined to one breast (though presence of ipsilateral axillary lymphadenopathy is acceptable), and c) no evidence of disseminated lymphoma must exist at the time of diagnosis. Whilst cases of Hodgkin’s disease localized to the breast have been described (7, 23, 29), the most common histology is non-Hodgkin’s lymphoma (4,7, 35, 38), predominantly of diffuse large cell type, in the latest published series (7, 17, 26, 31). In this review we focus on the clinical features and histopathological subtypes of seven PLB cases. In addition, we examine the mammary glandular tissue outside the different tumors, especially concerning the presence of local chronic inflammatory changes, in an attempt to contribute to an understanding of 1089
GIEDSING HANSEN et al.
their histogenesis, making a comparison with lymphomas of mucosa-associated lymphoid tissue (MALT).
low and anti-high molecular weight keratins. In addition, the mammary glandular tissue surrounding the tumor was examined especially for inflammatory changes with increased numbers of lymphocytes.
MATERIALS AND METHODS
RESULTS
During an eight-year period (1983 to 1991), seven patients fulfilling the criteria for PLB were registered at the Department of Pathology, Odense University Hospital. At diagnosis, all cases underwent a thorough clinical staging procedure, including careful history taking and physical examination, with particular attention to all lymphoid regions, ear, nose and throat examination, chest radiography, lymphangiography, bone marrow aspiration and biopsy (Islam needle), 99m Tc scintigraphy of the spleen and liver, and mammography. In addition, an abdominal CT scan was performed in case 4. A blood count and a biochemistry profile including s-calcium, s-copper, s-urate and liver function tests were also performed. All the histological material was reviewed and classified according to the updated Kiel classification, and translated to the modified International Working Formulation (IWF) (16, 18). In case 2, the amount of tissue was confined to a needle biopsy (Tru-cut), while excisional biopsies were available in the remaining six cases. The routine formalin-fixed and paraffin-embedded slides were stained with H&E, Giemsa, PAS and reticulin. Apart from case 2, all the cases were stained with NAS-D chloroacetate esterase. Immunohistochemistry (three layer immunoperoxidase techniques) was performed, including the following monoclonal antibodies: leukocyte common antigen, LCA (CD45, Dako), the B-lymphocyte marker L-26 (CD20, Dako), the T-lymphocyte marker UCHL- 1 (CD-45R0, Dako), anti-immunoglobulins with both light (polyclonal kappa and lambda, Dako) and heavy (polyclonal IgA, IgG and IgM, Dako) chains, and the epithelial antibodies LMW (Dako) and HMW (Dako) against low and high molecular weight keratins, respectively. In the search for interdigitating reticulum cells, case 5 was investigated with anti-S-100 protein (Dako). In five cases, unfixed frozen tumor tissue was available too, and, dependent on the amount of tissue, immunohistochemically (three-layer immunoperoxidase techniques upon acetone-fixed cryostat sections) investigated for the pan-B lymphocyte markers leu12 (CD19, Becton & Dickinson), B-1 (CD20, Coulter), leu14 (CD22, Becton & Dickinson), and the pan-T lymphocyte markers leu9 (CD7, Dako) and T-11 (CD2, Coulter), light chain immunoglobulins (polyclonal kappa and lambda, Dako), the proliferationassociated nuclear antigen, Ki-67 (Dako), and anti-
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Clinical data Patient characteristics, treatment regimens and outcome are summarized in Table 1. The material was collected retrospectively. All seven patients fulfilling the criteria for PLB were females. They all presented with a progressively enlarging breast tumor. Case seven had ipsilatera1 axillary lymphadenopathy and skin involvement. Constitutional symptoms were not seen. In three of the seven cases (nos. 1, 6 & 7) the mammogram gave a suspicion of malignancy, but n o features suggestive of PLB. Two patients (cases nos. 1 & 6 ) had a longstanding history of severe rheumatoid arthritis. Case seven had 18 months previously received local radiation therapy for a basal cell carcinoma of the nose.
All patients had normal blood count and biochemical parameters; chest radiography, liver / spleen scintigraphy (Tc-99m) and lymphangiography were also normal. The abdominal CT scan in case 4 was normal as well. Initially, case 3 was misdiagnosed a s medullary carcinoma and a mastectomy was carried out. The lymphoma diagnosis was not made
until 3.5 years later after a biopsy was taken from the site of a local relapse. Shortly afterwards the patient died from disseminated
lymphoma. The remaining six patients attained complete remission. At present they are all alive and well. Pathological data The histopathological results are summarized
in Tables 2 and 3.
Tumor tissue. Case 1 showed a follicular nonHodgkin’s lymphoma of centroblastic-centrocytic type (Kiel) or a follicular mixed small cleaved and large cell type (IWF) composed of large, sometimes confluent, areas of germ center cells, mostly centrocytes surrounded by a thin inhomogeneous mantle zone of small lymphocytes. We were not able to identify remains of lymph node
NON-HODGKIN’S LYMPHOMA OF THE BREAST
TABLE 1. Patient characteristics, treatment reaimens and outcome Case no. I 2 3 4 Age (years) 46 54 52 50 Post -menopausal no Yes Yes Yes Previous pregnancies no no Yes Yes Sided’ L R R R Size of tumor (cm)b’ 3 6 6 5 Duration of symptoms before 3 4 5 4 diagnosis (weeks) Stage IE IE IE IE Type of surgery‘) eb nb mast eb Cytoreductive treatmentd’ CT CT + RT CT + RT CT+RT Outcomee) CR CR DEAD CR Follow-UD(months) 79 22 42 18 d l R =right, L=left b’ largest diameter eb = excisional biopsy; nb = needle biopsy (Tru-cut); mast =mastectomy CT=chemotherapy; RT= radiotherapy e , CR =complete remission.
structure (Fig. l a x ) . This patient had for many years suffered from rheumatoid arthritis. The remaining tumors were classified as highgrade malignant non-Hodgkin’s B lymphomas, showing a diffuse growth pattern with densely packed large cells (Fig. 2). In one case (case 2) the tumor was composed of centroblasts of centrocytoid type, while the remaining five cases were all classified as centroblastic, two of these of the polymorphic type, in accordance with the updated Kiel classification (1 8). According to the modified International Working Formulation (IWF) these six cases were all of the diffuse large cell subtype (16).
5 37 no Yes L 2 6
6 70 Yes Yes R 3 3
L 4 4
IE eb RT CR 70
IE eb CT CR 10
IIE eb CT CR 7
7 58 no Yes
All tumors were poorly circumscribed, with the lymphoma cells diffusely infiltrating the breast tissue. Only focally, mostly in the periphery at the advancing edge of the lymphomas, were there a few remaining mammary ducts and acini, in most cases completely intact, although compressed and atrophic (Fig. lc). In two cases, the glandular elements were partly destroyed and invaded by large centroblastic lymphoma cells, lying intraepithelially. The tumors were relatively homogeneous, without transition to areas of lower malignancy. In particular, we did not find either lymphoepithelial lesions containing centrocyte-like cells, other areas consisting
TABLE 2.Histopathological results. including classification according to the updated Kiel classification and the modified International Working Formulation ( I W F ) HistoDathological data Case Final diagnosis Reactive changes no. Kiel IWF Ductectasia Resembling fibrous disease of the breast 1. Follicular CB/CC Mixed small cleaved + & large cell 2. Diffuse CB of CC type Diffuse large cell ? ? 3. Diffuse CB Diffuse large cell 4. Diffuse CB Diffuse large cell Diffuse large cell 5 . * ) Diffuse CB 6. Diffuse CB Diffuse large cell 7. Diffuse CB Diffuse large cell + + Abbreviations: CB =centroblastic; CB/CC=centroblastic-centrocytic; CB of CC =centroblasts of centrocytoid type ?: the needle biposy (Tru-cut) consisted only of tumor tissue *) presumably originating from a lymph node.
+ +
+ + +
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TABLE 3. Results of the immunohistochemimcal analysis Immunohistochemical results Case LCA L26 UCHL-1 Pan-B Pan-T Ki-67 LMWiHMW no. CD45 CD20 CD45RO CD19 CD2 n.d. n.d. n.d. 1. n.d. 50% 2. 50% 3. (+) 4. (+I n.d. 50% 5. n.d. n.d. 6. n.d. n.d. 7. (+I n.d. n.d. n.d. n.d. Abbreviations: LCA (CD45, Dako) =leukocyte marker; L26 (CD20)= pan-B marker; UCHL-1 (CD45R0, Dako) = pan-T marker; CD-19 (leu-12, Becton & Dickinson)= pan-B marker; CD-2 (T-11, Coulter)= pan-T marker; Ki-67 (Dako) =the proliferation-associated nuclear antigen; CD =cluster of differentiation; LMW / HMW = low and high molecular weight antikeratins (Dako), n.d. =not done.
+ + + + +
+ + + + + +
of small centrocyte-like cells, or components of monoclonal plasma cells. In case 5, we were able to recognize the remains of a lymph node structure with a cell population of small mature lymphocytes, including dispersed (anti-S-100 protein-positive, Dako) interdigitating reticulum cells, surrounded by a thin fibrous capsule, suggesting that the lymphoma originated from an intramammarian lymph node. In several cases we found a weak-to-moderate infiltration of mature lymphocytes at the tumor margin. Immunohistochemistry on formalin-fixed paraffin-embedded tissue demonstrated the following: only case 2 showed no staining with L26 (CD20, Dako), two cases (case nos. 4 & 6) were LCA (CD45, Dako) negative, and three cases also showed positive reaction to the T-cell marker UCHL- 1 (CD-45R0, Dako). However, occasionally weak cytoplasmic staining for this marker is seen in cases of diffuse centroblastic lymphomas (1 1). Staining reactions to immunoglobulins (light and heavy chains) were inconclusive. In case 2 the material was too scanty and in cases 1 and 4 the results were ambiguous.
+ + + + +
Immunohistochemistry performed on unfixed frozen tumor tissue mainly confirmed the results described above. Case 2, however, showed positive reactions to the pan-B markers B-1 (CD20, Coulter) and leu12 (CD19, Becton & Dickinson). Interestingly, case 4 turned out to be LCA (CD45, Dako) positive on frozen sections. Three cases were tested for the proliferation-associated nuclear antigen Ki-67 (Dako) with staining of more than 50% of the nuclei, suggesting the lymphomas to be high-grade malignancies ( 12). The lymphoid infiltration at the margin of the tumor mostly stained positive with UCHL- 1 (CD45R0, Dako), indicating that the cells are normal T cells. Mammary glandular tissue outside the tumor. The mammary glandular tissue outside the tumor was examined in six cases, as case 2 consisted only of tumor tissue. In case 5 the glandular tissue did not show any pathological changes. In four cases we found varying degrees of ductectasia, with a slight-to-moderate periductal inflammatory infiltration, composed of small mature lymphocytes and relatively few dispersed polyclonal plasma cells. The number of intraepithelially located lymphocytes was increased;
Fig. la. Follicular low-grade malignant B lymphoma of centroblastic-centrocytic type (Kiel) or mixed small cleaved and large cell (IWF) (case 1). L-26 x 32. Fig. Ih. Same case stained with reticulin to show the follicular structure more clearly. Reticulin x 20. Fig. 1c. Same case. The lymphoma cells do not affect the glandular tissue and do not form lymphoepithelial
lesions. L-26 x 200. Fig. 2. High-grade malignant B lymphoma of diffuse centroblastic (Kiel) or large cell (IWF) type. HE x 320.
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cases were all negative. No cases had bone marrow involvement. DISCUSSION
Fig. 3. Two atrophic mammary lobules with welldemarcated dense lymphocytic infiltrations. HE x 80.
they were lying single or in small clusters, having the appearance of “clear cells”. In addition, a remarkable inflammatory reaction was seen in four cases with rather welldemarcated and dense infiltration of small mature lymphocytes, located around ducts and vascular structures and around and within lobules. The lobules showed varying degrees of atrophia and fibrosis (Fig. 3). Germinal centers were not found. All these changes were found in the mammary parenchyma without continuity to either the tumor or the weak-to-moderate lymphoid infiltration at the margin of the tumor. Most of the lymphocytes located periductally, lobularly, vascularly and intraepithelially stained negative with L-26 (CD20, Dako) and positive with UCHL-1 (CD-45R0, Dako), and are thus assumed to represent normal T cells. There were only a few scattered L-26 (CD-20, Dako)-positive B lymphocytes, and very few polyclonal plasma cells. The six NAS-D chloroacetate esterase-stained 1094
Clinically PLBs are indistinguishable from breast carcinomas (4, 17, 19, 27, 29, 31, 36), although they usually present as relatively large breast tumors with rapid onset and growth (4, 7, 17, 20, 31, 32, 35, 38). PLBs are most frequently seen among the elderly (4, 7 , 17, 27, 35, 38). They are practically unknown among prepuberal females, but may be encountered among younger women (4, 7, 29, 31, 35). A few cases have been described which have presented as nipple edema without a concomitant breast tumor (5, 21). Postpartal cases of PLB, imitating postpartum mastitis, have been described, suggesting that endocrinological factors may be pathogenetically important (24, 30). The role of mammography as a diagnostic tool in PLB is questionable (19, 21, 22, 27, 39). In the present study mammography gave a suspicion of malignancy in only three of seven cases. The mammary glandular tissue is considered to be part of an integrated secretory immune system, where antigen-stimulated lymphocytes are distributed from gut-associated lymphoid tissue to exocrine glandular sites all over the body (2, 3, 9, 13, 14, 15). PLB might therefore belong to the low grade B lymphoma of the mucosa-associated lymphoid tissue (MALT) as described by Zsaacson et al. (6, 8, 13, 14, 15, 34). Today these lymphomas constitute a histopathological entity with several characteristic features, such as lymphoepithelial lesions, ability to overgrow germinal centers, and very low grade malignancy with tendency to “homing”, and the cell type is a centrocyte-like marginal zone lymphocyte with a distinct phenotype. These lymphomas are found particularly in the gastrointestinal tract and salivary glands (6, 8, 13, 14, 15, 34), though it has been claimed that some PLBs may represent lymphomas of the MALT (17, 25). None of the seven PLB cases possessed any of the above-mentioned characteristics, and we were not able to identify a component of monoclonal plasma cells. The only low-grade
NON-HODGKIN’S LYMPHOMA OF THE BREAST
lymphoma was of follicular centroblastic-centrocytic type (Kiel), composed of follicle center cells (FCC), correspondling to the follicular mixed small cleaved and large cell type (IWF) found in a patient with a long-standing autoimmune disease (rheumatoid arthritis). The development of many lymphomas of the MALT is believed to be preceded by a chronic inflammatory disease, resulting in an increase in the local amount of lymphoid tissue, as many of these sites lack the innate lymphoid tissue which develops during fetal life and is present at birth (8, 13, 14). In four of the seven cases the mammary glandular tissue showed ductectasia, with the characteristic inflammatory infiltration, mainly of T lymphocytes, located around the ectatic ducts and intraepithelially. Furthermore, in four cases we found numerous dense and well-demarcated groups of mature T lymphocytes located around otherwise normal ducts as well as around and within lobules, with fibrous obliteration of the epithelial structures. We have no explanation for these findings, which resemble the changes seen in so-called fibrous disease of the breast, a clinicopathological entity of unknown etiology, though there are elements which point to an immune-related disease (10). We do not know whether the inflammatory reaction here is primary or secondary to the lymphoma. Hence, even if the local amount of lymphoid tissue is increased, it is mainly composed of T lymphocytes, without significant hyperplasia of the B lymphocytes. If the malignant mutation takes place in acquired lymphoid tissue within the mammary gland, it is remarkable that we have not found any T lymphomas among our cases. The mutation possibly arises in the bone marrow, in a pre-B lymphoblast, which subsequently migrates to the breast (28). Histologically, five of the seven cases were of the diffuse centroblastic type (Kiel) or diffuse large cell type (IWF). Among several other extranodal lymphomas (localized to the testis and central nervous system) this subtype is also predominant (1, 33). Many PLBs have been histopathologically confused with anaplastic or medullary carcinomas, and thus erroneous mastectomies have been performed (4, 7, 17, 27, 29, 31, 36, 38). This also happened in case 3. The prognosis in the present series seems to
correspond to the reported prognosis of other localized high-grade large cell lymphomas, i.e. a five-year survival rate of approximately 70% in the latest series (4, 7, 26, 27, 31, 34, 37). In order to reach a histopathological diagnosis it is essential to include immunohistochemical analysis. When possible the biopsy should be excisional, thus providing the pathologist with more representative material.
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