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High grade MALT-lymphoma of the breast
The Netherlands Journal of Medicine 54 (1999) 235–238
Brief report
High grade MALT-lymphoma of the breast M.J.J. Kuper-Hommel a , L.W. Vrints b , J.W.W. Coebergh c , G. Vreugdenhil a , * a
Department of Internal Medicine, St. Joseph Hospital, Veldhoven, The Netherlands b Department of Pathology, Catharina Hospital, Eindhoven, The Netherlands c Comprehensive Cancer Center South ( IKZ), Eindhoven, The Netherlands Received 2 September 1998; received in revised form 10 December 1998; accepted 19 January 1999
Abstract A 65-year-old woman presented with a rapidly growing breast tumor, initially diagnosed as a carcinoma. Histology showed a breast lymphoma of high grade MALT-type. A lymphoma should always be considered in the differential diagnosis of a breast tumor, because it needs a different work-up and treatment. The subgroup of NHL of MucosaAssociated-Lymphoid-Tissue origin has different clinical behaviour, as illustrated in this report. 1999 Elsevier Science B.V. All rights reserved. Keywords: Breast lymphoma; High grade MALT-type; Gastric dissemination
Introduction About 50% of all lymphomas are primary extranodal non-Hodgkin’s lymphoma (NHL), and only about 2% of these are situated in the breast [1,2]. Primary breast lymphomas (PBL) sometimes have a mucosa-associated lymphoid tissue (MALT) origin [3–5], and then tend to metastasize to other MALTareas, such as the gastrointestinal tract or lungs, before or without nodal dissemination. In patients with MALT-lymphomas, screening of other MALTareas is generally not included in the staging procedure. Endoscopic evaluation of the gastrointestinal and upper respiratory tract, may detect early dissemination of MALT-lymphoma. We present a patient *Corresponding author. Tel.: 1 31-40-2588220; fax: 1 31-402588246.
with a MALT-lymphoma of the breast, which in a later stage appeared to be disseminated to the stomach, another MALT-site.
Case report In December 1995, a 65-year-old woman presented with a large (5 cm), palpable, rapidly growing painless tumor in the lateral upper quadrant of the right breast. She had a medical history of a left pneumonectomy for tuberculosis in 1953, a myocardial infarction in 1987 and acute congestive heart failure in 1989. Mammography showed a malignant imposing, irregular shaped nodule (4.5 cm), without microcalcifications. Nuclear lymphoscintigraphy, performed as part of a sentinel node procedure, showed two
0300-2977 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 99 )00010-8
236
M. J. J. Kuper-Hommel et al. / The Netherlands Journal of Medicine 54 (1999) 235 – 238
positive ipsilateral axillary lymph nodes. True cut biopsy and fine needle aspiration cytology both showed breast carcinoma. Because a T2 breast carcinoma was suspected, radical mastectomy was performed. Microscopy of the breast showed a large (3.9 cm) non-Hodgkin’s lymphoma of B-cell type. Subtyping according to the Revised European American Lymphoma (REAL) classification showed a diffuse large B-cell lymphoma, positive for leukocyte common antigen and B-cell marker L26 (CD 20), with a minor component of small cells and with mainly small B-lymphocytes infiltrating the ductal epithelium (so-called ‘‘lymphoepithelial lesion’’). Immunohistochemically on paraffin sections there was lambda light chain restriction in part of the lymphoid population, mainly in the cells with plasmacytoid differentiation. Although the sentinel node procedure showed two positive lymph nodes, none of the 14 resected axillary lymph nodes had malignant infiltration. Complete staging, including computed tomography of the thorax and abdomen, bone marrow aspiration and biopsy, and screening of the ear, nose and throat area (endoscopy included), showed no evidence of systemic involvement. According to the Ann Arbor classification, the patient was staged as IE; the disease being confined to the right breast. After surgery a course of local radiotherapy was administered, which was postponed after a dose of 10 Gy, because the patient suffered from an upper gastrointestinal bleeding. An active bleeding site could not be found at endoscopy, but several small and larger ulcers were seen at the small curvature. Microscopy showed a predominantly diffuse large B-cell lymphoma with immunohistochemically lambda light chain restriction and with scattered small B-lymphocytes infiltrating the gastric epithelium. Helicobacter pylori was found in the gastric mucosal biopsies. This histology showed similarity with the lymphoma in the breast and was considered compatible with a high grade MALT-lymphoma. The lymphoma was now staged as IVE, and the patient received CHOP chemotherapy (cyclophosphamide (750 mg / m 2 ), adriamycin (50 mg / m 2 ), oncovin (2 mg) and prednisone (100 mg)). After three courses, a restaging procedure was done, including chest X-ray, computed tomography of the thorax, mammography, gastric endoscopy and bone marrow aspiration and
biopsy. Residual tumor activity could not be found. However the patient suffered from a severe neuropathy and mucositis and impaired left ventricular ejection fraction (EF 40%). Chemotherapy was then stopped and irradiation of the stomach (40 Gy, fractionated 20 times 2 Gy) was carried out. Six months later the patient had severe back pain, caused by osteoporotic vertebral collapse. Mammography showed calcification in the lateral quadrant of the left breast, but no palpable tumor mass. Four months later the patient was admitted to hospital because of general malaise and physical examination showed a left supraclavicular lymphoma 2 cm in diameter. Before a biopsy could be performed the patient died suddenly of respiratory failure due to acute congestive heart failure. Autopsy was refused.
Discussion Between 0.12% and 0.53% of all mammary malignancies are PBL [4–7]. In a retrospective analysis of data from a population-based registry in the south of the Netherlands, covering a region of 2.03 million inhabitants, the incidence was 0.13% [8]. PBL occurs primarily in middle-aged women, with a peak incidence between the fifth and sixth decade. Unilateral breast involvement is most common, with the upper outer quadrant of the right breast being most frequently involved. Most lymphomas are diffuse B-cell lymphomas (REAL-classification) [4,6,7,9]. Part of the breast lymphomas have a MALT-origin [3–5,10]. This means that they share the same endodermal origin with the gastrointestinal and respiratory tract, Waldeyer’s ring and thyroid. MALT-lymphomas usually arise as a consequence of a pre-existing, antigen-driven disorder in mucosal sites like the stomach, salivary glands, thyroid or breast, where lymphoid tissue is not originally present [11,12]. The associated pre-existing disorder is a Helicobacter pylori infection in case of MALTlymphoma of the stomach, myo-epithelial sialadenitis (MESA) in MALT-lymphoma of the salivary glands, Hashimoto’s thyreoiditis in MALTlymphoma of the thyroid and a lymphocytic lobulitis in MALT-lymphoma of the breast [11–13].
M. J. J. Kuper-Hommel et al. / The Netherlands Journal of Medicine 54 (1999) 235 – 238
In MALT-tissues mucosal nodules of lymphoid tissue are situated beneath specialized epithelium, which itself is infiltrated by lymphocytes. After antigen stimulation, lymphocytes from the mucosal nodules leave the nodules and migrate through regional lymph nodes and into the circulation through the thoracic duct. They then home back to the mucosa, adjacent to their site of origin. These migrating lymphocytes, arising in MALT-tissues, are frequently of follicle center origin. They tend to localize around and invade epithelial structures. This clinicopathological pattern explains the characteristic features of low grade MALT-lymphomas, that were first described by Isaacson [14]. These features are infiltration of mucosal epithelium by small nonblastoid B-cells, hence the so-called lymphoepithelial lesion. Sometimes there is plasma cell differentiation, often with immunologic monoclonality. MALTlymphomas tend to remain at the original site for long periods of time and to metastasize to other MALT-areas prior to or without nodal dissemination. The presence of a small B-cell component of low grade MALT-lymphoma in a predominantly high grade NHL, is considered the most reliable criterium to classify a lymphoma as a high grade MALTlymphoma [11,13]. Incidence data of MALT-lymphomas as a subgroup of breast lymphomas are unknown, because epithelial infiltration by malignant lymphoma cells was generally disregarded. Lamovec [4] was the first one who recognized the existence of breast lymphomas with the characteristics of MALT-lymphomas. He found lymphoepithelial lesions in 75% (6 / 8) of the PBL, with 50% of the relapses in MALT-sites. The breast lymphoma of our patient fulfilled the criteria for a high grade MALT-lymphoma. The lymphoma in the breast consisted predominantly of diffuse large B-cell lymphoblasts with a lambda light chain restriction, alternated with scattered small Blymphocytes, some of which were infiltrating and destroying the glandular duct epithelium. Because the lymphoma in the stomach had a similar histologic pattern with the same lambda light chain restriction, sparse infiltration with small B-lymphocytes causing lymphoepithelial lesions and the presence of the Helicobacter pylori micro-organism in the gastric mucosa, we concluded that this patient
237
had two localizations of high grade MALT-lymphoma. Traditionally, the cornerstone in the management of a localized PBL was surgery with or without local radiotherapy, in a dose of at least 40 Gy [6,7]. However the high rate of distant failures in predominantly diffuse large B-cell lymphomas [10], has changed the treatment into anthracyclin-based chemotherapy with or without local radiotherapy [9]. In conclusion, if a patient presents with a rapidly growing breast tumor, a primary lymphoma should be considered before any surgical intervention is performed. A PBL can be of MALT origin with this subgroup having preference for dissemination to extranodal MALT-areas above nodal sites. A careful history and physical examination with respect to symptoms and signs related to other potential localizations of MALT-lymphoma, should be done, in order to establish the right clinical stage. The benefit of routine upper endoscopy in all patients with MALT-lymphoma is uncertain.
References [1] Otter R, Gerrits WBJ, vd Sandt MM, Hermans J, Willemze R. Primary extranodal and nodal non-Hodgkin’s lymphoma; a survey of a population-based registry. Eur J Cancer Clin Oncol 1989;25:1203–10. [2] Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252–60. [3] Economopoulos Th, Asprou N, Stathakis N et al. Primary extranodal non-Hodgkin’s lymphoma in adults: Clinicopathological and survival characteristics. Leukemia Lymphoma 1996;21:131–6. [4] Lamovec J, Jancar J. Primary malignant lymphoma of the breast: Lymphoma of mucosa-associated lymphoid tissue. Cancer 1987;60:3033–41. [5] Hugh JC, Jackson FI, Hanson J, Poppema S. Primary breast lymphoma: An immunohistologic study of 20 new cases. Cancer 1990;66:2602–11. [6] de Souza LJ, Tavalkar GV, Morjaria JH. Primary malignant lymphoma of the breast. Ind J Cancer 1978;15:30–5. [7] Giardini R, Piccolo C, Rilke F. Primary non-Hodgkin’s lymphomas of the female breast. Cancer 1992;69:725–35. [8] Kuper-Hommel MJJ, Vrints LW, Coebergh JWW et al. Primary breast lymphoma; a retrospective analysis of 18 unselected patients. Blood 1997;90(10 Suppl. 1):261B. [9] Ha CS, Dubey P, Goyal LK, Hess M, Cabanillas F, Cox JD. Localized primary non-Hodgkin lymphoma of the breast. Am J Clin Oncol 1998;21(4):376–80. [10] Cohen PL, Brooks JJ. Lymphomas of the breast. A
238
M. J. J. Kuper-Hommel et al. / The Netherlands Journal of Medicine 54 (1999) 235 – 238
clinicopathologic and immunohistochemical study of primary and secondary cases. Cancer 1991;67:1359–69. [11] Zucca E, editor, How to manage MALT-lymphomas, ESMO Educational Book, 1998, pp. 175–8. [12] Elston CW, Ellis IO, editors, Systemic pathology: The Breast, 3rd ed, Churchill Livingstone, 1998, pp. 453–7.
[13] Isaacson PG, Norton AJ. Extranodal lymphomas. Churchill Livingstone. 1994:5-32, 67-81, 103-15 and 291-4. [14] Isaacson P, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 1984;53:2515–24.
Brief report
High grade MALT-lymphoma of the breast M.J.J. Kuper-Hommel a , L.W. Vrints b , J.W.W. Coebergh c , G. Vreugdenhil a , * a
Department of Internal Medicine, St. Joseph Hospital, Veldhoven, The Netherlands b Department of Pathology, Catharina Hospital, Eindhoven, The Netherlands c Comprehensive Cancer Center South ( IKZ), Eindhoven, The Netherlands Received 2 September 1998; received in revised form 10 December 1998; accepted 19 January 1999
Abstract A 65-year-old woman presented with a rapidly growing breast tumor, initially diagnosed as a carcinoma. Histology showed a breast lymphoma of high grade MALT-type. A lymphoma should always be considered in the differential diagnosis of a breast tumor, because it needs a different work-up and treatment. The subgroup of NHL of MucosaAssociated-Lymphoid-Tissue origin has different clinical behaviour, as illustrated in this report. 1999 Elsevier Science B.V. All rights reserved. Keywords: Breast lymphoma; High grade MALT-type; Gastric dissemination
Introduction About 50% of all lymphomas are primary extranodal non-Hodgkin’s lymphoma (NHL), and only about 2% of these are situated in the breast [1,2]. Primary breast lymphomas (PBL) sometimes have a mucosa-associated lymphoid tissue (MALT) origin [3–5], and then tend to metastasize to other MALTareas, such as the gastrointestinal tract or lungs, before or without nodal dissemination. In patients with MALT-lymphomas, screening of other MALTareas is generally not included in the staging procedure. Endoscopic evaluation of the gastrointestinal and upper respiratory tract, may detect early dissemination of MALT-lymphoma. We present a patient *Corresponding author. Tel.: 1 31-40-2588220; fax: 1 31-402588246.
with a MALT-lymphoma of the breast, which in a later stage appeared to be disseminated to the stomach, another MALT-site.
Case report In December 1995, a 65-year-old woman presented with a large (5 cm), palpable, rapidly growing painless tumor in the lateral upper quadrant of the right breast. She had a medical history of a left pneumonectomy for tuberculosis in 1953, a myocardial infarction in 1987 and acute congestive heart failure in 1989. Mammography showed a malignant imposing, irregular shaped nodule (4.5 cm), without microcalcifications. Nuclear lymphoscintigraphy, performed as part of a sentinel node procedure, showed two
0300-2977 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 99 )00010-8
236
M. J. J. Kuper-Hommel et al. / The Netherlands Journal of Medicine 54 (1999) 235 – 238
positive ipsilateral axillary lymph nodes. True cut biopsy and fine needle aspiration cytology both showed breast carcinoma. Because a T2 breast carcinoma was suspected, radical mastectomy was performed. Microscopy of the breast showed a large (3.9 cm) non-Hodgkin’s lymphoma of B-cell type. Subtyping according to the Revised European American Lymphoma (REAL) classification showed a diffuse large B-cell lymphoma, positive for leukocyte common antigen and B-cell marker L26 (CD 20), with a minor component of small cells and with mainly small B-lymphocytes infiltrating the ductal epithelium (so-called ‘‘lymphoepithelial lesion’’). Immunohistochemically on paraffin sections there was lambda light chain restriction in part of the lymphoid population, mainly in the cells with plasmacytoid differentiation. Although the sentinel node procedure showed two positive lymph nodes, none of the 14 resected axillary lymph nodes had malignant infiltration. Complete staging, including computed tomography of the thorax and abdomen, bone marrow aspiration and biopsy, and screening of the ear, nose and throat area (endoscopy included), showed no evidence of systemic involvement. According to the Ann Arbor classification, the patient was staged as IE; the disease being confined to the right breast. After surgery a course of local radiotherapy was administered, which was postponed after a dose of 10 Gy, because the patient suffered from an upper gastrointestinal bleeding. An active bleeding site could not be found at endoscopy, but several small and larger ulcers were seen at the small curvature. Microscopy showed a predominantly diffuse large B-cell lymphoma with immunohistochemically lambda light chain restriction and with scattered small B-lymphocytes infiltrating the gastric epithelium. Helicobacter pylori was found in the gastric mucosal biopsies. This histology showed similarity with the lymphoma in the breast and was considered compatible with a high grade MALT-lymphoma. The lymphoma was now staged as IVE, and the patient received CHOP chemotherapy (cyclophosphamide (750 mg / m 2 ), adriamycin (50 mg / m 2 ), oncovin (2 mg) and prednisone (100 mg)). After three courses, a restaging procedure was done, including chest X-ray, computed tomography of the thorax, mammography, gastric endoscopy and bone marrow aspiration and
biopsy. Residual tumor activity could not be found. However the patient suffered from a severe neuropathy and mucositis and impaired left ventricular ejection fraction (EF 40%). Chemotherapy was then stopped and irradiation of the stomach (40 Gy, fractionated 20 times 2 Gy) was carried out. Six months later the patient had severe back pain, caused by osteoporotic vertebral collapse. Mammography showed calcification in the lateral quadrant of the left breast, but no palpable tumor mass. Four months later the patient was admitted to hospital because of general malaise and physical examination showed a left supraclavicular lymphoma 2 cm in diameter. Before a biopsy could be performed the patient died suddenly of respiratory failure due to acute congestive heart failure. Autopsy was refused.
Discussion Between 0.12% and 0.53% of all mammary malignancies are PBL [4–7]. In a retrospective analysis of data from a population-based registry in the south of the Netherlands, covering a region of 2.03 million inhabitants, the incidence was 0.13% [8]. PBL occurs primarily in middle-aged women, with a peak incidence between the fifth and sixth decade. Unilateral breast involvement is most common, with the upper outer quadrant of the right breast being most frequently involved. Most lymphomas are diffuse B-cell lymphomas (REAL-classification) [4,6,7,9]. Part of the breast lymphomas have a MALT-origin [3–5,10]. This means that they share the same endodermal origin with the gastrointestinal and respiratory tract, Waldeyer’s ring and thyroid. MALT-lymphomas usually arise as a consequence of a pre-existing, antigen-driven disorder in mucosal sites like the stomach, salivary glands, thyroid or breast, where lymphoid tissue is not originally present [11,12]. The associated pre-existing disorder is a Helicobacter pylori infection in case of MALTlymphoma of the stomach, myo-epithelial sialadenitis (MESA) in MALT-lymphoma of the salivary glands, Hashimoto’s thyreoiditis in MALTlymphoma of the thyroid and a lymphocytic lobulitis in MALT-lymphoma of the breast [11–13].
M. J. J. Kuper-Hommel et al. / The Netherlands Journal of Medicine 54 (1999) 235 – 238
In MALT-tissues mucosal nodules of lymphoid tissue are situated beneath specialized epithelium, which itself is infiltrated by lymphocytes. After antigen stimulation, lymphocytes from the mucosal nodules leave the nodules and migrate through regional lymph nodes and into the circulation through the thoracic duct. They then home back to the mucosa, adjacent to their site of origin. These migrating lymphocytes, arising in MALT-tissues, are frequently of follicle center origin. They tend to localize around and invade epithelial structures. This clinicopathological pattern explains the characteristic features of low grade MALT-lymphomas, that were first described by Isaacson [14]. These features are infiltration of mucosal epithelium by small nonblastoid B-cells, hence the so-called lymphoepithelial lesion. Sometimes there is plasma cell differentiation, often with immunologic monoclonality. MALTlymphomas tend to remain at the original site for long periods of time and to metastasize to other MALT-areas prior to or without nodal dissemination. The presence of a small B-cell component of low grade MALT-lymphoma in a predominantly high grade NHL, is considered the most reliable criterium to classify a lymphoma as a high grade MALTlymphoma [11,13]. Incidence data of MALT-lymphomas as a subgroup of breast lymphomas are unknown, because epithelial infiltration by malignant lymphoma cells was generally disregarded. Lamovec [4] was the first one who recognized the existence of breast lymphomas with the characteristics of MALT-lymphomas. He found lymphoepithelial lesions in 75% (6 / 8) of the PBL, with 50% of the relapses in MALT-sites. The breast lymphoma of our patient fulfilled the criteria for a high grade MALT-lymphoma. The lymphoma in the breast consisted predominantly of diffuse large B-cell lymphoblasts with a lambda light chain restriction, alternated with scattered small Blymphocytes, some of which were infiltrating and destroying the glandular duct epithelium. Because the lymphoma in the stomach had a similar histologic pattern with the same lambda light chain restriction, sparse infiltration with small B-lymphocytes causing lymphoepithelial lesions and the presence of the Helicobacter pylori micro-organism in the gastric mucosa, we concluded that this patient
237
had two localizations of high grade MALT-lymphoma. Traditionally, the cornerstone in the management of a localized PBL was surgery with or without local radiotherapy, in a dose of at least 40 Gy [6,7]. However the high rate of distant failures in predominantly diffuse large B-cell lymphomas [10], has changed the treatment into anthracyclin-based chemotherapy with or without local radiotherapy [9]. In conclusion, if a patient presents with a rapidly growing breast tumor, a primary lymphoma should be considered before any surgical intervention is performed. A PBL can be of MALT origin with this subgroup having preference for dissemination to extranodal MALT-areas above nodal sites. A careful history and physical examination with respect to symptoms and signs related to other potential localizations of MALT-lymphoma, should be done, in order to establish the right clinical stage. The benefit of routine upper endoscopy in all patients with MALT-lymphoma is uncertain.
References [1] Otter R, Gerrits WBJ, vd Sandt MM, Hermans J, Willemze R. Primary extranodal and nodal non-Hodgkin’s lymphoma; a survey of a population-based registry. Eur J Cancer Clin Oncol 1989;25:1203–10. [2] Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252–60. [3] Economopoulos Th, Asprou N, Stathakis N et al. Primary extranodal non-Hodgkin’s lymphoma in adults: Clinicopathological and survival characteristics. Leukemia Lymphoma 1996;21:131–6. [4] Lamovec J, Jancar J. Primary malignant lymphoma of the breast: Lymphoma of mucosa-associated lymphoid tissue. Cancer 1987;60:3033–41. [5] Hugh JC, Jackson FI, Hanson J, Poppema S. Primary breast lymphoma: An immunohistologic study of 20 new cases. Cancer 1990;66:2602–11. [6] de Souza LJ, Tavalkar GV, Morjaria JH. Primary malignant lymphoma of the breast. Ind J Cancer 1978;15:30–5. [7] Giardini R, Piccolo C, Rilke F. Primary non-Hodgkin’s lymphomas of the female breast. Cancer 1992;69:725–35. [8] Kuper-Hommel MJJ, Vrints LW, Coebergh JWW et al. Primary breast lymphoma; a retrospective analysis of 18 unselected patients. Blood 1997;90(10 Suppl. 1):261B. [9] Ha CS, Dubey P, Goyal LK, Hess M, Cabanillas F, Cox JD. Localized primary non-Hodgkin lymphoma of the breast. Am J Clin Oncol 1998;21(4):376–80. [10] Cohen PL, Brooks JJ. Lymphomas of the breast. A
238
M. J. J. Kuper-Hommel et al. / The Netherlands Journal of Medicine 54 (1999) 235 – 238
clinicopathologic and immunohistochemical study of primary and secondary cases. Cancer 1991;67:1359–69. [11] Zucca E, editor, How to manage MALT-lymphomas, ESMO Educational Book, 1998, pp. 175–8. [12] Elston CW, Ellis IO, editors, Systemic pathology: The Breast, 3rd ed, Churchill Livingstone, 1998, pp. 453–7.
[13] Isaacson PG, Norton AJ. Extranodal lymphomas. Churchill Livingstone. 1994:5-32, 67-81, 103-15 and 291-4. [14] Isaacson P, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 1984;53:2515–24.