Multifocal primary breast lymphoma.

Abstract: Primary breast lymphoma (PBL) is a rare condition, accounting for only 0.04 to 0.5% of breast malignancies and less than 2% of extranodal lymphomas. Clinical presentation and imaging may suggest a benign condition. Reports of treatment vary widely. Surgical therapy has been reported to include only biopsy or extend to partial mastectomy, total mastectomy, or even radical mastectomy. Chemotherapy with various agents is often used. Radiotherapy has been used in the adjuvant setting or as primary local therapy. Immunotherapy and radioimmunotherapy have shown some promise in other lymphomas and may be useful here as well. There is no standard or consensus of treatment for PBL. This report describes a case of multifocal PBL in a 45-year-old female and discusses the physical findings, diagnosis, and treatment options for this condition.

Key Words: breast lymphoma, primary breast lymphoma, breast neoplasms, lymphoma, B-cell lymphoma

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Primary breast lymphoma (PBL) accounts for only 0.04 to 0.53% of breast malignancies and 0.22 to 2.2% of extranodal lymphomas. (1-3) Most physicians will, however, encounter this disease during their careers. Treatment varies widely and surgical therapy ranges from biopsy to modified radical mastectomy. (4) Chemotherapy has more recently become the mainstay of treatment, with the use of various agents. Radiotherapy may be used as adjuvant therapy or as primary local therapy. Treatment options may also include immunotherapy or radioimmunotherapy. There is no standard or consensus of treatment for this uncommon malignancy. Physical findings and imaging often suggest a benign condition.

Case Report

A 45-year-old female in good health noted a nodule in the upper portion of the left breast. She reported no other symptoms or family history of cancer. Examination revealed three smooth, rubbery nodules in the left breast, 1 to 2.5 cm in diameter. There was no lymphadenopathy or secondary signs of malignancy. A mammogram revealed five unilateral, benign-appearing nodules in the left breast. There were no microcalcifications and no areas of architectural distortion (Fig. 1). Ultrasound demonstrated each of these five lesions to be well-defined, hypoechoic nodules with low-level internal echoes and enhanced through transmission, consistent with fibroadenomas (Fig. 2). Fine-needle aspiration cytology found large malignant cells with irregular nuclei and numerous mitotic figures. Subsequent excision of a lesion confirmed the diagnosis of malignant lymphoma, B-cell phenotype (Fig. 3). Diagnosis was supported by immunohistochemical stains that were negative for S100, EMA, CK20, CK7, and pan keratin and positive staining for CD20 and leukocyte common antigen. The patient underwent an extensive staging evaluation, including complete CT scanning and bone marrow biopsy, confirming this as a primary breast lymphoma, stage 1E. The patient was treated with six cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), resulting in complete clinical resolution. Adjuvant radiotherapy was administered to the entire breast in 25 fractions, using 4,500 cGy with 180 cGy per fraction. She was clinically disease free, with normal follow-up mammograms at 1 year. Eighteen months after therapy, the patient had development of bilateral pulmonary and mediastinal recurrences. Combination immunotherapy and chemotherapy with rituximab, cyclophosphamide, prednisone, and vincristine (R-EPOCH) was used without response, ultimately ending in her death.

Discussion

Most PBLs are B-cell, diffuse, large-cell type. (3,5,6) To be considered as PBL, most reports use criteria described by Wiseman and Liao: (1) There is an adequate pathologic specimen demonstrating close association of the lymphomatous infiltrate and breast tissue; (2) there is no evidence of concurrent widespread disease or preceding extramammary lymphoma; (3) the breast is the clinical site of presentation, but ipsilateral lymph node involvement is considered acceptable if both lesions develop simultaneously. (7)

PBLs most commonly present as a solitary palpable mass in a middle-aged female. Men are rarely affected. Less common presentations include bilateral palpable masses, unilateral or bilateral diffuse breast enlargement, or multiple unilateral nodules. Rarely, the lesions are accompanied by pain or systemic "B" symptoms. (8-11) Many studies report that PBL is more common in the right breast and upper outer quadrant. (8,11-13) Others have not found these predominate locations. (1,14,15)

The physical findings of PBL may vary. Typically, however, a solitary palpable mass is noted. It is usually nontender, mobile, and nonadherent to the overlying skin. Secondary signs of malignancy such as skin thickening, erythema, edema, and nipple retraction are rarely seen. Pain and tenderness are infrequent. (8-12) Many patients will have ipsilateral axillary lymphadenopathy (31 to 75%). Less commonly, there will be diffuse enlargement of one or both breasts, or multiple nodules. (3,10,11,13,16)

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PBLs are not usually discovered by screening mammography. Domchek et al (17) demonstrated no increased detection of breast lymphomas by screening mammogram. However, mammograms obtained after the identification of a palpable mass demonstrate a parenchymal abnormality in most cases. There is no specific mammographic characteristic to suggest a diagnosis of lymphoma. The most common mammographic finding is a solitary well-defined mass that may have an irregular border. Diffuse parenchymal densities or multiple lesions, as in this case, have been rarely reported. Skin thickening has been noted uncommonly in mammographic studies. PBLs rarely demonstrate calcifications or a spiculated appearance on mammography. Mammography is often used in assessing tumor response to therapy. (8,16,17)

Ultrasound evaluation of PBL usually demonstrates a hypoechoic lesion and well-defined borders without significant posterior enhancement or acoustic shadowing. The lesion may be markedly hypoechoic and may, in fact, be mistaken for a benign cyst. (10,12,16) However, other ultrasound findings in PBL have been reported, including variations in contour, diffuse borders, and echogenicity. (3,18) Given that PBL most often presents with benign characteristics on physical examination and by imaging studies, pursuing a tissue diagnosis of discrete breast lesions should be strongly considered.

Historically, treatment for PBL has varied dramatically. Surgery, radiation, and chemotherapy have been used alone or in combination. Treatment with chemotherapy, (such as CHOP [cyclophosphamide, hydroxydaunomycin, Oncovin [vincristine], and prednisone), with or without adjuvant radiotherapy, is the most common approach. (19,20) There are no data to suggest that PBL should be treated differently or has a different prognosis than lymphomas elsewhere in the body, taking into account histologic type and stage. For diffuse large B-cell lymphomas in general, improved outcomes have been reported by using chemotherapy in combination with immunotherapy or radioimmunotherapy. (21) Monoclonal antibodies such as rituximab have been combined with CHOP regimens, resulting in increased event-free and overall survival--and without added toxicity--in certain patients with lymphoma. Pilot studies have shown that combining radiolabeled antibodies with chemotherapy may be effective as well. (21) Although this combination therapy has not been specifically described in the treatment of PBL, it does show promise in the treatment of other B-cell lymphomas and thus may be of use in PBL.

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Recent literature suggests that the role of surgery in PBL is limited to obtaining adequate tissue for accurate diagnosis and classification of the lymphoma, with treatment similar to therapy for lymphomas at other sites. (13,17,22,23) However, other investigators have recommended modified radical mastectomy, simple mastectomy, or lumpectomy with axillary dissection. (1,2,4,8,13-17,24) It is thought that the efficacy of immunotherapy with rituximab is greatest when the tumor mass is smaller. (21) Thus, if rituximab therapy is chosen, surgery may play a more significant role than simply obtaining a biopsy specimen.

Survival rates for PBL are compatible to lymphoma in general and are favorable when compared with breast carcinoma. (1,14) Prognosis for individual patients is particularly dependent on histologic tumor grade. The impact of tumor size and stage has varied with different reports. (1,8,14) The International Prognostic Index may also be useful for prognostic purposes. The International Prognostic Index takes into account age, LDH levels, performance status, Ann Arbor staging, and the presence of extranodal tumor in predicting 5-year survival. (25)

Conclusion

This patient had an unusual presentation of PBL with multiple benign-appearing unilateral lesions. Varied clinical presentations and radiographic features often suggest a benign process. This makes clinical diagnosis of PBL difficult and reinforces the need for a tissue diagnosis. There is no consensus for therapy of PBL, making prognosis and effectiveness of individual treatments difficult to predict. Chemotherapy with or without the addition of radiotherapy to the breast seems to be the most commonly used treatment. Immunotherapy or radioimmunotherapy may also have a role. Surgical therapy may include only biopsy or may extend to partial mastectomy, total mastectomy, or modified radical mastectomy, although mastectomy is less often used.

References

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Randal Baker, MD, Geoffrey Slayden, MD, and William Jennings, MD

From the Department of Surgery, University of Oklahoma College of Medicine, Tulsa, OK.

Reprint requests to William Jennings, MD, 4502 East 41st Street, 2E28 Tulsa, OK 74135-2512. E-mail: [e-mail]

Accepted June 8, 2005.

The authors report no commercial, financial, or proprietary interest in any drug, device, or equipment mentioned in the article.

RELATED ARTICLE: Key Points

* An adequate pathologic specimen is needed that demonstrates close association of the lymphomatous infiltrate and breast tissue.

* There should be no evidence of concurrent widespread disease or preceding extramammary lymphoma.

* The breast must be the clinical site of presentation, but ipsilateral lymph node involvement is considered acceptable if both lesions develop simultaneously.