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Non-Hodgkin's lymphoma of the breast: a review of 18 primary and secondary cases
Annals of Diagnostic Pathology 10 (2006) 144 – 148
Non-Hodgkin’s lymphoma of the breast: a review of 18 primary and secondary cases Virginia E. Duncan, MD, Vishnu V.B. Reddy, MD, Nirag C. Jhala, MD, David C. Chhieng, MD, Darshana N. Jhala, MD, B MUS (Assistant Professor)4 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL-35249-7331, USA
Abstract
We evaluated the clinical features, morphology, and incidence of 18 cases of breast lymphoma over 10 years at the University of Alabama at Birmingham. Fine needle aspiration was performed in 7 of 18 patients, and tissue biopsy/resection was available for all 18 cases. Patients were 33 to 91 years old (median, 61); 17 were women and 1 was a man. Fine needle aspiration was consistent with the tissue diagnosis in 6 of the 7 cases (86%). One case was diagnosed by fine needle aspiration as atypical cells, favor benign; the biopsy revealed diffuse large B-cell lymphoma. Tissue diagnoses revealed that 11 cases (61%) represented diffuse large B-cell lymphoma and 3 (17%) were follicular lymphomas. The remaining 4 cases (22%) were plasma cell neoplasm, T- cell neoplasm, Burkitt’s lymphoma, and precursor B-cell lymphoblastic lymphoma. Flow cytometry and/or gene rearrangement supported the diagnosis of lymphoma in 8 cases. Although rare, lymphoma should be considered in the differential diagnosis of a breast mass. Fine needle aspiration can facilitate appropriate triage of patients for further management. D 2006 Elsevier Inc. All rights reserved.
Keywords:
Breast; Breast lymphoma; Non-Hodgkin’s lymphoma; Fine needle aspirations; Cytology
1. Introduction Breast lymphoma, either a manifestation of primary extranodal disease or secondary involvement by systemic disease, is a rare malignancy, and the literature addressing this subject is sparse. Primary breast lymphoma (PBL) has a reported incidence ranging from 0.04% to 0.5% of all breast malignancies. It comprises less than 1% of all patients with non-Hodgkin’s lymphoma and approximately 1.7% of all extranodal non-Hodgkin’s lymphoma [1-9]. Secondary breast lymphoma is less well-studied than primary in the literature and is also rare, with a reported incidence of 0.07% [1,5,6,10-13]. It comprises 17% of all malignancies metastatic to the breast, making it the most common metastatic disease involving the breast [14]. The clinical presentation and radiological features of breast lymphoma and carcinoma are similar. The most
4 Corresponding author. Division of Anatomic Pathology, Department of Pathology, South, Birmingham, AL-35249-7331, USA. Tel.: +1 205 975 8890; fax: +1 205 975 7284. E-mail address: [email protected] (D.N. Jhala). 1092-9134/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.09.018
common presentation for either malignancy is a painless enlarging breast mass, although some reports suggest that lymphomatous masses tend to be larger [13]. Patients with secondary lymphomas may or may not exhibit B symptoms. On mammogram, lymphomas may lack the irregular borders of infiltrating carcinoma and more than half exhibit no calcification. However, there is considerable overlap in these features, and pathology remains the only way to differentiate the 2 malignancies [13,15-17]. Despite the clinical and radiographic similarities, the treatment differs radically. For this reason, it is important to correctly differentiate lymphoma from other breast malignancies to appropriately triage patients for treatment. Fine needle aspiration (FNA) cytology is a commonly used procedure in the evaluation of lesions in many organs [18], and recent studies have begun to focus on its diagnostic utility in breast lymphoproliferative lesions [19-21]. Although diagnostic pitfalls exist in the use of FNA to diagnose lymphoproliferative disorders, its overall sensitivity approaches 90% [18,21-23]. Confirmatory core needle biopsy is recommended by most authors for suspected primary lesions. However, cytology may be useful in
V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
145
this scenario to facilitate gathering of appropriate material for ancillary studies. Under certain clinical scenarios, particularly in suspected secondary breast lymphoma, cytology may help prevent unnecessary biopsy and surgery. This study retrospectively evaluates the clinical features, morphology, and incidence of breast lymphoma and examines the diagnostic utility of FNA for lymphoproliferative breast disease. 2. Materials and methods We retrospectively reviewed the pathology records of 18 patients with breast lymphoma at the University of Alabama at Birmingham between 1989 and 1999. For all patients, a tissue biopsy and/or resection were performed. Seven patients also had FNA. All available hematoxylin and eosin–stained slides from histologic sections and cytology slides were reviewed in conjunction with the original surgical pathology and/or cytopathology reports. For 7 patients, slides from histologic sections were not available for review, and the diagnosis was retrieved from the original pathology reports. All cases were reclassified according to the World Health Organization 2001 classification scheme for tumors of lymphoid tissues [24]. For the categorization of breast lymphoma into primary and secondary forms, we used the criteria originally developed by Wiseman and Liao [25] for PBL: (1) adequate pathological material, (2) close association of mammary tissue and malignant lymphomatous infiltrate, and (3) concurrent widespread disease or preceding extramammary lymphoma excluding ipsilateral axillary node involvement. Cases not fulfilling the latter criterion were designated as secondary. Table 1 Clinical characteristics for breast lymphomas Diagnosis
Age (y)
Sex
Clinical
Site
Ancillary studies
TCRBCL TCRBCL DLBCL Burkitt DLBCL DLBCL T cell DLBCL DLBCL DLBCL DLBCL FL LB
37 60 71 81 59 72 35 73 91 54 65 72 44
F F F F F F F F F F F F F
Primary Primary Primary Primary Primary Secondary Secondary Secondary Secondary Secondary Secondary Secondary Secondary
R R L L B L L R L R L R B
DLBCL FL FL TCRBCL PCN
85 62 51 33 49
F F F M F
Unknown Unknown Secondary Secondary Unknown
Unknown L R L L
Flow IHC Flow, IHC IHC IHC Flow CG, IHC IHC IHC Flow None None CG, flow, EM IHC IHC Flow CG, flow IHC
TCRBCL indicates T-cell–rich B-cell lymphoma; LB, precursor B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia; EM, electron microscopy; R, right; L, left; B, bilateral; Flow, flow cytometry; CG, cytogenetics.
Fig. 1. Diffuse large B-cell lymphoma. High-power photomicrograph showing a population of atypical large lymphoid cells with numerous mitotic figures.
Immunophenotyping was performed on paraffin embedded tissue for most specimens at the time of the original diagnosis. For several consult cases, the referring institution performed and reported the results of immunophenotyping. Flow cytometric analysis in 7 patients, cytogenetic analysis in 3 patients, and electron microscopy in 1 patient were performed. 3. Results Eighteen cases of hematologic malignancy involving the breast were identified in the University of Alabama at Birmingham database between 1989 and 1999; 17 (94%)
Fig. 2. Diffuse large B-Cell lymphoma. High-power photomicrograph of a Diff-Quik–stained touch imprint of the same surgical specimen as in Fig. 1, showing single atypical appearing large cells with numerous lymphoglandular bodies.
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V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
Fig. 3. Follicular lymphoma. Scanning photomicrograph showing a nodular lymphoid infiltrate invading breast stroma.
were women and 1 (6%) was a man. Table 1 summarizes the clinical information and findings for all cases. Nine cases (50%) involved the left breast, 6 (33%) the right breast, and 2 (12%) bilateral breasts. In one case, the laterality was not reported. In both cases where bilaterality was seen, it was asynchronous, with the contralateral breast involvement observed 2 to 3 years after the initial breast involvement. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype and was diagnosed in 11 cases (61%; Figs. 1 and 2). Follicular lymphoma (FL) was the second most common subtype, diagnosed in 3 cases (17%; Figs. 3 and 4). One case (6%) of each of the following was diagnosed: precursor B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia, T- cell neoplasm, plasma cell neoplasm (PCN), and Burkitt’s lymphoma (BL).
Median age at diagnosis for all cases was 61 years with a range of 33 to 91 years. The median age for PBL was 60 years (range, 37-81 years) and for secondary breast lymphoma, 68.5 years (range, 35-91 years). When the 2 most common diagnoses are examined, median age for DLBCL was 65 years (range, 33-91 years) and for FL, 62 years (range, 51-72). Immunohistochemistry (IHC) data were available for 10 cases, flow cytometric data for 7 cases, and cytogenetic analysis for 3 cases (Table 1). These ancillary studies supported the tissue diagnosis in all cases. Fine needle aspiration data are available for 7 cases. Overall, FNA at least raised the suspicion of breast lymphoproliferative disease in 6 (86%) cases. Table 2 summarizes the FNA data for all cases in which FNA was performed. Five cases (28%) were classified as primary, 10 cases (56%) were classified as secondary, and in 3 cases (17%), insufficient information was available for classification. Of the secondary cases, 4 presented with breast masses and were found on subsequent clinical workup to have disseminated disease. Fine needle aspiration was performed in 2 of these cases for which a correct diagnosis of lymphoma was rendered, followed by a needle and /or excisional biopsy for confirmation. The remaining 6 patients with secondary disease carried a previous diagnosis of hematologic malignancy and later presented with a breast mass representing metastatic or recurrent disease. The initial sites of lymphoma were parotid (2 cases), spleen (1), and small bowel mesentery (1); 1 patient had acute lymphoblastic leukemia with a recurrence in the breast, and another had been previously diagnosed with Langerhans cell granulomatosis, which was revised to a diagnosis of cutaneous T-cell lymphoma with subsequent breast involvement. One of these 6 patients underwent FNA which raised the suspicion for lymphoma and all patients had needle and/or excisional biopsies. Table 2 Cases with FNA diagnoses rendered
Fig. 4. Follicular lymphoma. High-power photomicrograph showing a monotonous population of small lymphoid cells with irregular angulated nuclei, scant cytoplasm, and inconspicuous nucleoli.
Final diagnosis
Primary/ secondary
FNA diagnosis
DLBCL
Secondary
TCRBCL
Primary
TCRBCL
Primary
Follicular lymphoma
Secondary
Lymphoblastic lymphoma Plasma cell neoplasm BL
Secondary
Positive for malignancy, favor lymphoma Atypical cells, differential diagnosis includes infection and lymphoma (Mass) Atypical cells, favor benign (LN) negative for malignancy (LN) Atypical lymphocyte population highly suspicious for lymphoma (Mass) Negative with acute and chronic inflammation Positive for malignancy, suspicious for lymphoma Atypical plasmacytoid population, suspicious for multiple myeloma Single undifferentiated cells suggestive of lymphoma
Unknown Primary
LN, lymph node; TCRBCL, T-cell–rich B-cell lymphoma.
V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
Patients with PBL presented with palpable breast masses and had no evidence of disseminated disease on further workup. Three of these patients underwent FNA and the interpretation of a lymphoproliferative disorder was made in 2 cases. In the remaining case, the FNA was interpreted as benign and was subsequently shown to be the T-cell–rich variant of DLBCL. All patients had needle and/or excisional biopsies, and 1 patient underwent mastectomy. Of the cases with insufficient clinical information to classify as primary or secondary, 1 had FNA diagnosed as suspicious for PCN (which was confirmed on subsequent histologic examination), and all had needle or excisional biopsies. 4. Discussion Breast lymphomas are rare with a reported incidence of 0.04% to 0.5% of all breast malignancies [1-9,13,15]. Wiseman and Liao [25] are credited with first defining clinical criteria for the classification of PBL. Their categorization likely underrepresents the incidence of primary disease because primary lymphomas, which have become disseminated at the time of diagnosis will be classified as a secondary process. The incidence of secondary breast lymphoma is less well-represented in the literature, reported to be 0.07% [1,5,6,10-13]. The frequency of primary relative to secondary cases is quite variable; in our series, secondary outnumbered PBL cases. This study demonstrates a broad morphological and clinical spectrum of breast lymphomas seen at our institution. When primary and secondary cases are considered together, DLBCL is the most common type reported in the literature, representing 45 to 79% of all cases [1,4,6,8,11,15,26]. Overall, in our series, DLBCL was most common, followed by FL. Similarly, when only PBL is considered, most case series also show DLBCL as the most common type. Gholam et al [27] reviewed 13 case series of PBL, with publication dates from 1990 to 2003, and Brogi and Harris [17] reviewed 12 case series with publication dates ranging from 1972 to 1994. Of the series, 6 were reviewed in both papers. Most case series were relatively small (7- 41 patients), and most show a broad diversity of lymphoma types and clinical behaviors. However, in the Gholam et al review, all but one
147
case series (of the 12 where subclassification of lymphoma is reported) shows DLBCL as the most common subtype. Secondary breast lymphomas are less well represented in the literature and, when reported, are usually included in case series along with primary cases. Table 3 reviews the findings for secondary breast lymphoma cases in 7 of the most recent breast lymphoma case series [1,5,10,11,13,15,26]. Diffuse large B-cell lymphoma was the most common type in 5 of the 7 series, and FL was the most common type in 2 series. Other less common types varied widely in their frequencies. Our series of breast lymphomas, although small when subdivided into primary and secondary categories, shows a predominance of DLBCL for both primary and secondary cases. A broad review of the literature reveals no consensus on distinguishing features between the clinical characteristics of breast lymphoma and other breast malignancies, particularly carcinomas. Both lymphoma and carcinoma of the breast are diseases of the middle-aged and elderly, although a small subset of lymphomas (Burkitt’s or Burkitt-like lymphomas) presents at a young age, typically with bilateral involvement and rapid progression. The reported median age for breast lymphoma ranges from 51 to 60 years, typically with a wide range [4,6,8,11,27,28]. The median age at diagnosis of patients with breast lymphoma in our study (61 years) corresponded well with the literature. Studies to date have also found no consistent or diagnostic radiological differences between lymphoma and carcinoma of the breast, although there is a suggestion that lymphoma tends not to have the calcification or desmoplastic reaction that often characterizes the mammographic appearance of carcinoma [13,29,30]. Most studies have reported a preponderance of rightsided presentation in breast lymphoma [4,6,11,13,25,28,31], although some, as in our series, have reported the opposite [28,32]. Bilaterality has been reported to occur in 1% to 14% of breast lymphoma cases [4,6,11] and occurred in 11% of cases in our study. Although distinction between lymphoma and carcinoma is not possible on purely clinical or radiological grounds, accurate diagnosis of lymphoma is necessary because the treatment differs radically from that of carcinoma. The histologic differential diagnosis of lymphoma includes reactive lymphoid infiltrate, medullary
Table 3 Literature review of secondary breast lymphoma most common types and their frequencies Ref (no. of pts)
DLBCL (n [%])
FL
[11] (18) [10] (22) [5] (18) [26] (5) [1] (21) [13] (15) [15] (13)
14 4 9 5 6 6 4
3 10 3 0 7 2 1
(78) (18) (50) (100) (29) (40) (31)
(17) (46) (17) (33) (13) (8)
SLL/CLL
LB
MALT
MCL
BL
TCN
0 1 2 0 3 1 0
1 1 3 0 1 2 0
0 4 (18) 0 0 2 (10) 0 3 (23)
0 0 0 0 0 3 (20) 0
0 0 0 0 0 1 (7) 3 (23)
0 0 0 0 0 0 1 (8)
(5) (11) (14) (7)
(6) (5) (17) (5) (13)
Ref indicates reference; pts, patients; SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukemia; MALT, mucosa-associated lymphoid tissue type lymphoma; MCL, mantle cell lymphoma; TCN, T-cell neoplasm.
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carcinoma, amelanotic melanoma, lobular carcinoma, and poorly differentiated ductal carcinoma. Separating these entities is usually straightforward with the aid of IHC and/or flow cytometry performed on surgical specimens. However, when lymphoma is not suspected on presentation, material is often not obtained for flow cytometry, and lumpectomy or mastectomy (unnecessary treatments for lymphoma) may be performed. Fine needle aspiration can diagnose lymphoma overall with a reported sensitivity of more than 90% and is typically higher when combined with ancillary studies such as IHC or flow cytometry [18,23]. For breast lymphoma, the reported sensitivity approximates that for lymphoma overall, ranging from 83% to 100% [19-21]. In our series, the suspicion of lymphoma was raised in 86% of the cases subsequently diagnosed as a lymphoproliferative disorder by histology. Fine needle aspiration can be useful in the diagnosis of breast lymphoma by diagnosing lymphoma outright or by raising the suspicion of the presence of lymphoma, thus facilitating the collection of material for ancillary studies at the time of FNA or on subsequent surgical specimens. In cases of primary disease, most centers advocate obtaining a confirmatory histologic diagnosis [21,23]. In conclusion, breast lymphoma is a rare disease, and published case series are small. This series demonstrates the broad morphological and clinical spectrum of breast lymphomas seen at our institution and reported in the literature. Despite its rarity, breast lymphoma should be considered in the differential diagnosis of a breast mass because a high index of suspicion for lymphoma can facilitate the accurate triage of breast biopsy specimens for ancillary studies. Fine needle aspiration, along with ancillary studies, is useful for the initial diagnosis of breast lymphoma because it can facilitate appropriate triage of patients for further management. A heightened clinical suspicion for lymphoma exists in secondary breast lymphoma, and FNA can be useful to confirm the suspected diagnosis. References [1] Domchek SM, Hecht JL, Fleming MD, et al. Lymphomas of the breast. Cancer 2002;94:6 - 13. [2] Farinha P, Andre S, Cabecadas J, et al. High frequency of MALT lymphoma in a series of 14 cases of primary breast lymphoma. Appl Immunohistochem Mol Morphol 2002;10:115 - 20. [3] Wong WW, Schild SE, Halyard MY, et al. Primary non-Hodgkin lymphoma of the breast: the Mayo Clinic experience. J Surg Oncol 2002;80:19 - 25. [4] Jeon HJ, Akagi T, Hoshida Y, et al. Primary non-Hodgkin malignant lymphoma of the breast: an immunohistochemical study of seven patients and literature review of 152 patients with breast lymphoma in Japan. Cancer 1992;70:2451 - 9. [5] Arber DA, Simpson JF, Weiss LM, et al. Hon-Hodgkin’s lymphoma involving the breast. Am J Surg Pathol 1994;18:288 - 95. [6] Brustein S, Kimmel M, Lieberman PH, et al. Malignant lymphoma of the breast: a study of 53 patients. Ann Surg 1987;205:144 - 50. [7] Hugh JC, Jackson FI, Hanson J, et al. Primary breast lymphoma: an immunohistologic study of 20 cases. Cancer 1990;66:2602 - 11.
[8] Giardini R, Piccolo C, Rilke F. Primary non-Hodgkin’s lymphomas of the female breast. Cancer 1992;69:725 - 35. [9] Park YH, Kim SH, Choi S, et al. Primary malignant lymphoma of the breast: clinicopathological study of nine cases. Leuk Lymphoma 2004;45:327 - 30. [10] Mattia AR, Ferry JA, Harris NL. Breast lymphoma: a B-cell spectrum including the low grade B-cell lymphoma of mucosa associated lymphoid tissue. Am J Surg Pathol 1993;17:574 - 87. [11] Cohen PL, Brooks JJ. Lymphomas of the breast: a clinicopathologic and immunohistochemical study of primary and secondary cases. Cancer 1991;67:1359 - 69. [12] van Hoeven KH, Hibbard CA, Flax H, et al. Metastatic malignant neoplasms and secondary lymphomatous involvement of the breast: a study of 43 cases. Pathol Annu 1993;28:221 - 41. [13] Sabate JM, Gomez A, Torrubia S, et al. Lymphoma of the breast: clinical and radiologic features with pathologic correlation in 28 patients. Breast J 2002;8:294 - 304. [14] Vizcaino I, Torregrosa A, Higueras V, et al. Metastasis to the breast from extramammary malignancies: a report of four cases and a review of literature. Eur Radiol 2001;11:1659 - 65. [15] Kuper-Hommel MJJ, Snijder S, Janssen-Heijnen MLG, et al. Treatment and survival of 38 female breast lymphomas: a population-based study with clinical and pathological reviews. Ann Hematol 2003;82:397 - 404. [16] Bartella L, Kaye J, Perry NM, et al. Metastases to the breast revisited: radiological-histopathological correlation. Clin Radiol 2003;58: 524 - 31. [17] Brogi E, Harris NL. Lymphomas of the breast: pathology and clinical behavior. Semin Oncol 1999;26:357 - 64. [18] Stewart CJR, Jackson R, Farquharson M, et al. Fine-needle aspiration cytology of extranodal lymphoma. Diagn Cytopathol 1998;19:260 - 6. [19] Singh NG, Kapila K, Dawar R, et al. Fine needle aspiration cytology diagnosis of lymphoproliferative disease of the breast. Acta Cytol 2003;47:739 - 43. [20] Gupta RK, Naran S, Lallu S, et al. Diagnostic value of needle aspiration cytology in the assessment of palpable axillary lymph nodes: a study of 336 cases. Acta Cytol 2003;47:550 - 4. [21] Levine PH, Zamuco R, Yee HT. Role of fine-needle aspiration cytology in breast lymphoma. Diagn Cytopathol 2004;30:332 - 40. [22] Verma K, Kapila K. The role of fine needle aspiration cytology of breast lumps in the management of patients. Indian J Med Res 1989; 90:135 - 9. [23] Meda BA, Buss DH, Woodruff RD, et al. Diagnosis and subclassification of primary and recurrent lymphomas: the usefulness and limitations of combined fine-needle aspiration cytomorphology and flow cytometry. Am J Clin Pathol 2000;113:688 - 99. [24] Jaffi ES, Harris NL, Stein H, et al, editors. World Health Organization Classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon (France)7 IARC press; 2001. p. 351. [25] Wiseman C, Liao KT. Primary lymphoma of the breast. Cancer 1972;29:1705 - 12. [26] Au WY, Chan ACL, Chow LWC, et al. Lymphoma of the breast in Hong Kong Chinese. Hematol Oncol 1997;15:33 - 8. [27] Gholam D, Bibeau F, Weshi AE, et al. Primary breast lymphoma. Leuk Lymphoma 2003;44:1173 - 8. [28] Dao AH, Adkins RB, Glick AD. Malignant lymphoma of the breast: a review of 13 cases. Am Surg 1992;58:792 - 6. [29] Liberman L, Giess CS, Dershaw DD, et al. Non-Hodgkin lymphoma of the breast: imaging characteristics and correlation with histopathologic findings. Radiology 1994;192:157 - 60. [30] Meyer JE, Kopans DB, Long JC. Mammographic appearance of malignant lymphoma of the breast. Radiology 1980;135:623 - 6. [31] Mambo NC, Chb MB, Burke JS, et al. Primary malignant lymphomas of the breast. Cancer 1977;39:2033 - 40. [32] Dixon JM, Lumsden AB, Krajewski A, et al. Primary lymphoma of the breast. Br J Surg 1987;74:214 - 7.
Non-Hodgkin’s lymphoma of the breast: a review of 18 primary and secondary cases Virginia E. Duncan, MD, Vishnu V.B. Reddy, MD, Nirag C. Jhala, MD, David C. Chhieng, MD, Darshana N. Jhala, MD, B MUS (Assistant Professor)4 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL-35249-7331, USA
Abstract
We evaluated the clinical features, morphology, and incidence of 18 cases of breast lymphoma over 10 years at the University of Alabama at Birmingham. Fine needle aspiration was performed in 7 of 18 patients, and tissue biopsy/resection was available for all 18 cases. Patients were 33 to 91 years old (median, 61); 17 were women and 1 was a man. Fine needle aspiration was consistent with the tissue diagnosis in 6 of the 7 cases (86%). One case was diagnosed by fine needle aspiration as atypical cells, favor benign; the biopsy revealed diffuse large B-cell lymphoma. Tissue diagnoses revealed that 11 cases (61%) represented diffuse large B-cell lymphoma and 3 (17%) were follicular lymphomas. The remaining 4 cases (22%) were plasma cell neoplasm, T- cell neoplasm, Burkitt’s lymphoma, and precursor B-cell lymphoblastic lymphoma. Flow cytometry and/or gene rearrangement supported the diagnosis of lymphoma in 8 cases. Although rare, lymphoma should be considered in the differential diagnosis of a breast mass. Fine needle aspiration can facilitate appropriate triage of patients for further management. D 2006 Elsevier Inc. All rights reserved.
Keywords:
Breast; Breast lymphoma; Non-Hodgkin’s lymphoma; Fine needle aspirations; Cytology
1. Introduction Breast lymphoma, either a manifestation of primary extranodal disease or secondary involvement by systemic disease, is a rare malignancy, and the literature addressing this subject is sparse. Primary breast lymphoma (PBL) has a reported incidence ranging from 0.04% to 0.5% of all breast malignancies. It comprises less than 1% of all patients with non-Hodgkin’s lymphoma and approximately 1.7% of all extranodal non-Hodgkin’s lymphoma [1-9]. Secondary breast lymphoma is less well-studied than primary in the literature and is also rare, with a reported incidence of 0.07% [1,5,6,10-13]. It comprises 17% of all malignancies metastatic to the breast, making it the most common metastatic disease involving the breast [14]. The clinical presentation and radiological features of breast lymphoma and carcinoma are similar. The most
4 Corresponding author. Division of Anatomic Pathology, Department of Pathology, South, Birmingham, AL-35249-7331, USA. Tel.: +1 205 975 8890; fax: +1 205 975 7284. E-mail address: [email protected] (D.N. Jhala). 1092-9134/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.09.018
common presentation for either malignancy is a painless enlarging breast mass, although some reports suggest that lymphomatous masses tend to be larger [13]. Patients with secondary lymphomas may or may not exhibit B symptoms. On mammogram, lymphomas may lack the irregular borders of infiltrating carcinoma and more than half exhibit no calcification. However, there is considerable overlap in these features, and pathology remains the only way to differentiate the 2 malignancies [13,15-17]. Despite the clinical and radiographic similarities, the treatment differs radically. For this reason, it is important to correctly differentiate lymphoma from other breast malignancies to appropriately triage patients for treatment. Fine needle aspiration (FNA) cytology is a commonly used procedure in the evaluation of lesions in many organs [18], and recent studies have begun to focus on its diagnostic utility in breast lymphoproliferative lesions [19-21]. Although diagnostic pitfalls exist in the use of FNA to diagnose lymphoproliferative disorders, its overall sensitivity approaches 90% [18,21-23]. Confirmatory core needle biopsy is recommended by most authors for suspected primary lesions. However, cytology may be useful in
V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
145
this scenario to facilitate gathering of appropriate material for ancillary studies. Under certain clinical scenarios, particularly in suspected secondary breast lymphoma, cytology may help prevent unnecessary biopsy and surgery. This study retrospectively evaluates the clinical features, morphology, and incidence of breast lymphoma and examines the diagnostic utility of FNA for lymphoproliferative breast disease. 2. Materials and methods We retrospectively reviewed the pathology records of 18 patients with breast lymphoma at the University of Alabama at Birmingham between 1989 and 1999. For all patients, a tissue biopsy and/or resection were performed. Seven patients also had FNA. All available hematoxylin and eosin–stained slides from histologic sections and cytology slides were reviewed in conjunction with the original surgical pathology and/or cytopathology reports. For 7 patients, slides from histologic sections were not available for review, and the diagnosis was retrieved from the original pathology reports. All cases were reclassified according to the World Health Organization 2001 classification scheme for tumors of lymphoid tissues [24]. For the categorization of breast lymphoma into primary and secondary forms, we used the criteria originally developed by Wiseman and Liao [25] for PBL: (1) adequate pathological material, (2) close association of mammary tissue and malignant lymphomatous infiltrate, and (3) concurrent widespread disease or preceding extramammary lymphoma excluding ipsilateral axillary node involvement. Cases not fulfilling the latter criterion were designated as secondary. Table 1 Clinical characteristics for breast lymphomas Diagnosis
Age (y)
Sex
Clinical
Site
Ancillary studies
TCRBCL TCRBCL DLBCL Burkitt DLBCL DLBCL T cell DLBCL DLBCL DLBCL DLBCL FL LB
37 60 71 81 59 72 35 73 91 54 65 72 44
F F F F F F F F F F F F F
Primary Primary Primary Primary Primary Secondary Secondary Secondary Secondary Secondary Secondary Secondary Secondary
R R L L B L L R L R L R B
DLBCL FL FL TCRBCL PCN
85 62 51 33 49
F F F M F
Unknown Unknown Secondary Secondary Unknown
Unknown L R L L
Flow IHC Flow, IHC IHC IHC Flow CG, IHC IHC IHC Flow None None CG, flow, EM IHC IHC Flow CG, flow IHC
TCRBCL indicates T-cell–rich B-cell lymphoma; LB, precursor B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia; EM, electron microscopy; R, right; L, left; B, bilateral; Flow, flow cytometry; CG, cytogenetics.
Fig. 1. Diffuse large B-cell lymphoma. High-power photomicrograph showing a population of atypical large lymphoid cells with numerous mitotic figures.
Immunophenotyping was performed on paraffin embedded tissue for most specimens at the time of the original diagnosis. For several consult cases, the referring institution performed and reported the results of immunophenotyping. Flow cytometric analysis in 7 patients, cytogenetic analysis in 3 patients, and electron microscopy in 1 patient were performed. 3. Results Eighteen cases of hematologic malignancy involving the breast were identified in the University of Alabama at Birmingham database between 1989 and 1999; 17 (94%)
Fig. 2. Diffuse large B-Cell lymphoma. High-power photomicrograph of a Diff-Quik–stained touch imprint of the same surgical specimen as in Fig. 1, showing single atypical appearing large cells with numerous lymphoglandular bodies.
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V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
Fig. 3. Follicular lymphoma. Scanning photomicrograph showing a nodular lymphoid infiltrate invading breast stroma.
were women and 1 (6%) was a man. Table 1 summarizes the clinical information and findings for all cases. Nine cases (50%) involved the left breast, 6 (33%) the right breast, and 2 (12%) bilateral breasts. In one case, the laterality was not reported. In both cases where bilaterality was seen, it was asynchronous, with the contralateral breast involvement observed 2 to 3 years after the initial breast involvement. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype and was diagnosed in 11 cases (61%; Figs. 1 and 2). Follicular lymphoma (FL) was the second most common subtype, diagnosed in 3 cases (17%; Figs. 3 and 4). One case (6%) of each of the following was diagnosed: precursor B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia, T- cell neoplasm, plasma cell neoplasm (PCN), and Burkitt’s lymphoma (BL).
Median age at diagnosis for all cases was 61 years with a range of 33 to 91 years. The median age for PBL was 60 years (range, 37-81 years) and for secondary breast lymphoma, 68.5 years (range, 35-91 years). When the 2 most common diagnoses are examined, median age for DLBCL was 65 years (range, 33-91 years) and for FL, 62 years (range, 51-72). Immunohistochemistry (IHC) data were available for 10 cases, flow cytometric data for 7 cases, and cytogenetic analysis for 3 cases (Table 1). These ancillary studies supported the tissue diagnosis in all cases. Fine needle aspiration data are available for 7 cases. Overall, FNA at least raised the suspicion of breast lymphoproliferative disease in 6 (86%) cases. Table 2 summarizes the FNA data for all cases in which FNA was performed. Five cases (28%) were classified as primary, 10 cases (56%) were classified as secondary, and in 3 cases (17%), insufficient information was available for classification. Of the secondary cases, 4 presented with breast masses and were found on subsequent clinical workup to have disseminated disease. Fine needle aspiration was performed in 2 of these cases for which a correct diagnosis of lymphoma was rendered, followed by a needle and /or excisional biopsy for confirmation. The remaining 6 patients with secondary disease carried a previous diagnosis of hematologic malignancy and later presented with a breast mass representing metastatic or recurrent disease. The initial sites of lymphoma were parotid (2 cases), spleen (1), and small bowel mesentery (1); 1 patient had acute lymphoblastic leukemia with a recurrence in the breast, and another had been previously diagnosed with Langerhans cell granulomatosis, which was revised to a diagnosis of cutaneous T-cell lymphoma with subsequent breast involvement. One of these 6 patients underwent FNA which raised the suspicion for lymphoma and all patients had needle and/or excisional biopsies. Table 2 Cases with FNA diagnoses rendered
Fig. 4. Follicular lymphoma. High-power photomicrograph showing a monotonous population of small lymphoid cells with irregular angulated nuclei, scant cytoplasm, and inconspicuous nucleoli.
Final diagnosis
Primary/ secondary
FNA diagnosis
DLBCL
Secondary
TCRBCL
Primary
TCRBCL
Primary
Follicular lymphoma
Secondary
Lymphoblastic lymphoma Plasma cell neoplasm BL
Secondary
Positive for malignancy, favor lymphoma Atypical cells, differential diagnosis includes infection and lymphoma (Mass) Atypical cells, favor benign (LN) negative for malignancy (LN) Atypical lymphocyte population highly suspicious for lymphoma (Mass) Negative with acute and chronic inflammation Positive for malignancy, suspicious for lymphoma Atypical plasmacytoid population, suspicious for multiple myeloma Single undifferentiated cells suggestive of lymphoma
Unknown Primary
LN, lymph node; TCRBCL, T-cell–rich B-cell lymphoma.
V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
Patients with PBL presented with palpable breast masses and had no evidence of disseminated disease on further workup. Three of these patients underwent FNA and the interpretation of a lymphoproliferative disorder was made in 2 cases. In the remaining case, the FNA was interpreted as benign and was subsequently shown to be the T-cell–rich variant of DLBCL. All patients had needle and/or excisional biopsies, and 1 patient underwent mastectomy. Of the cases with insufficient clinical information to classify as primary or secondary, 1 had FNA diagnosed as suspicious for PCN (which was confirmed on subsequent histologic examination), and all had needle or excisional biopsies. 4. Discussion Breast lymphomas are rare with a reported incidence of 0.04% to 0.5% of all breast malignancies [1-9,13,15]. Wiseman and Liao [25] are credited with first defining clinical criteria for the classification of PBL. Their categorization likely underrepresents the incidence of primary disease because primary lymphomas, which have become disseminated at the time of diagnosis will be classified as a secondary process. The incidence of secondary breast lymphoma is less well-represented in the literature, reported to be 0.07% [1,5,6,10-13]. The frequency of primary relative to secondary cases is quite variable; in our series, secondary outnumbered PBL cases. This study demonstrates a broad morphological and clinical spectrum of breast lymphomas seen at our institution. When primary and secondary cases are considered together, DLBCL is the most common type reported in the literature, representing 45 to 79% of all cases [1,4,6,8,11,15,26]. Overall, in our series, DLBCL was most common, followed by FL. Similarly, when only PBL is considered, most case series also show DLBCL as the most common type. Gholam et al [27] reviewed 13 case series of PBL, with publication dates from 1990 to 2003, and Brogi and Harris [17] reviewed 12 case series with publication dates ranging from 1972 to 1994. Of the series, 6 were reviewed in both papers. Most case series were relatively small (7- 41 patients), and most show a broad diversity of lymphoma types and clinical behaviors. However, in the Gholam et al review, all but one
147
case series (of the 12 where subclassification of lymphoma is reported) shows DLBCL as the most common subtype. Secondary breast lymphomas are less well represented in the literature and, when reported, are usually included in case series along with primary cases. Table 3 reviews the findings for secondary breast lymphoma cases in 7 of the most recent breast lymphoma case series [1,5,10,11,13,15,26]. Diffuse large B-cell lymphoma was the most common type in 5 of the 7 series, and FL was the most common type in 2 series. Other less common types varied widely in their frequencies. Our series of breast lymphomas, although small when subdivided into primary and secondary categories, shows a predominance of DLBCL for both primary and secondary cases. A broad review of the literature reveals no consensus on distinguishing features between the clinical characteristics of breast lymphoma and other breast malignancies, particularly carcinomas. Both lymphoma and carcinoma of the breast are diseases of the middle-aged and elderly, although a small subset of lymphomas (Burkitt’s or Burkitt-like lymphomas) presents at a young age, typically with bilateral involvement and rapid progression. The reported median age for breast lymphoma ranges from 51 to 60 years, typically with a wide range [4,6,8,11,27,28]. The median age at diagnosis of patients with breast lymphoma in our study (61 years) corresponded well with the literature. Studies to date have also found no consistent or diagnostic radiological differences between lymphoma and carcinoma of the breast, although there is a suggestion that lymphoma tends not to have the calcification or desmoplastic reaction that often characterizes the mammographic appearance of carcinoma [13,29,30]. Most studies have reported a preponderance of rightsided presentation in breast lymphoma [4,6,11,13,25,28,31], although some, as in our series, have reported the opposite [28,32]. Bilaterality has been reported to occur in 1% to 14% of breast lymphoma cases [4,6,11] and occurred in 11% of cases in our study. Although distinction between lymphoma and carcinoma is not possible on purely clinical or radiological grounds, accurate diagnosis of lymphoma is necessary because the treatment differs radically from that of carcinoma. The histologic differential diagnosis of lymphoma includes reactive lymphoid infiltrate, medullary
Table 3 Literature review of secondary breast lymphoma most common types and their frequencies Ref (no. of pts)
DLBCL (n [%])
FL
[11] (18) [10] (22) [5] (18) [26] (5) [1] (21) [13] (15) [15] (13)
14 4 9 5 6 6 4
3 10 3 0 7 2 1
(78) (18) (50) (100) (29) (40) (31)
(17) (46) (17) (33) (13) (8)
SLL/CLL
LB
MALT
MCL
BL
TCN
0 1 2 0 3 1 0
1 1 3 0 1 2 0
0 4 (18) 0 0 2 (10) 0 3 (23)
0 0 0 0 0 3 (20) 0
0 0 0 0 0 1 (7) 3 (23)
0 0 0 0 0 0 1 (8)
(5) (11) (14) (7)
(6) (5) (17) (5) (13)
Ref indicates reference; pts, patients; SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukemia; MALT, mucosa-associated lymphoid tissue type lymphoma; MCL, mantle cell lymphoma; TCN, T-cell neoplasm.
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V.E. Duncan et al. / Annals of Diagnostic Pathology 10 (2006) 144 – 148
carcinoma, amelanotic melanoma, lobular carcinoma, and poorly differentiated ductal carcinoma. Separating these entities is usually straightforward with the aid of IHC and/or flow cytometry performed on surgical specimens. However, when lymphoma is not suspected on presentation, material is often not obtained for flow cytometry, and lumpectomy or mastectomy (unnecessary treatments for lymphoma) may be performed. Fine needle aspiration can diagnose lymphoma overall with a reported sensitivity of more than 90% and is typically higher when combined with ancillary studies such as IHC or flow cytometry [18,23]. For breast lymphoma, the reported sensitivity approximates that for lymphoma overall, ranging from 83% to 100% [19-21]. In our series, the suspicion of lymphoma was raised in 86% of the cases subsequently diagnosed as a lymphoproliferative disorder by histology. Fine needle aspiration can be useful in the diagnosis of breast lymphoma by diagnosing lymphoma outright or by raising the suspicion of the presence of lymphoma, thus facilitating the collection of material for ancillary studies at the time of FNA or on subsequent surgical specimens. In cases of primary disease, most centers advocate obtaining a confirmatory histologic diagnosis [21,23]. In conclusion, breast lymphoma is a rare disease, and published case series are small. This series demonstrates the broad morphological and clinical spectrum of breast lymphomas seen at our institution and reported in the literature. Despite its rarity, breast lymphoma should be considered in the differential diagnosis of a breast mass because a high index of suspicion for lymphoma can facilitate the accurate triage of breast biopsy specimens for ancillary studies. Fine needle aspiration, along with ancillary studies, is useful for the initial diagnosis of breast lymphoma because it can facilitate appropriate triage of patients for further management. A heightened clinical suspicion for lymphoma exists in secondary breast lymphoma, and FNA can be useful to confirm the suspected diagnosis. References [1] Domchek SM, Hecht JL, Fleming MD, et al. Lymphomas of the breast. Cancer 2002;94:6 - 13. [2] Farinha P, Andre S, Cabecadas J, et al. High frequency of MALT lymphoma in a series of 14 cases of primary breast lymphoma. Appl Immunohistochem Mol Morphol 2002;10:115 - 20. [3] Wong WW, Schild SE, Halyard MY, et al. Primary non-Hodgkin lymphoma of the breast: the Mayo Clinic experience. J Surg Oncol 2002;80:19 - 25. [4] Jeon HJ, Akagi T, Hoshida Y, et al. Primary non-Hodgkin malignant lymphoma of the breast: an immunohistochemical study of seven patients and literature review of 152 patients with breast lymphoma in Japan. Cancer 1992;70:2451 - 9. [5] Arber DA, Simpson JF, Weiss LM, et al. Hon-Hodgkin’s lymphoma involving the breast. Am J Surg Pathol 1994;18:288 - 95. [6] Brustein S, Kimmel M, Lieberman PH, et al. Malignant lymphoma of the breast: a study of 53 patients. Ann Surg 1987;205:144 - 50. [7] Hugh JC, Jackson FI, Hanson J, et al. Primary breast lymphoma: an immunohistologic study of 20 cases. Cancer 1990;66:2602 - 11.
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