Spontaneous Regression of a Clinically-Advanced Histologically Low-Grade Follicular Lymphoma Involving the Breast: Case Report and Review of the Literature

Abstract

A 68-year-old woman was diagnosed as having grade 1 follicular lymphoma of the left breast in November 2012. Bone marrow infiltration was noted histologically and confirmed by Southern blot analysis of the IgHJH locus. The clinical stage was IVA, advanced stage. According to the Follicular Lymphoma International Prognostic Index, the patient was classified into the high risk group. The general condition was good and there were no organ symptoms, therefore, the patient was kept under observation without treatment. After one year and 2 months of follow up, The mass was regressed spontaneously. As previous studies have suggested a poor prognosis of patients with an advanced clinical stage of the disease, careful follow-up of our patient is necessary.

Introduction

Breast lymphomas, including primary and secondary lymphomas, are rare, accounting for less than 0.5 % of all breast tumors [1] and 0.38–0.7 % of all non-Hodgkin’s lymphomas [2]. In addition, previous studies have shown that most breast lymphomas are mostly diffuse large B cell lymphomas (DLBCL) [1, 3–5], and there have been only two reports of small-scale studies of follicular lymphoma (FL) of the breast: one report of primary FL [6] and another of secondary FL [2]. According to these two reports, both primary and secondary FLs have a poor prognosis. Therefore, it is necessary to conduct large-scale studies after accumulating further cases to determine the clinical features, molecular biological characteristics and prognosis of FL of the breast.

Case Report

The patient was a 68-year-old woman with a category 3 mass (according to the Breast Imaging Reporting and Data System [7]) in the left breast detected by mammographic screening for breast cancer. Her medical history included surgery for acute appendicitis at age 19, surgery for uterine myoma at age 39, and sudden right hearing loss at age 64. She had no significant family history. Screening for breast cancer by mammography in October 2012 revealed a mass in the left breast, and the patient visited the Department of Breast Surgery of our hospital in November. Needle biopsy of the left breast mass led to the diagnosis of grade 1 FL, and she was referred to our department.

At the time of hospitalization, general physical and systemic examination was unremarkable except for a palpable mass in the left breast that was about 12.5 mm in diameter, non-tender, elastic-soft in consistency, and mobile. The overlying skin and the nipple were normal. There was no palpable lymphadenopathy or abdominal organomegaly.

At the first examination, laboratory findings revealed no abnormalities of the blood counts, coagulation profile, immunological indices, or urinalysis results. Biochemical tests revealed only a mild increase of the serum LDH (260 IU/l, institutional reference range 119–229 IU/l). Serum soluble IL-2 receptor levels were within normal range (381 U/ml, institutional reference range 145–519 U/ml).

Mammography showed a high-density mass with a smooth border in the left upper quadrant of the left breast (red arrow in Fig. 1a); Ultrasound revealed a hypoechoic lesion measuring 9.4 × 6.7 × 9.3 mm in size, with evidence of rich blood flow (blue arrows in Fig. 1b) ¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET–CT) revealed FDG accumulation in the left mammary gland (standardized uptake value [SUV] max = 1.5; yellow arrows in Fig. 2a, b), mesentery (SUV max = 1.8; yellow arrow in Fig. 2c),

Fig. 1.

a Mammography showed a high-density mass with a smooth border measuring 9 mm in diameter in the left upper quadrant of the left breast (red arrow) b, Breast ultrasound revealed a hypoechoic lesion measuring 9.4 × 6.7 × 9.3 mm in size, with evidence of rich blood flow (blue arrows)

Fig. 2.

¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET–CT) revealed FDG accumulation in the left mammary gland (standardized uptake value [SUV] max = 1.5; yellow arrows in a, b), mesentery (SUV max = 1.8; yellow arrow in c)

Histopathologic findings of needle biopsy specimens obtained from the breast mass were as follows: Examination of hematoxylin-eosin (HE)-stained sections under low magnification showed formation of somewhat indistinct lymphoid follicles (Fig. 3a); examination under high magnification showed that the germinal center was composed mainly of small cells (Fig. 3b). Positive staining for Bcl 2, CD10 and CD20 was observed, and the MIB 1 index was 10 % (Fig. 3c–g). The B-cells showed surface kappa light chain restriction. Fluorescence in situ hybridization of the needle biopsy specimens revealed the IgH-BCL 2 reciprocal translocation (not shown). Histopathologic examination of bone marrow biopsy specimens raised the suspicion of bone marrow infiltration, as small paratrabecular lymphoid aggregates (yellow arrows) were found on the slide (Fig. 3h). Southern blot analysis of the bone marrow blood cells revealed rearrangement of the IgHJH gene (Fig. 4). Based on the above, the patient was diagnosed as having grade 1 FL, and the clinical stage was diagnosed as stage IVA, based on the detection of bone marrow infiltration. The patient was classified as a high-risk patient according to the Follicular Lymphoma International Prognostic Index, based on the age, increased LDH levels, and clinical stage. Her general condition was good and there were no organ symptoms, therefore, the patient was kept under observation without treatment. As of November 2013, after one year and 2 months of follow up, her general condition remains good, with no palpable mass in the breast. The mass was regressed spontaneously.

Fig. 3.

Histopathologic findings of needle biopsy specimens obtained from the breast mass a HE staining (×40) show formation of somewhat indistinct lymphoid follicles. b HE staining (×600) showed that the follicles were composed mainly of small cells. c Follicles showing positive staining for Bcl 2 (×40). d Positive CD10 staining of the follicles (×40). e Positive CD10 staining of the follicles (×600). f Positive CD20 staining of the follicles (×40). g The MIB 1 index was 10 % (×40). h Histopathologic findings of HE-stained sections of the bone marrow (×40) showed small paratrabecular lymphoid aggregates (yellow arrows)

Fig. 4.

Southern blot analysis for Ig(H)JH in bone marrow blood cells: The restriction enzymes are: lane 1, EcoR I; lane 2, BamH + Hind III; and lane 3, Hind III. A gene rearrangement band was detected (red arrow), leading to the diagnosis of bone marrow infiltration

Discussion

A strict definition of primary breast lymphoma was first proposed by Wiseman and Liao as follows: (1) adequate pathological evaluation, (2) presence of both mammary tissue and lymphomatous infiltrate in close association, and (3) exclusion of systemic lymphoma or previous extramammary lymphoma [8]. There is also a report that a breast lesion is defined as a primary lesion if it is the main lesion, regardless of the disease stage and the presence/absence of infiltration of other organs [9]. Thus, there are differences in the definition of the primary lesion among reports, but lesions other than the primary lesions are considered to be secondary lesions.

It has been reported that the incidence of primary breast lymphoma is almost the same as [10] or slightly lower than [11] that of secondary breast lymphoma, but most of both primary and secondary breast lymphomas are B cell lymphomas. DLBCL is common among primary breast lymphoma [5, 12, 13]. However, there are some reports suggesting that DLBCL is also common among secondary breast lymphomas [10, 14–17] and some reports that FL is common [11, 18].

Most detailed analyses of breast lymphomas have involved patients with DLBCL [1, 3–5], and there have been only two reports of studies analyzing FL of the breast in detail: a retrospective study of 36 patients with primary FL [6] and another retrospective study of 15 patients with secondary FL [2].

To the best of our knowledge, there have been a total of 179 reported cases of FL of the breast, including 91 cases of primary FL, 73 cases of secondary FL (including the present case) and 15 cases of primary or secondary FL (Table 2) [1, 2, 4–6, 9–12, 14–16, 18]. Most of these cases have been described in case reports or additionally described in reports of other lymphomas such as DLBCL, and the molecular biological characteristics, clinical symptoms, prognosis, etc., of FL of the breast have not yet been clarified in detail. However, Talwalkar et al. [2] described that the molecular biological characteristics of secondary FL were similar to those of nodal FL, based on a study of 15 patients with secondary FL. Future studies on a larger number of cases are expected.

In the study reported by Martinwlli et al. [6], who retrospectively analyzed the data of 36 primary FL patients followed up for a mean observation period of 44 months, 14 patients died, the 10-year overall survival was 47 %, and the progression-free survival was 28 %, the outcome being worse than that in patients with localized nodal FL treated by a “watch-and-wait” approach.

A retrospective study by Talwalkar et al. [2] of 15 patients with secondary FL of the breast showed that the outcome of this disease was extremely poor, with a median overall survival of 24 months and a median disease-free survival of 14 months. From the above, it is speculated that the prognoses of both primary and secondary FL are poor. Actually, Ganjoo et al. [4] reported that the usual treatment for low-grade lymphoma should be given to patients with advanced stages or clinical symptoms. However, these data were obtained before rituximab became available for treatment, and it is considered essential to analyze the data after accumulation of patients treated with rituximab.

The prognoses of both primary and secondary FL may be poor, and it is necessary to conduct large-scale studies after accumulating a larger number of cases in the future to determine the molecular biological characteristics and prognostic factors of FL of the breast. Furthermore, it will be desirable to establish new treatment strategies including rituximab. This case was due to distant LN involvement, there is a possibility of secondary involvement of breast by grade 1 FL which is also an uncommon instance.