Keywords
Breast lymphoma - chemotherapy - diffuse large b-cell lymphoma - rituximab
Introduction
Primary breast lymphoma (PBL) is a rare form of extranodal non-Hodgkin’s lymphoma
(NHL) and accounts for <0.5% of all breast malignancies It represents <1% of all NHL
and 2.2% of extranodal NHL.[1]
[2] It is postulated that PBL originates in the lymphatic tissue present within the
breast adjacent to ducts and lobules or from intramammary nodes.[3]
[4] Wiseman and Liao,[5] first proposed the diagnostic criteria for PBL as follows
The clinical site of presentation is the breastA history of previous lymphoma or evidence
of widespread disease is absent at diagnosisLymphoma is demonstrated with close association
to breast tissue in the pathologic specimenIpsilateral lymph node may be involved
if they develop simultaneously with the primary breast tumor.
This definition of PBL comprises only tumor that are Stage I (lymphoma limited to
the breast) and Stage II (lymphoma limited to the breast and axillary lymph nodes),
excluding those tumor that may have originated at nonbreast sites. Surgery, radiotherapy,
and chemotherapy have been used alone or in combination in its management.[6] However, the optimal therapy of PBL still remains undefined.
We report three cases of PBL which we have diagnosed and managed. The issues involved
in its diagnosis and management are discussed in this communication.
Materials and Methods
In a retrospective analysis, the medical records of all diagnosed with NHL between
the period January 2004 and December 2014 at the Department of Hematology were searched
for cases of PBL.
Three cases were diagnosed to have PBL as per the criteria defined by Wiesman and
Liao.[5] The diagnosis was established on histopathological evidence of tumor specimen based
on the WHO nomenclature.[7] All the patients underwent computed tomography (CT) of the chest, abdomen, and pelvis
and bone marrow biopsy for staging of the disease as per the Ann Arbor staging system.[8]
Results
The clinical and laboratory findings and treatment outcome are summarized in [Table 1] and [Table 2].
Table 1
Clinical and pathological profile of the primary breast lymphoma patients
|
Case number
|
Age (years)
|
Year of diagnosis
|
Duration of symptoms
|
Site of tumor
|
Size of tumor (cm)
|
Lymph nodes
|
Performance status ECOG
|
Ann arbor staging
|
Histological subtype
|
|
DLBCL – Diffuse large B-cell lymphoma; ALCL – Anaplastic large cell lymphoma; ECOG
– Eastern Cooperative Oncology Group
|
|
1
|
66
|
2004
|
5 months
|
Left breast
|
7×6
|
Single ipsilateral axillary
|
3
|
IIE
|
DLBCL
|
|
2
|
52
|
2007
|
1 month
|
Right breast
|
4×2
|
Right axillary
|
1
|
IIE
|
DLBCL
|
|
3
|
50
|
2011
|
12 months
|
Right breast
|
7×5
|
Right axillary
|
3
|
IIE
|
ALCL
|
Table 2
Treatment and follow-up of primary breast lymphoma patients
|
Case number
|
Treatment
|
Type of response
|
Follow-up
|
Remarks
|
|
1
|
Radical mastectomy plus CHOP X 6 cycles
|
Complete remission
|
84 months
|
Relapsed after 7 years. developed 2x3 lump right breast. DLBCL
|
|
2
|
R-CHOP X 8 cycles Triple intrathecal chemotherapy
|
Complete remission
|
96 months
|
In remission
|
|
3
|
No treatment
|
-
|
-
|
|
Clinical and laboratory features
Three multiparous postmenopausal females were diagnosed with PBL. The mean age at
presentation was 56 (range 50–66) years. All three patients presented with unilateral
breast mass. Two patients (Cases 2 and 3) swelling in the right breast and the third
case (case1) had a left breast mass. The average time from onset of symptoms to presentation
at the hospital was 6 (range 1–12) months. None of the patients had any symptoms or
signs of local inflammation or tumor infiltration (local erythema, puckering of the
skin, or nipple retraction) at presentation. “B” symptoms were reported in only two
patients. None of the three patients had any clinical features to suggest central
nervous system involvement (CNS) at the time of initial presentation. The clinical
stage of the disease was IIE in all the three cases [Table 1].
Radiological evaluation showed the disease localized to the breast tissue only; there
was no evidence of systemic disease [Figure 1a] and [b]. On histopathological examination (HPE), two patients had CD 20 positive diffuse
large B cell lymphoma (DLBCL) [Figure 2] and [3]. The third patient (Case 3) had anaplastic large cell lymphoma (ALCL).
Figure 1: (a) Mammography of the right breast inpatient Case 2, shows smooth radiodense
mass without spiculations or calcification. (b) Contrast-enhanced computed tomography
of the thorax in the axial plane at the level of the breast in Case 2 shows enhance
round mass lesion in the right breast
Figure 2: (Case 1) Diffuse large B-cell lymphoma. The sections show breast parenchyma
with infiltration by sheets and cords of atypical lymphoid cells in a dense fibrocollagenous
stroma. The cells display high n/c ratio, round-to-oval nuclei, dispersed chromatin,
and scant cytoplasm
Figure 3: (Case 3) Diffuse large B-cell lymphoma. The section from the right breast
lump shows diffuse sheet and cords of atypical lymphoid cells infiltrating the fibrocollagenous
stroma. The tumor cells are round to irregular have moderately pleomorphic hyperchromatic
nuclei and variable amount of cytoplasm, Mitotic figures are discernible
Treatment and outcome
Case 1 underwent modified radical mastectomy along with axillary lymph node resection.
Postoperatively, the patient received a total of 6 cycles of cyclophosphamide, doxorubicin,
vincristine, and prednisolone (CHOP) chemotherapy, No radiotherapy was given, and
the patient achieved complete remission (CR) after the end of the treatment. Case
2 underwent a core tissue biopsy for the evaluation of the right breast mass. The
biopsy was suggestive of CD 20 positive DLBCL and the patient received rituximab plus
CHOP (Rituximab 375 mg/m2 IV on day 1 plus CHOP) chemotherapy administered every 3
weeks. Before the third cycle of chemotherapy, she developed hoarseness of voice,
difficulty in swallowing, and weakness of the left side of the face. Clinical examination
revealed lower motor neuron type of unilateral left 7th cranial nerve and bilateral 9th and 10th cranial nerve palsies. Magnetic resonance imaging showed no focal deposits of lymphoma.
Cytological examination of cerebrospinal fluid showed the presence of atypical lymphoid
cells suggestive of CNS involvement. The patient was administered triple intrathecal
(methotrexate, cytosine arabinoside, and hydrocortisone) chemotherapy as per recommendations
for her CNS disease. No cranial irradiation was given. The patient showed complete
resolution of her CNS disease following further therapy. The subsequent clinical course
was uneventful, and the patient received a total of eight cycles of R-CHOP chemotherapy.
The third patient who was diagnosed to have ALCL of breast refused treatment for socioeconomic
reasons.
Follow-up and survival
Both case 1 and 2 achieved CR following chemotherapy. Case 1 remained in disease-free
state for the next 84 months of follow-up. In April 2011, the patient developed a
new lump in the right breast measuring 2 cm × 3 cm in size. A lumpectomy was performed,
and the HPE was diagnostic of DLBCL. The patient was counseled for disease relapse;
however, she refused further treatment. Case 2 remains in clinical remission for the
last 96 months (8 years) of follow-up.
Discussion
PBL is a rare but potentially curable disease. The term PBL is used to define NHL
occurring exclusively in the breast tissue with or without regional draining lymph
node involvement and absence of any evidence of disease at another site. The disease
usually occurs in the 5th and 6th decade of life and presents as a unilateral rapidly expanding painless mass.[9]
[10] The right breast is more frequently involved 3:2 ratio. Bilateral breast involvement
is seen in 6% to 11% of cases.[11] The mass may be associated with local pain and signs of inflammation in up to 12%
of patients.[9]
The pathogenesis of PBL is still not clear. It is postulated that the tumor arises
from mucosa-associated lymphoid tissue (MALT). It may also develop from the lymphatic
tissue present within the breast adjacent to ducts and lobules or from surrounding
lymph nodes.[3]
[4] Majority of the PBL are B-cell lymphomas and express CD 20 antigen. DLBCL is the
most common histological type and accounts for 50% of all cases. Follicular lymphoma
15% and MALT 12.2% are the next frequent subtypes.[12]
On mammography, the tumor appears as oval shaped margins high-density mass without
speculated margins or calcifications.[13] Fine-needle aspiration cytology, tissue core, or excisional biopsy of the breast
mass and draining lymph nodes are essential to establish the histopathological diagnosis.
Bone marrow biopsy, CT of the thorax, and abdomen and positron emission tomography
scan are required to rule out systemic NHL and for staging of disease.
Patients with PBL have been treated with radical mastectomy, chemotherapy, and radiotherapy
either alone or in combination with varying results. Disease stage, tumor size, performance
status, and IPI score influence the disease prognosis.[14] Early-stage disease is associated with good prognosis and tumor size >4 cm has an
adverse prognosis.[9]
Ganjoo et al.[11] in a retrospective analysis of 37 patients with PBL found that DBL was the most
common histologic subtype (49%). Seventy percentage of the DLBCL patients were treated
with doxorubicin-based chemotherapy and involved field radiotherapy (IFRT). The 5-year
progression-free survival (PFS) was 61% with median follow-up of 3.8 years and a 5-year
overall survival (OS) was estimated at 82%.
Ryan et al.[14] in a retrospective study of 204 patients with PBL (DLBCL subtype) attending the
International ExtraNodal Lymphoma Study Group found that there was no benefit from
mastectomy. Chemotherapy was associated with a median OS of 8.0 years and median PFS
of 5.5 years. They concluded that limited surgery combined with chemotherapy and IFRT
is associated with better outcome.
Avilés et al.[15] in a prospective study of 96 patients with PBL compared treatment outcome with radiotherapy
(n = 30), chemotherapy (CHOP-21 × 6 cycles; n = 32), and combined therapy (radiotherapy 30 Gy plus CHOP × 6 cycles; n = 34). CR was observed in 66.71% (20/30) treated with radiotherapy, 59.4% (19/30)
with chemotherapy, and 88.2% (30/34) with combined modality. At 10 years median follow-up,
the event-free survival was 50%, 57%, and 83%, respectively (P < 0.01) and the OS was 50%, 50% and 76% (P < 0.01), respectively.
In a meta-analysis of 464 PBL cases diagnoses between 1972 and 2005, by Jennings et al.,[13] it was observed that 53% of all cases were of DLBCL subtype and the median age of
presentation was 54 (range 17–95) years. Mastectomy showed no benefit regarding OS
and recurrence rate. Radiotherapy showed benefit in survival and recurrence rates
in Stage I patients. Chemotherapy showed benefit in Stage II patients. Rituximab is
anti-CD 20 monoclonal antibody addition, of this agent with CHOP chemotherapy (R-CHOP),
has shown high efficacy for DLBCL. Avilés et al.[16] observed no CNS relapse in PBL patients treated with R-CHOP regimen compared to
that CHOP regimen alone. THE CNS relapse rate was 11% in patients treated with CHOP
regimen only. Sun et al.[17] have observed that patients treated with rituximab plus chemotherapy have a superior
5-year PFS and local control. A study comparing the OS in patients with PBL and nodal
DLBCL treated with R-CHOP and IFRT found no difference between the two groups.[18]
The role of CNS prophylaxis in PBL-DLBCL has been much debated A CNS relapse rate
of 11.0%–17.6% has been reported in some studies.[15]
[19] In contrast, other studies have reported a lower relapse rate of 4% to 5%, which
is similar to that observed in nodal DLBCL.[14]
[20] Nearly 5%–14% has been observed in various retrospective studies.[9]
[14] The present consensus is that PBL patients should be treated similar to nodal lymphoma
of the same stage and histology. Anthracycline-based chemotherapy in combination with
IFRT is the recommended modality of treatment.[6]
Conclusion
At our institute, both our PBL-DLBCL patients (Case 1 and 2) were treated with chemotherapy
alone and had a DFS of 84 and 96 months, respectively. No CNS disease relapse or recurrence
was observed in both our patients during the follow up period.
