Secondary breast involvement by peripheral T-cell lymphoma, not otherwise specified

Abstract

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is an aggressive nodal lymphoma that rarely manifests as breast involvement and may mimic mastitis or inflammatory breast cancer. We describe a 74-year-old woman with 1 month of progressive left breast pain, erythema, swelling, and fever, initially treated as refractory mastitis, who was later found to have secondary breast involvement by PTCL-NOS. Mammography revealed diffuse left breast skin/trabecular thickening, and ultrasound demonstrated a breast fluid collection with axillary lymphadenopathy. Cross-sectional imaging demonstrated extensive cervical, axillary, thoracic, and abdominal lymphadenopathy with secondary venous and lymphatic congestion of the breast. Axillary and inguinal lymph node biopsies confirmed the diagnosis of PTCL-NOS. The case highlights the diagnostic challenge of lymphoma-related breast manifestation, emphasizes the importance of early biopsy, and underscores the role of multidisciplinary collaboration among breast imaging, dermatopathology, and hematology–oncology.

Introduction

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas (NHLs) derived from mature T-lymphocytes, accounting for approximately 10%-15% of NHL cases in Western populations [1,2]. Peripheral T-cell lymphoma not otherwise (PTCL-NOS) is a diagnosis of exclusion, defined as a mature T-cell lymphoma that does not fulfill criteria for another specific PTCL entity [1]. Breast lymphomas are rare, representing approximately 0.04%-0.5% of all breast malignancies, and the vast majority are of B-cell lineage, with T-cell phenotypes reported predominantly as isolated case reports or small series [3]. This case report describes a 74-year-old woman who presented with breast involvement by peripheral T-cell lymphoma, which can closely mimic inflammatory breast cancer and infectious/inflammatory processes such as mastitis. This case demonstrates the value of multidisciplinary expertise across dermatopathology, oncology, and breast imaging as well as the importance of obtaining a detailed clinical history when confronting lymphoma-related breast manifestations.

Case report

A 74-year-old woman presented with left axillary pain followed within days by left breast pain, erythema, swelling, warmth, and fever developing over the span of 1 month. Multiple antibiotic treatments were administered over the next month for presumed mastitis, but symptoms persisted. Diagnostic mammogram showed diffuse left breast skin and trabecular thickening, and an enlarged left axillary lymph node (Fig. 1A). Ultrasound demonstrated a 6.4 cm fluid collection in the left breast at 6 o’clock position, 12 cm from the nipple, and morphologically abnormal left axillary lymph nodes (Fig. 1B and C). Differential considerations at this point included persistent mastitis with early abscess and inflammatory breast cancer, given lack of response to antibiotics. Findings were categorized as BI-RADS 4. Ultrasound (US)-guided aspiration of the fluid collection and biopsy of the axillary lymph node were recommended, followed by clinical follow-up for the skin thickening and repeat left mammography and ultrasound in 3 weeks.

Fig. 1.

A 74-year-old woman presented with a 1-month history of left breast pain, left axillary pain, erythema, warmth, and fever. (A) Mediolateral oblique (MLO) mammographic images of both breasts demonstrating asymmetric skin and trabecular thickening in the left breast (arrows). (B) Grayscale sonographic image demonstrating a fluid collection in the inferior left breast (arrow) measuring 6.4 cm. (C) Grayscale sonographic image demonstrating a morphologically abnormal lymph node with cortical thickening (arrow), corresponding to the abnormal lymph node seen on mammography.

US-guided left breast aspiration of the fluid collection yielded inflammation and debris with negative cultures. Skin punch biopsy at 6 o’clock periareolar position was negative for malignancy and showed chronic inflammation, edema, and reactive vascular changes. US-guided left axillary lymph node biopsy was performed at an outside facility; while results were pending, the patient was instructed to return to the emergency department should symptoms worsen.

Soon thereafter, she presented to our hospital and was admitted for further evaluation. Left axillary ultrasound confirmed several enlarged and morphologically abnormal lymph nodes, with skin and subcutaneous edema in the left breast and axilla. Chest computed tomography (CT) scan was performed for hypoxia and it demonstrated extensive left axillary adenopathy and left breast and axillary edema, as well as mediastinal, hilar, and supraclavicular adenopathy (Fig. 2). Outside institution’s skin punch and left axillary lymph node biopsies were reviewed by our pathologists and showed findings consistent with PTCL-NOS (Fig. 3, Fig. 4).

Fig. 2.

Contrast-enhanced chest CT in a 74-year-old woman with biopsy-proven peripheral T-cell lymphoma. Axial postcontrast CT image demonstrates bilateral axillary adenopathy, left greater than right, with matted left axillary lymph nodes (arrow).

Fig. 3.

Left breast skin punch biopsy performed to evaluate infection vs underlying malignancy. (A) Hematoxylin and eosin (H&E) stain at 40× magnification demonstrates atypical lymphoid infiltrate (arrows) in the dermis. (B) H&E stain at 400× magnification shows a dense collection of lymphocytes with abnormal morphology (arrow). (C) Immunohistochemical (IHC) stain at 100× magnification demonstrates that the atypical lymphoid infiltrate is composed of T-lymphocytes staining diffusely positive for CD3 (arrow). (D) IHC stain at 100× magnification for CD20, a marker for B-lymphocytes, is negative. (E) Keratin-AE1/3 IHC stain at 100× magnification is negative, confirming the absence of invasive carcinoma.

Fig. 4.

Left axillary lymph node biopsy confirms peripheral T-cell lymphoma. (A) H&E stain at 40× magnification demonstrates effacement of normal lymph node architecture by diffuse neoplastic lymphoid infiltrate (arrows). (B) H&E stain at 100× magnification shows densely distributed, morphologically abnormal lymphocytes. (C) IHC stain at 100× magnification shows neoplastic lymphoid cells are T-lymphocytes that are diffusely positive for CD3 (arrows). (D) IHC stain at 100× magnification demonstrates neoplastic T-lymphocytes are negative for CD20 (arrow). (E) IHC stain at 100× magnification shows aberrant loss of CD4 in neoplastic T-lymphocytes. (F) IHC stain at 100× magnification demonstrates aberrant loss of CD8 in neoplastic cells, with CD8 positivity confined to reactive T-lymphocytes.

Staging whole-body [18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) demonstrated extensive hypermetabolic lymphadenopathy in cervical, thoracic, and abdominal stations, consistent with widespread lymphoma (Fig. 5). Asymmetric left breast and axillary swelling were attributable to bulky axillary adenopathy causing venous and lymphatic congestion. Excisional biopsy of an inguinal lymph node provided definitive histopathologic confirmation of PTCL-NOS. Our oncology team recommended rehab to improve functional status prior to initiation of treatment, bone marrow biopsy, and an outpatient palliative care consultation. Patient planned to follow up with her local oncology team, and no further clinical information has been available since discharge from our institution.

Fig. 5.

Staging FDG PET/CT. Coronal maximum intensity projection (MIP) demonstrates extensive hypermetabolic lymphadenopathy at cervical, thoracic, and abdominal lymphadenopathy, with moderate left breast edema and faint hypermetabolism (arrow).

Histopathologic evaluation of the left axillary core biopsy and left inguinal excisional lymph node biopsy demonstrated diffuse effacement of nodal architecture by atypical T-cells expressing pan-T-cell markers CD3 and CD45RO, consistent with a mature T-cell population. Immunohistochemistry showed aberrant loss or diminution of CD4, CD5, CD7, and CD43, with CD8 expression confined to reactive T-cells. Flow cytometric immunophenotyping confirmed a CD4-negative and CD8-negative T-cell population with loss of CD5 and proliferation index (MIB-1 stain) of approximately 40%-50%, consistent with a clonal peripheral T-cell neoplasm. Neoplastic cells were positive for Beta F1, ICOS (CD278), PD-1 (CD279), and BCL-6 in a subset. CD21 immunostaining showed expanded follicular dendritic cell networks. CXCL13, CD10, CD30, TdT, CD20, and Epstein–Barr virus (EBV) in situ hybridization were negative.

Under the WHO-HAEM5 and International Consensus Classification (ICC), PTCL-NOS is defined as a mature T-cell lymphoma that does not meet criteria for any specific PTCL entity [2,4]. There is no significant difference in the classification of PTCL-NOS under WHO-HAEM5 and ICC. The main differences between the 2 classification systems are pronounced in some B-cell lymphomas and in certain myeloid neoplasms such as AML. In our case, the neoplastic cells expressed some TFH-associated markers, including ICOS and PD-1 with partial BCL-6 expression but lacked more specific TFH markers such as CXCL13 and CD10, and were EBV-negative, indicating a partial TFH immunophenotype rather than a definitive nodal TFH lymphoma. Furthermore, lack of CD30 expression in the neoplastic cells and lack of cohesive sheets of large anaplastic cells argued against anaplastic large cell lymphoma (ALCL). Taken together, the histomorphology, immunohistochemical profile, and flow cytometric findings in this mature T-cell neoplasm support a final diagnosis of PTCL-NOS.

Earlier breast skin punch biopsy had demonstrated an atypical perivascular lymphoid infiltrate; however, polymerase chain reaction analysis for T-cell receptor gene rearrangement was negative and only sparse perivascular CD3-positive lymphocytes without cytologic atypia were seen. These findings support a reactive cutaneous process rather than primary cutaneous T‑cell lymphoma. Inflammatory breast cancer would manifest with dermal lymphatic invasion by malignant cells, which was not appreciated in this case. Previously aspirated left breast fluid collection yielded negative cultures for infection or cells for malignancy and appeared as clear yellow, non-cloudy fluid, findings consistent with lymphatic fluid.

Discussion

Breast involvement by T-cell lymphomas is extremely rare, with PTCL-NOS reported only as isolated primary and secondary cases in larger series of breast lymphomas [5]. Using established criteria, primary breast lymphoma is defined by the absence of prior documented lymphoma, clinical presentation involving the breast, and disease confined to the breast with or without regional lymph node involvement. In contrast, secondary breast lymphoma is diagnosed when the patient has generalized (Stage III or IV) disease at the time breast involvement is identified or when lymphoma has been documented at another site prior to breast diagnosis [6]. Our case is best characterized as secondary breast involvement by PTCL-NOS rather than primary breast lymphoma, given widespread nodal disease at the time breast involvement was identified.

Mastitis presents with acute-onset erythema, warmth, pain, and systemic symptoms of fever and chills. Symptoms often improve over 48-72 hours with effective antibiotic therapy. In our case, persistent symptoms despite multiple antibiotic courses, along with progressive lymphadenopathy, were atypical for uncomplicated mastitis, and clinical suspicion for malignancy was heightened. Inflammatory breast cancer does not improve with antibiotics, is not associated with fever, and can manifest as rapid breast enlargement over weeks to months, sometimes associated with the classic peau d’orange skin texture. Unlike inflammatory breast cancer and mastitis, lymphoma can be present with bilateral involvement and systemic lymphadenopathy [7]. Initial presentation of either primary or secondary breast lymphoma can pose clinical mimicry to infection and breast carcinoma as seen by our case and those cited elsewhere [8]. When clinical differentiation is difficult, a low threshold for biopsy is warranted to exclude lymphoma and other malignancies, particularly when symptoms fail to respond to appropriate therapy.

Immunophenotyping was critical in establishing the diagnosis of PTCL-NOS. Under both WHO-HAEM5 and ICC classification systems, PTCL-NOS is a diagnosis of exclusion that requires absence of a definitive TFH-phenotype (expression of ≥2 TFH markers), negative EBV status (to exclude EBV-positive nodal T- and NK-cell lymphoma), and features that do not meet criteria for other defined PTCL entities (such as ALCL). Beyond histological classification, recent work has shown that PTCL-NOS can be subdivided into 2 major molecular subgroups, PTCL-GATA3 and PTCL-TBX21, which differ in biology and prognosis. PTCL-GATA3 is associated with a T-helper type 2 (Th2) differentiation, greater genomic complexity, deletions in key tumor suppressor genes (TP53, PTEN, etc.), and inferior overall survival in several cohorts. In contrast, PTCL-TBX21 shows a T-helper type 1 (Th1) and cytotoxic T-cell differentiation and often carries mutations in epigenetic regulators suggesting involvement of a distinct oncogenic pathway [[9], [10], [11]]. In our patient, an outside pathology report from initial axillary lymph node biopsy indicated GATA-3 positivity in the neoplastic T-cells, suggesting higher-risk disease biology. GATA3/TBX21 subclassification informs prognostic and biologic risk but does not yet change standard initial therapy.

Standard initial therapy for PTCL-NOS is anthracycline-based combination chemotherapy such as cyclophosphamide–doxorubicin–vincristine–prednisolone (CHOP), with possible addition of etoposide [1]. For patients who achieve remission, consolidation with autologous stem cell transplant is often recommended given high relapse risk and poor long-term survival with chemotherapy alone [2,12]. Large retrospective cohort and registry data show 5-year overall survival of approximately 28%-32% for PTCL-NOS treated primarily with CHOP-like regimens and progression-free survival close to 20%-30%. Emerging data suggests incorporating molecularly targeted and epigenetic agents into front-line and relapsed settings may improve these outcomes [12,13]. Given the rarity and aggressive clinical course of PTCL-NOS, radiologic recognition of atypical presentations, prompt tissue diagnosis, and coordinated multidisciplinary management are critical in facilitating timely oncologic evaluation and enrollment in disease-specific, biology-driven clinical trials. Unfortunately, the patient was lost to follow-up after discharge from our institution, and her subsequent treatment course and outcomes remain unknown despite repeated attempts to contact her and her local oncology team.

Based on current guidelines for nodal PTCL-NOS and prior reports of breast-involved PTCL-NOS, our patient would have been treated with CHOP-based systemic chemotherapy with consideration of consolidative autologous stem cell transplantation in first remission if her performance status allowed [[1], [2], [3],12,13]. We could have directed her towards enrollment in clinical trials investigating novel or GATA3-directed strategies given her high-risk molecular profile. In the largest series of T-cell breast lymphomas to date, Gualco et al. [5] identified only 2 cases of PTCL, unspecified (now known as PTCL-NOS): 1 primary and 1 secondary breast PTCL-NOS with cervical and axillary nodal disease [5]. Primary PTCL-NOS case involved a 70-year-old female that presented with a 1.5 cm right breast mass and was treated with stage-adapted chemotherapy plus radiotherapy, remaining alive at 5 months of follow-up. Secondary PTCL-NOS case was a 31-year-old female with cervical and axillary nodal disease treated with systemic chemotherapy who had survival of 29 months at last follow-up. Muroya et al. [3] reported a primary breast PTCL-NOS treated with 6 cycles of CHOP that achieved nearly complete remission but relapsed within months and the patient expired at 17 months after diagnosis [3]. Comparison to our GATA3-positive, secondary breast PTCL-NOS is limited due to loss to follow-up and is further constrained by differences in era and depth of biologic characterization, as the earlier series predate or do not incorporate modern GATA3/TBX21-based molecular subclassification. Given the rarity of breast-involved PTCL-NOS and the increasingly recognized prognostic impact of transcriptional and genomic subtypes, future case reports and series should aim to include comprehensive immunophenotypic and molecular profiling alongside detailed documentation of presentation, treatment, response, and long-term outcomes. This can help to better refine risk stratification and guide the development of biology-driven therapeutic strategies in this poorly characterized population.

Patient consent

Informed consent for publication of this case and accompanying images was obtained from the patient.