Both cases of lymphoma involving the breast described here represent rare lymphoma subtypes, and hence presented diagnostic challenges. The case of ALK-negative ALCL occurred in a clinical setting in which malignancy was not suspected, and the malignant cells were initially overlooked. ALCL is characterized by the presence of large cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei, termed “hallmark cells”, with expression of CD30, and often loss of multiple pan-T-cell antigens. The presence of the anaplastic lymphoma kinase
) gene translocation and expression of ALK protein defines ALK-positive ALCL, which occurs in children and young adults and has a relatively favorable prognosis, while ALK-negative ALCL occurs in older individuals who often present with advanced disease and has a worse outcome, although better than that for peripheral T-cell lymphoma, not otherwise specified [12
]. ALK-negative ALCL should be distinguished from primary cutaneous ALCL, which also lacks ALK, but which presents with localized skin involvement and has a favorable prognosis [15
As summarized by two recent studies, there have been 12 reported cases of ALCL arising as a primary breast neoplasm in association with prosthetic silicone or saline implants, ten of which were confirmed to be ALK-negative [16
]. In the majority of these cases (8/12, 67%) the presenting symptom was the formation of a peri-implant seroma; the remaining patients presented with a mass or ulceration [16
]. ALK-negative ALCL has been identified after both cosmetic augmentation and reconstruction following mastectomy for primary breast carcinomas. Most affected patients have had a good prognosis with prolonged disease-free survival despite negativity for ALK, leading some investigators to suggest that this clinicopathologic entity may be more closely related to the primary cutaneous form of ALCL [17
]. Indeed, prognosis in nonnodal ALCL may be more closely related to site of presentation than to ALK status [23
Although breast implants do not appear to increase the risk of subsequent development of breast carcinoma [24
], there may be an etiologic association between prolonged exposure to silicone from breast implants and the rare development of ALK-negative ALCL [16
]. There is speculation that exposure to silicone, due to microscopic leaks from silicone-filled implants or from saline-filled implants containing silicone-impregnated capsules, drives an immunologic reaction that leads to T-cell activation, clonal expansion, and the eventual development of lymphoma [16
The diagnosis in this case was challenging for several reasons. At the time of the first silicone implant removal and replacement, malignancy was not suspected. Not only was the patient in complete remission from her breast cancer, but there existed at that time only isolated case reports in the literature of the association between ALK-negative ALCL, breast implant capsules, and seroma formation [18
], so there was little awareness of this diagnostic entity. On morphological examination, the initial capsulectomy specimen was sparsely cellular, with only rare partially degenerated atypical cells. The diagnosis of ALK-negative ALCL was rendered on an aspirate of the seroma fluid that was sent for cytologic evaluation in which cellular detail was well-preserved, leading to the identification of frankly malignant nuclear features and review of the previous specimen. The second capsulectomy specimen showed more extensive involvement by lymphoma with greater tumor cell viability and more conspicuous “hallmark cells”. This case highlights the importance of careful morphologic evaluation of paucicellular or degenerated samples, even in instances where the clinical suspicion for malignancy is low. It also illustrates the importance of maintaining an awareness of emerging diagnostic entities associated with specific clinical and pathological settings, even those that occur with low frequency.
The case of hairy cell leukemia exhibited classic morphologic and immunophenotypic features of this entity [27
], but the diagnosis was challenging because of the unusual clinical presentation in the breast. The clinical symptom of leg pain, in combination with the radiological findings of masses in both the breasts and femur, was more suggestive of metastatic breast carcinoma than a hematologic malignancy. The initial core biopsy of the breast showing DCIS reinforced this clinical suspicion. In this context, the morphological differential diagnosis of a breast tumor composed of small discohesive cells with abundant cytoplasm included invasive lobular carcinoma [10
]. The relatively small nuclear size and minimal cytological atypia were subtle clues to the lymphoid, rather than epithelial, nature of the cells. Importantly, knowledge of the patient's concurrent diagnosis of hairy cell leukemia involving the femur and bone marrow led to the performance of an appropriate panel of immunohistochemical stains and confirmation of the diagnosis.
Hairy cell leukemia typically involves bone marrow and spleen but may also involve other sites including the central nervous system, gastrointestinal and urogenital tracts, heart, lungs, skeletal muscle, skin, thymus, and thyroid [28
]. Breast involvement, either at the time of diagnosis or later in the disease course, has not been reported to our knowledge. Since breast tissue is rarely sampled at the time of autopsy, the breast may be an under-recognized site of involvement in established disease. Lymph node and skeletal involvement have been reported in hairy cell leukemia and typically occur at an advanced stage of disease [27
]. Therefore, a striking feature in this case is the prominent degree of breast and axillary sentinel lymph node involvement and involvement of a localized bone lesion at the time of diagnosis, in the absence of extensive bone marrow involvement or splenomegaly.
In summary, we report two unusual cases of lymphoma involving the breast that presented diagnostic challenges. In the case of seroma-associated ALK-negative ALCL, the presence of malignancy was unsuspected clinically and was initially overlooked, but the clinical findings of a long-standing breast implant complicated by recurrent peri-implant seroma formation fit the clinical profile of an emerging diagnostic entity, and repeat cytologic evaluation with an appropriate panel of immunohistochemical stains led to the correct diagnosis. In the case of hairy cell leukemia, the patient presented with clinical findings suggestive of metastatic carcinoma rather than lymphoma. Careful attention to the concomitant diagnosis of hairy cell leukemia involving other sites helped to avoid a misdiagnosis of invasive carcinoma. Both cases illustrate the importance of performing a careful and thorough clinical and pathological evaluation when considering a diagnosis of a rare lymphoma subtype involving the breast.