Advances in Anatomic Pathology:
Department of Pathology and Laboratory Medicine, University of Florida College of Medicine, Jacksonville, FL
The authors have no funding or conflicts of interest to disclose.
Reprints: Shahla Masood, MD, Department of Pathology and Laboratory Medicine, University of Florida College of Medicine, 655 West 8th St., Box C-505, Jacksonville, FL 32209 (e-mail: email@example.com).
Prominent lymphocytic periductal inflammation has been previously described in association with diabetes mellitus type I and II, other autoimmune diseases such as lupus, thyroid disease, and connective tissue abnormalities, and even lymphomas. When incidentally detected in a breast biopsy and without evidence of systemic disease in the patient’s history, it may be prudent to alert the treating clinician to the possibility of an underlying systemic disease process, in order to ensure recognition and appropriate clinical follow-up for these patients. The purpose of this review is to familiarize the reader with this commonly encountered incidental feature on breast biopsies and to emphasize the importance and clinical implications of recognizing possible underlying systemic disease and communicating these findings to the treating physicians.
In our practice, we frequently encounter cases with the incidental finding of isolated perilobular and periductal lymphoplasmacytic inflammation, which can clinically be correlated to an underlying systemic disease, most commonly diabetes and thyroid disease.
We recently encountered a case exemplifying this situation. A 45-year-old lady with a suspicious screening mammogram underwent stereotactic core-needle biopsy. Pathologic evaluation of the biopsy revealed benign breast tissue with focal microcalcifications and extensive periductal and perilobular chronic inflammation (Fig. 1) suggestive of diabetes mellitus or other autoimmune disease. To alert the clinician to the possibility of an underlying systemic disease that may need clinical follow-up, a comment was added to the final diagnosis of the benign breast biopsy. The patient was subsequently diagnosed with diabetes mellitus, thereby allowing early treatment and care. Had the clinician not been alerted, the patient may not have been diagnosed until more severe symptoms arose with more serious clinical consequences.
Lymphocytic mastopathy with prominent lobulocentric periductal lymphocytic inflammation has previously been described in association with diabetes mellitus type I1–3 and II,3–5 other autoimmune diseases such as lupus erythematosus,6,7 thyroid disease,1,8 connective tissue abnormalities,1 and even lymphomas.9,10 Isolated periductal or perilobular mononuclear inflammatory infiltrate seems to be a very early stage of this disease process and is not uncommonly seen on breast biopsy material.
The etiology of lymphocytic mastopathy secondary to autoimmune diseases has yet to be completely elucidated, but multiple authors have suggested a possible autoimmune pathogenesis.1,11 The following is a review of the association reported between diabetes, lupus, thyroid disease, and lymphoma with lymphocytic inflammatory changes in breast biopsies.
Diabetic mastopathy, first described by Soler and Khardori in 1984,1 is a fibroinflammatory breast lesion, which is typically seen in patients with long-standing type I diabetes,2 but can also occur in type II diabetes with or without end-organ manifestations.3–5 It is thought to be secondary to an autoimmune reaction to the extracellular accumulation of abnormal matrix and advanced glycosylated end products induced by hyperglycemia, which act as “neoantigens” resulting in B-cell proliferation and autoantibody formation.1,11 The inflammatory infiltrates are composed of lymphocytes and variable amounts of plasma cells; immunostaining for B-cell and T-cell markers demonstrates a reactive pattern with B-cell predominance.11,12 Diabetic mastopathy may present as a palpable breast mass that is histologically characterized by dense keloid-like fibrosis associated with periductal, perivascular, or perilobular lymphocytic inflammation.2 Because the lesions seem to progress through stages with earlier stages characterized by a heavy inflammatory infiltrate and later stages characterized by increased fibrosis and decreased inflammation,8 the incidental presence of isolated periductal mononuclear inflammation in a biopsy may represent an early stage of this disease process, potentially allowing the timely recognition of diabetes in breast biopsies.
Lupus mastitis is a rare presentation of lupus erythematosus profundus or lupus panniculitis with <25 reported cases in the literature. The pathophysiology of lupus mastitis is thought to be autoimmune related, supported by evidence of immune complexes found at the basement membrane of the vasculature and the dermal-epidermal junction of the overlying skin of affected areas13 as well as improvement with immunosuppressive therapy.6 It may present clinically as a palpable breast mass and has distinct histologic features including lymphocytic lobular panniculitis with nodular, diffuse, or periductal lymphoplasmacytic infiltrates, hyaline fat necrosis, and lymphocytic vasculitis.7 Immunohistochemical studies demonstrate a mixed population of inflammatory cells indicating a reactive process. This periductal infiltrate is very similar to that seen in diabetic patients; however, the lymphocytic infiltrate in lupus mastitis is usually more extensive than in patients with diabetes. Although lupus mastitis is mostly seen in patients with known history of systemic or discoid lupus, it may be the initial presentation of lupus in others,6 especially when only periductal lymphocytic inflammation is seen on a breast biopsy.
Almost half the patients in Soler’s original case series on diabetic mastopathy also had thyroid gland abnormalities and high titers of antimicrosomal antibodies suggesting an immunologic link that may be implicated in the pathogenesis of the inflammatory breast lesions.1 Lammie et al8 reported a case series of lymphocytic mastopathy in which one patient had known thyroid microsomal antibodies and type I diabetes and another patient later developed Hashimoto disease. This demonstrates that the perilobular inflammatory infiltrates seen on a breast biopsy may be an early indicator of autoimmune thyroid disease and is likely underdiagnosed. Early recognition may have tremendous impact on the patient’s disease process.
An abundant periductal lymphocytic infiltrate may raise the differential diagnosis of lymphoma. Aozasa et al9 described 19 cases of mammary lymphoma, of which most cases were B-cell lymphomas and were associated with coexisting or antecedent lymphocytic mastopathy. Molecular and immunophenotypic studies by Valdez et al12 demonstrated no increased risk of mammary B-cell lymphoma in patients with lymphocytic mastopathy despite the marked B-cell infiltrates and frequent presence of lymphoepithelial lesions. Immunostaining can be helpful in differentiating lymphoproliferative disorders from a reactive benign process such as lymphocytic mastopathy secondary to autoimmune processes (Fig. 2).
As previously described, these breast lesions seem to progress through stages with earlier stages characterized by a heavy inflammatory infiltrate and later stages characterized by increased fibrosis and decreased inflammation.8 Many of these reports on lymphocytic and diabetic mastopathy reflect cases in which breast biopsies were taken for palpable breast masses. This indicates that these lesions most likely represent relatively late stages of this disease process in which fibrosis is dense enough to present as a mass. In contrast, our current case represents an early stage of this same process in which there is only incidental lymphoplasmacytic inflammation without the sclerotic component. This kind of isolated periductal and/or perilobular lymphocytic infiltrate is often seen in patients with known diabetes or other autoimmune disease and therefore should encourage correlation with the patient’s clinical history. When no evidence of systemic disease is found in the patient’s history, it may be advisable to communicate the possibility of an underlying systemic disease process to the clinician in order to ensure appropriate clinical follow-up for the patient.
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