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Abstract

Despite tremendous efforts placed on advances in diagnosis and treatment of the spectrum of breast disease, the impact of systemic diseases on the breast has remained under recognized. Distinction between a variety of benign breast diseases versus those that are manifestations of a systemic disease is critically important for appropriate treatment planning and follow-up of patients. This article is designed to provide an overview of different systemic diseases that can present as a breast lesion. Attempts are made to highlight the significance of the distinction between benign breast disease versus benign conditions that present as the result of a systemic disease. Naturally, distinction between any benign condition versus breast carcinoma is a part of the evaluation process.

Keywords

autoimmune disease breast lesions HIV infection metastatic disease systemic disease

Similar to the spectrum of changes of benign, premalignant and malignant breast disease, systemic disease may manifest as a palpable lesion, an image-detected abnormality or present with skin changes and/or breast pain. Familiarity with clinical imaging and morphologic features of systemic disease in the breast is most useful in rendering an accurate diagnosis and recommending an appropriate follow-up therapy. In addition, this recognition may potentially alleviate the anxiety of a patient when the diagnosis of a primary breast cancer is excluded. It is generally known that aside from localized infectious and inflammatory processes, the breast can be involved in a variety of systemic diseases as the result of a generalized illness. Although manifestations of systemic disease may be rare, their occurrence is an alarming experience. This is best exemplified by the increasing number of tuberculosis cases related to HIV infection. Mammary tuberculosis has even been reported in a patient who was not initially known to be seropositive for HIV and was thought to have a pyogenic breast abscess. In this case, further analysis of mycobacterial smears, culture and serology for HIV infection resulted in an accurate diagnosis. Therefore, awareness of the association between systemic processes with localized breast mass of an unusual nature is an important step in the accurate characterization of breast lesions [1].

Hematologic disorders

Lymphoma

Lymphoproliferative disorders rarely involve the breast, manifesting either as a primary lesion or as part of a generalized process. The frequency of primary breast lymphoma is variable, ranging from 0.12 to 0.53% of all malignant breast tumors [2 –4]. Primary lymphoma may originate from a migratory lymphocyte or arise within an intramammary lymph node. It occurs in patients of all ages, ranging from 9 to 88 years of age, with a median of 50 years of age. The majority of patients present with a unilateral, palpable mass [4]. Patients with primary lymphoma complain of pain and may suffer from night sweats, fever and weight loss. The lesion may be multiple and can cause skin changes similar to those seen with breast carcinomas. Axillary lymph node involvement is seen in 30–40% of patients with primary breast lymphoma [5]. Mammographically, lymphoma presents as a relatively circumscribed mass, focal or diffuse densities, or discrete nodules with irregular margins and no evidence of calcification or retraction [6].

Grossly, the tumors seen in primary breast lymphoma are well defined, fleshy, with a tan to gray coloring and has an average size of 2–3 cm. Microscopically, the histologic features of primary breast lymphoma are similar to those of primary nodal involvement. Tumors occurring in pregnant and lactating women correspond to Burkitt's-type lymphoma [7]. Morphologic distinction between primary lymphoma and secondary involvement is impossible. Lymphomas of the breast are frequently diffuse, large B-cell types [8].

The prognosis of primary lymphoma of the breast depends on the stage of the disease and the histologic type of the tumor. For example, lymphoblastic-type lymphoma of the breast progresses rapidly to leukemia and requires aggressive chemotherapy [9]. While some investigators believe that primary breast lymphomas have a poor prognosis [10,11], some believe that the prognosis for these tumors is comparable with that for other localized extranodal lymphomas. The recommended treatment for primary breast lymphoma is debulking surgery followed by combination chemotherapy with and without radiation therapy [12].

Hodgkin's disease

Hodgkin's disease only rarely involves the breast. In a comprehensive review of 2365 patients with Hodgkin's disease, Meis et al. reported only four cases of recurrent Hodgkin's disease of the breast [13]. Recurrent Hodgkin's disease in the breast or chest wall is probably caused by spread along the intramammary or internal mammary lymph nodes or via direct mediastinal extension to the chest wall. Patients with Hodgkin's disease who undergo radiotherapy and/or chemotherapy have an increased risk of breast carcinoma. Therefore, it is important to distinguish between a recurrence, a second primary malignancy and benign breast disease in a patient treated for Hodgkin's disease [14 –16].

Granulocytic sarcoma (chloroma)

A rare manifestation of granulocytic leukemia, granulocytic sarcoma or chloroma is an uncommon localized tumor composed of immature myeloid cells occurring in an extramedullary site [17]. This tumor often develops during the course of myeloid leukemia. However, rarely, it may precede evidence of leukemia on peripheral blood or bone marrow studies by months or possibly years. The tumor may involve any tissue or organ [17 –19]. It is unusual for granulocytic sarcoma to involve the breast, as was shown in an extensive autopsy study performed on patients with myelogenous leukemia [20]. In the few reported cases of leukemia involving the breast, the granulocytic sarcoma mimicked a primary breast tumor both clinically and mammographically [21,22].

Lymphoproliferative disorders

Plasmacytoma

Extramedullary plasmacytoma, an extremely rare occurrence in the breast, is an unusual presentation of myeloma [23,24]. It has also been reported in patients with no evidence of systemic disease [25]. However, such patients should be followed with serologic and immunologic studies for early detection of multiple myeloma. Our experience is limited to one fine-needle aspiration biopsy (FNAB) diagnosis of localized plasmacytoma in the breast. The predominant cytologic features were plasma cells isolated and in aggregates, atypia and binucleated cells. Immunostains on cell-block preparations showed evidence of monoclonality. The patient developed multiple myeloma 7 months after the diagnosis of plasmacytoma by FNAB [26]. Other conditions to be considered in the differential diagnosis are lesions characterized by tumor cells with eccentric nuclei, such as colloid carcinoma and the small cell variant of infiltrating duct cell carcinoma that occurs in older women. The presence of mucin in a background of colloid carcinoma and the coarse chromatin pattern seen in infiltrating duct cell carcinoma may facilitate correct diagnosis. Confirmation of monoclonality by immunocytochemistry and flow cytometry also eliminates other possibilities [26].

Sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease)

Sinus histiocytosis with massive lymphadenopathy or Rosai–Dorfman disease (RDD) occurs mostly in children but may present at any age. Approximately one-third of patients with RDD have extranodal manifestation. Only a few cases have occurred in the breast. The patients were young and of black race, and other sites were also involved [27]. An aspirate from one patient with RDD who presented with a palpable breast lesion and had no evidence of a lymphoproliferative disorder contained a polymorphic population of lymphoid cells with frequent plasma cells and lymphohistiocytic aggregates. The histiocytes had abundant cytoplasm with vesicular nuclei, prominent nucleoli and slight atypia. The diagnosis of RDD was suggested by FNAB and confirmed by histologic findings. A diagnosis of RDD as a localized lesion in the breast should alert the clinician to the possibility of systemic involvement [28].

Metastatic breast disease

Metastatic carcinoma

Unlike metastases from the contralateral breast, the incidence of metastatic tumors from extramammary sites is extremely low and accounts for only 0.4–2.0% of clinically observed breast malignancies. In autopsy studies, the incidence varies from 1.4 to 6.6% of patients with malignant breast tumors [29 –31]. In the largest series reported by Hajdu and Urban at Memorial Hospital in New York, metastatic tumors of the breast accounted for 1.2% of all breast malignancies, with 44 women and nine men affected [32]. As in other studies, the most common extramammary primaries in women were, in order of decreasing frequency: melanoma, lymphoma, lung carcinoma, ovarian carcinoma and soft tissue sarcoma, followed by gastrointestinal and genitourinary primaries. Studies have shown that melanoma and prostate cancer are the most common extramammary cancer sites reported in men [33 –35,101,102].

The clinical presentation of metastatic carcinoma is similar to that of primary cancer; however, nipple retraction and discharge are not observed. The lesion is usually well defined, firm and often movable. Axillary lymph node involvement is seen only when the metastatic tumor is in the axillary tail of the breast or when lymphoma or leukemic processes involve breast and lymph nodes simultaneously. Metastatic breast tumors have a variable mammography appearance, ranging from an appearance similar to that of benign breast lesions, such as cysts, fibroadenomas or proliferative breast disease, to an appearance similar to that of malignancies, such as medullary carcinoma [31].

The prognosis for patients with metastatic breast tumor is often poor, with 80% of patients dying within 1 year of diagnosis [29 –32]. Patients with malignant lymphoproliferative disorders respond to chemotherapy and live longer [36]. Overall, the average age of patients with metastatic breast tumor is younger, usually under 50 years of age compared with the average age of patients with primary breast cancer [37]. This may be due to the better blood supply in younger age groups, which may predispose the breast to be a site of metastasis. Histologically, metastatic breast tumors can simulate primary breast cancer, leading to mastectomy [38]. Necrosis, calcification and in situ lesions are not typical histologic findings in metastatic breast carcinoma. Metastatic tumors are characteristically well demarcated and show evidence of periductal infiltration. Cytomorphologic differentiation between primary and metastatic breast disease is also difficult. Poorly differentiated adenocarcinoma, in particular, is easily confused with ductal carcinoma. Nonetheless, when combined with appropriate clinical history and the use of ancillary studies, a minimally invasive sampling procedure, such as FNAB, is an effective tool in the diagnosis of a metastatic tumor of the breast [39]. However, occasionally, distinction between primary and metastatic breast tumors may require surgical biopsy for definitive diagnosis [40].

Autoimmune disorders

Diabetic mastopathy

Diabetic mastopathy often presents as a nontender palpable breast mass that can be single or multiple in either breast or seen as a bilateral disease [41]. Mammographic features of diabetic mastopathy are not specific and often mimic carcinoma. MRI has no role in establishing the diagnosis of diabetic mastopathy; the ultimate diagnosis is made via tissue sampling [42].

Diabetic mastopathy occurs in up to 13% of patients with Type 1 diabetes [42,43]. It rarely presents in older women with long standing Type 2 diabetes mellitus [44]. The etiology of diabetic mastopathy is poorly defined; however, it is suggested that it is secondary to an autoimmune reaction to the extracellular accumulation of abnormal matrix and advanced glycosylated end products induced by hyperglycemia, which acts as neoantigens resulting in proliferation of lymphoid cells of the B-cell type and autoantibody formation [45,46]. The inflammatory infiltrate are composed of lymphocytes and variable amounts of plasma cells. Immunostaining for B- and T-cell markers demonstrates a reactive pattern with B-cell predominance [46,47]. Diabetic mastopathy progresses from the early stage of hyperglycemia inflammatory infiltrate to later stages of the disease characterized by increased fibrosis and decreased inflammation [48]. An incidental presence of isolated periductal mononuclear inflammatory cells in a biopsy may present at an early stage of this disease process, potentially allowing early recognition of diabetes mellitus in breast biopsies [49]. There are no suggested strategies to prevent the development of diabetic mastopathy [42]. Associated with the clinical history of diabetes, excision of diabetic mastopathy is not necessary. This diagnosis is incredibly important in the subsequent management of patients with diabetic mastopathy as tissue biopsy may not be required if a similar abnormality is observed later in life. Minimizing the number of tissue biopsies in patients with diabetic mastopathy will also eliminate the consequence of delayed wound healing and infection following tissue sampling that is commonly seen in these patients.

Diabetic mastopathy may also be associated with thyroid gland abnormalities. It is suggested that high levels of antimicrosomal antibodies induce an immunocytic link that may be implicated in the pathogenesis of inflammatory changes in breast cancer [45]. There are reported case series of lymphocytic mastopathy in patients with known thyroid microsomal antibodies, Type 1 diabetes and Hashimoto thyroiditis [48]. This demonstrates that the perilobular inflammatory infiltrates seen on a breast biopsy may be an early indication of autoimmune thyroiditis. Early diagnosis of this entity may impact a patient's management.

Sarcoidosis

Sarcoidosis is a systemic granulomatous inflammation with no known etiology that can involve multiple organs such as the lymph nodes, lung, skin and joints. The breast is rarely affected by systemic sarcoidosis. It can present as a palpable breast mass or be seen on a mammogram [50]. Breast imaging by mammography and ultrasound often present with a mass, asymmetric density or architectural distortion simulating malignancy [51,52].

Cellular tissue diagnosis is necessary for confirmation of diagnosis after other possibilities, such as idiopathic granulomatous mastitis, tuberculosis, cat-scratch disease, fungal infection and other autoimmune diseases are excluded [52]. The recommended therapy is administrating corticosteroids [51].

Lupus

Lupus mastitis is a rare manifestation of systemic lupus erythematosus profundus or lupus panniculitis. It is considered an autoimmune disorder that responds to immunosuppressive therapy [53]. It often presents as single or multiple subcutaneous modules that may be tender or painful or become ulcerated. Breast imaging may show areas of calcification [54]. It is morphotypically characterized by lymphocytic lobular panniculitis with nodular, diffuse and periductal lymphoplasmacytic infiltrate, hyaline fat necrosis and lymphocytic vasculitis [54]. Rarely, these features in a breast biopsy may be the initial presentation of this disease. Clinically, they may respond to antimalarial agents or corticosteroid therapy. In cases refractory to therapy, surgery may become an option [53].

Wegener's granulomatosis

Wegener's granulomatosis may present as unilateral or bilateral palpable breast lesions with necrosis, abscess formation and ulcerations [55,56]. Breast imaging findings are nonspecific and diagnosis is made based on clinical history and tissue biopsy. Pathologic analysis often shows vasculitis of the medium-sized vessels in association with necrosis and granulomatosis inflammation [57]. Immunosuppressive therapy is the initial therapeutic approach. In refractory cases, mastectomy may be considered [55,58].

Giant-cell arteritis

As a rare entity, giant-cell arteritis may occur in postmenopausal women and present as single or multiple breast lesions with occasional redness and tenderness. It may be associated with systemic symptoms such as low-grade fever, myalgia and arthralgia [59]. Definitive diagnosis is made by tissue biopsy. Occasionally, clinical presentation and a halo sign by ultrasound may be helpful [55,60]. Pathology shows disruption of the elastica, giant-cell infiltration and thickening of the vessel walls. Administration of corticosteroid therapy is the treatment of choice [59].

Polyarteritis nodosa

As a systemic inflammatory disorder, polyarteritis nodosa may rarely involve skin and/or parenchyma of the breast mimicking malignancy or mastitis. Mammography may present with calcification of arteries or show no abnormalities [61]. On tissue biopsy, polyarteritis nodosa demonstrates evidence of segmental transmural inflammation of muscular arteries, inflammatory infiltrate and areas of fibrinoid necrosis [62]. Debridement of localized necrotic tissue and immunosuppressive therapy are considered effective [63].

Amyloidosis

This rare entity is a localized manifestation of systemic amyloidosis and can present as a breast mass or abnormal mammographic findings. Microscopically, hyaline amorphous material positive for congo-red stain for amyloidosis confirms the diagnosis [64,65].

Infectious disease

HIV infection

Reports in the literature have defined a spectrum of changes that directly and indirectly affects breast tissue among HIV-positive patients. These include changes in glandular, mesenchymal and intramammary lymphoid tissue, as well as involvement with infectious agents [66 –68]. Aside from tuberculosis, other associated infectious agents such as cryptococcosis, Molluscum contagiosum, Salmonella and Pseudomonas aeruginosa may present as skin lesions or a breast abscess [66 –70]. HIV-infected patients are also at an increased risk for development of several infectious-related cancers, such as those associated with Epstein–Barr virus and lymphoma. This effect is believed to be primarily mediated by lowered host immunity because of the depletion of CD4⁺ cells [71].

In a retrospective study of 46 individuals with a 9 year follow-up, Pantarowitz et al. in 2002 reported the spectrum of benign breast disease, atypical lesions and breast cancers among HIV-infected patients [66]. They found that HIV-related disease occurs more commonly in women. In men, gynecomastia was detected in 56% of patients, which was believed to be the result of antiretroviral therapy.

The incidence of breast carcinoma among HIV-infected women is reported to be lower than the general female population [72 –74]. It has been suggested that breast cancer in the setting of HIV disease is associated with a more aggressive clinical course and poorer outcome [75]. However, these findings have remained controversial [76,77]. In addition, the accelerated aging process of HIV-infected women may warrant the discussion of earlier mammography screening for these women, as they may be susceptible to developing breast cancer earlier in life when compared with the general population [78].

Future perspective

In recent years, increased public breast cancer awareness and the widespread use of mammography screening have resulted in an increased number of tissue biopsies for assessment of clinically or image-detected abnormalities. More women seek consultations for breast lesions that would not have been evaluated in the past. The abovementioned changing trends have resulted in the recognition of the spectrum of pathological changes that are manifestations of various system disorders rather than a primary breast abnormality. These lesions occasionally may simulate breast cancer both clinically and by breast imaging. Therefore, it is critically important to emphasize the significance of correctly identifying these entities. The distinction between primary breast lesions and those related to systemic disease requires careful attention to the clinical history of each patient. There is no doubt that integrating clinical presentations, breast imaging findings and pathologic features into clinical practice is the key to our ability to accurately diagnose and treat our patients.

Executive summary

There are various systemic disorders that may present as a breast mass and/or abnormal imaging findings that require distinction from the various spectrum of benign and malignant breast disease.

Systemic disorders affecting breast tissue include hematologic disorders, lymphoproliferative disorders, metastatic breast disease, autoimmune processes and infectious processes.

Distinction between manifestations of a systemic disorder on breast tissue and those occurring as primary breast disease is clinically important. As an example, a variety of primary benign entities of breast origin diagnosed by needle biopsy may require surgical excision of the lesion. By contrast, conditions, such as diabetic mastopathy, require no follow-up surgical intervention.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Characteristics of Systemic Diseases in the Breast: Clinical,Imaging and Pathologic Features