Mammary Gland Sarcoidosis

Abstract

Sarcoidosis is a benign systemic granulomatous pathology of unknown etiology. Mammary involvement is rare, less than 1% of all cases. That is the reason that makes necessary an optimal differential diagnosis to rule out malignant pathology as the main diagnosis. Imaging tests such as mammography, ultrasound, or MRI contribute to the diagnosis but are unable to establish a certain diagnosis. When a mammary sarcoidosis is suspected by fine needle aspiration cytology, exceptional procedures are necessary to confirm the disease and to exclude a coexisting carcinoma. Malignancy may develop in patients with sarcoidosis, sarcoidosis may develop in patients with breast cancer, the two diseases may develop in tandem, or breast cancer may cause a sarcoidosis-like granulomatous response. Other illnesses that should rule out are granulomatous diseases, which could be differentiated into infectious causes such as tuberculosis and primary inflammatory diseases such as idiopathic granulomatous mastitis. The silicone of gel breast implants may originate a sarcoidosis-like reaction as the result of an acceleration of an already existing hypersensitivity response, resulting in breast sarcoidosis. The management of sarcoidosis in the breast is usually enough with an excisional biopsy. The prognosis of mammary sarcoidosis in not unknown.

1. Introduction

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology [1]. Our knowledge of the pathogenesis of sarcoidosis has improved and provided more potential causes of this pathology. Any adjuvant agent of sarcoidosis must be able to cause noncaseating granulomas that are the pathologic hallmark of the disease accompanied by a heterogeneous clinical features [2].

The origin is the failure of the cellular immune response after exposure to an environmental, occupational, or infectious hazard and may affect multiple organs, inclusive breast tissue [3].

Almost 80–90% of patients have lung or hilar lymph nodes affected. These are the most frequent organs involved. Although, the effect on the eyes, skin, nervous system, locomotors system, lacrimal and salivary glands, heart, locomotors system, and kidney in sarcoidosis has also been described [1]. Sarcoid involvement of the mammary gland parenchyma has been extremely infrequent in patients with this pathology, less than 1% of the overall diagnosed patients. African American, Afro-Caribbean, Swedish, and Danish individuals are more frequent affected. It is more common in women in their third and fourth decade of life and may often seem to be breast carcinoma [4].

The descriptions of mammary gland sarcoidosis differ from nodules with ill-defined margins or spiculated as observed in malignant tumors, negative imaging, or other nonspecific appearances [3]. The most common symptom is a palpable breast lesion. Because sarcoidosis can mimic breast cancer, it makes the differential diagnosis necessary and not easy [3].

2. Etiology

Sarcoidosis was first described more than 100 years ago, and since then its origin is uncertain, the etiologic determinants causing this disease remain uncertain. The bibliography suggests that host immunologic, genetic, and environmental adjuvants interact together to develop sarcoidosis. The most typical immunological characteristic is noncaseating granulomas, promoting local expression of T helper-1 (and Th17) cytokines and chemokines, dysfunctional regulatory T-cell responses, dysregulated Toll-like receptor signaling, and oligoclonal proliferation of CD4+ T cells consistent with chronic antigenic stimulation. A lot of environmental adjuvants have been proposed to be the origin of sarcoidosis.

Publications of several groups associate mycobacterial or propionibacterial organisms in the etiology of sarcoidosis based on tissue analyses and immunologic responses in sarcoidosis patients. Despite the studies, there is no agreement on the origin of a microbial pathogenesis of sarcoidosis. Others groups postulate that sarcoidosis is caused by an active viable replicating infection, while other groups contend there is no clinical, pathologic, or microbiologic evidence for such a pathogenic mechanism [2]. The authors postulate a new hypothesis that proposes that sarcoidosis is triggered by a hyperimmune Th1 response to pathogenic microbial and tissue antigens associated with the aberrant aggregation of serum amyloid A within granulomas, which promotes chronic granulomatous inflammation with no infection.

3. Clinical manifestations

In the mammary gland, the symptomatology is a breast mass that could be unique or multiple and unilateral or bilateral. Patients do not present infectious or inflammatory symptoms with no effect on the skin. Moreover, the masses are not painful. During the examination it is important not to forget systemic symptoms than can orient our diagnosis because although breast sarcoidosis may be the first affected organ, most of the times the diagnosis is already done.

4. Diagnosis

The symptomatology of sarcoidosis is strongly related to the extent of granulomatous inflammation and the function of the affected organs.

To make a correct diagnosis and establish a correct treatment are very important to assess the impact of sarcoidosis in the organs functions, as well as the impact on quality of life to avoid premature death.

In the mammary gland, the most common symptom is a breast nodule, single or multiple. It is essential to make a differential diagnosis. Starting with the physical examination, usually finding a nontender, firm, and mobile lesion, with a normal nipple. Sometimes it may have axillary lymphadenopathy and other times the mass is fixed, tender, and suggests a carcinoma instead a benign lesion.

Continuing with the study, the next step is the imaging techniques. The first one usually is the mammography that shows a nonspecific, ill-defined lesion with low density, poorly outlined without microcalcifications. There are no definite patterns on ultrasound, so it does not lead to a definitive diagnosis, but we can point out the irregularity of the contours, hypoechoic spiculation, and nonhomogeneous internal echostructure of the nodule (Figure 1) [5].

Figure 1.

Ultrasound test with two nonspecific hypoechoic nodules.

The high-field system MR is complementary to the previous ones. Images can show the nodule to be an isolated signal-intensive inhomogeneous tumor with irregular contours, fast contrast enhancement, and an early “washout” phenomenon often observed in carcinomas or in inflammatory lesions of the breast. Therefore, we must not forget that imaging test does not offer a definitive diagnosis, and we must confirm it with pathological studies.

Also you may rule out infection origin, performing microbiologic test as stains for acid-fast bacilli and fungi.

The pathological study of a biopsy of the breast demonstrates chronic granulomatous inflammatory process, with epithelioid granulomas and non-necrotizing giant cells (Figure 2).

Figure 2.

Chronic granulomatous inflammatory process, with epithelioid granulomas and non-necrotizing giant cells.

Breast sarcoidosis is very rare; generally, a fine needle biopsy is not enough, and an excisional biopsy is necessary to confirm the diagnosis.

The diagnosis is suspected by the typical radiologic manifestations and supported by histologic evidence of noncaseating granulomas in the absence of infection and exclusion of other types of granulomatous affections [6].

5. Differential diagnosis

We should rule out some diseases before the diagnosis of sarcoidosis in the breast (Table 1).

Neoplasia	Benign	Fibroadenoma
		Cyst
		Fibrocystic changes
		Galactocele
		Breast abscess
		Radial scar
		Fat necrosis
		Fibrosis
		Diabetic mastopathy
	Malignant	Invasive carcinoma
		Breast lymphoma
		Metastasis
Granulomatous disease	Infectious causes	Tuberculosis
		Fungal infections
		Actinomycosis
		Histoplasmosis
	Inflammatory diseases	Wegener’s granulomatosis
		Idiopathic granulomatous mastitis

Table 1.

Differential diagnosis of breast sarcoidosis.

5.1 Malignant pathology

The most important and the most frequent is malignant pathology of the breast. The American Cancer Society (ACS) estimates that almost 300,000 women will receive a diagnosis of malignant breast per year. A breast mass is suspicious until proven otherwise. The first step is imaging test such as mammography, ultrasound, and MRI.

As we have described, there are no pathognomonic patterns in the imaging test for sarcoidosis in mammary gland, and it is the same with breast cancer.

Thus, we need to confirm the diagnosis after those techniques; we should perform pathological test and immunohistochemistry to confirm the definitive diagnosis, prognosis criterion, and treatment.

5.2 Idiopathic granulomatous mastitis (IGM)

Idiopathic granulomatous mastitis is an infrequent, chronic, and benign breast pathology, which may imitate mammary gland abscess, cancer, or other granulomatous diseases. Most patients present in the third or fourth decade of life, and it typically is seen in women of childbearing potential from 6 months to 6 years postpartum. It is a diagnosis of exclusion and requires a high index of suspicion [7, 8].

Usually the first diagnose is bacterial mastitis, scheduling multiple antibiotic regimens. When those treatments are not successful, an inflammatory breast cancer is suspected, thus no healing breast nodules. Imaging test and fine needle biopsy for pathological study are not enough to confirm the diagnosis, and an excisional biopsy is mandatory.

Idiopathic granulomatous mastitis is an exclusion diagnosis. Made after demonstration of granulomatous inflammation on mammary gland biopsy and excluding other granulomatous diseases, such as tuberculosis and sarcoidosis.

In sarcoidosis, the most frequent affectation is lung disease (90%), that is why when you suspect a granulomatous disease, you need to rule out this pathology with a chest X-ray, which confirms that no presence of hilar lymphadenopathy [8].

Many cases do not need any treatment and resolve themselves. When an extensive breast affectation exists for a long time with no clinical improvement, other treatments are necessary such as methotrexate, corticosteroids, or surgical excision.

5.3 Tuberculosis

Breast tuberculosis is a pathology characterized by the presence of granulomas. This disease is unusual in Europe, it only presents 0.1% of all mammary gland tumors, but in endemic areas, it increases until 4.5%. Is necessary to rule out other breast pathologies such as abscess, sarcoidosis, idiopathic granulomatous mastitis, or a malignant lesion.

Risk factors for the development of breast TB include lactation, multiparty, immunosuppression, and previous exposure to TB [9, 10].

Usually the main symptom is a single mass; with minor infection or inflammation than in other infectious mastitis. Diagnosis of breast tuberculosis is not easy. Most of the times multiple clinic consultations and tissue biopsies are necessary, Ziehl-Neelsen stain and QuantiFERON-TB Gold test should be performed to help differentiate between breast sarcoidosis and tuberculosis. That is the reason why the treatment is delayed [11].

5.4 Sarcoidosis-like reaction

An event known as autoimmune/inflammatory syndrome triggered by adjuvants might be caused by the combination of silicone implants and sarcoidosis-like reaction with a strange body granulomatous response. Silicone acts as an immunologic adjuvant to generate antigen-specific immune response that causes the proliferation and activation of B and T cells [12].

There are others cases published in the bibliography that report this type of reaction, it may appear in the breast skin, subcutaneous tissue, axillary lymph nodes, and brain, spinal cord, or digestive tract. The pathophysiological mechanism remains unclear. The first hypothesis is a direct granulomatous reaction against silicon particles following extensive systemic dissemination. Finding local granulomatous reaction to silicone after implant rupture and systemic dissemination of silicone gel. The other hypothesis is a full-blown sarcoidosis triggered by silicon as an external adjuvant, in a predisposed patient, which could be included in the context of an autoimmune syndrome induced by adjuvant [13].

5.5 Sarcoidosis mimicking metastatic breast cancer

Sarcoidosis commonly affects the lungs; however, any organ can be involved.

In patients with a history of a malignant disease, when an abnormal nodule is observed in imaging studies, the tendency is to suspect a metastatic lesion. Some studies suggest an increased incidence of sarcoidosis in the event of malignancy and its treatment. Malignancy itself is immunosuppressant; chemotherapy might downregulate sarcoidosis [14, 15]. In addition, an infection acquired during chemotherapy might lead to a sarcoidosis activation.

Other authors propose that a tumor antigen(s) might be the triggering and oligoclonal T-cell hyper-reactivity toward granulomatous disease.

6. Treatment

The treatment of mammary gland sarcoidosis is usually the same as systemic sarcoidosis. To confirm the diagnosis, most of the times, we need an excisional biopsy. When there are no other symptoms, systemic treatment is not necessary.

Conflict of interest

The authors declare no conflict of interest.