Morphological features in granulomatous mastitis: A window to the etiopathogenesis

Ravi Pratap Singh; Meetu Agrawal; Neha Kwatra Madan; Charanjeet Ahluwalia; Megha Tandon

doi:10.4103/ijhi.ijhi_4_20

ORIGINAL ARTICLE

Year : 2018 | Volume : 7 | Issue : 1 | Page : 1-7

Morphological features in granulomatous mastitis: A window to the etiopathogenesis

Ravi Pratap Singh¹, Meetu Agrawal¹, Neha Kwatra Madan¹, Charanjeet Ahluwalia¹, Megha Tandon²
¹ Department of Pathology, Vardhman Mahaveer Medical College & Safdarjung Hospital (VMMC & SJH), New Delhi, India
² Department of Surgery, Vardhman Mahaveer Medical College & Safdarjung Hospital (VMMC & SJH), New Delhi, India

Date of Submission	30-Jun-2020
Date of Decision	20-Oct-2021
Date of Acceptance	27-Oct-2021
Date of Web Publication	11-Mar-2022

Correspondence Address:
Meetu Agrawal
Department of Pathology, Vardhman Mahaveer Medical College & Safdarjung Hospital (VMMC & SJH), New Delhi.
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/ijhi.ijhi_4_20

Abstract

Background: Granulomatous mastitis holds a special place amongst the various non-neoplastic lesions of breast. Most granulomas at various sites are thought to be and turn out to be tubercular, especially in a high tuberculosis prevalence country. However, a physiologically dynamic organ-like breast can have granulomas due to various causes, which have different therapeutic implications. Further, these lesions are usually mass-forming and close mimickers of malignancy. A careful analysis of histopathology can provide important clues to the etiopathogenesis. Aims: The aim of this study was to perform a detailed histopathological examination of cases of granulomatous mastitis and correlate it with clinical characteristics and follow-up data wherever applicable. Materials and Methods: A retrospective analysis of cases retrieved was carried out by two pathologists (RPS and MA). The morphological details were analyzed against the clinical, surgical, and follow-up data. Results and Conclusion: With careful analysis, the nature of constituent cells, relative proportion of cells and associated pathological findings can provide a clue as to the etiology of granulomas.

Keywords: Granulomatous, mastitis, plasma cell mastitis, tubercular mastitis

How to cite this article:
Singh RP, Agrawal M, Madan NK, Ahluwalia C, Tandon M. Morphological features in granulomatous mastitis: A window to the etiopathogenesis. Int J Histopathol Interpret 2018;7:1-7

How to cite this URL:
Singh RP, Agrawal M, Madan NK, Ahluwalia C, Tandon M. Morphological features in granulomatous mastitis: A window to the etiopathogenesis. Int J Histopathol Interpret [serial online] 2018 [cited 2023 Mar 25];7:1-7. Available from: https://www.ijhi.org/text.asp?2018/7/1/1/339327

Introduction

A granuloma is a reactional organization of macrophages, giant cells with a variable number of lymphocytes against offending agents (organic and certain inorganic agents). Neutrophils, eosinophils, fibroblasts, and plasma cells can also be seen in variable proportion in a granuloma. The distribution and quantification of cells in granulomas can provide a clue to the etiology.^{[1],[2],[3],[4]}

Granulomatous mastitis was first described in 1972 by Kessler and Wolloch.^[3] It is a rare benign inflammatory disease of the breast, morphologically characterized by presence of granulomas along with chronic inflammation. In the breast, granulomas could be due to infections, autoimmunity, trauma, endocrine abnormalities, sutures/foreign body, lactation, and silicone implants.^[2] Cases where a definitive cause cannot be identified are termed idiopathic granulomatous mastitis.

Clinically, granulomatous mastitis presents as firm, unilateral breast lumps, and mimic breast tumor on clinical and radiological examination. There is no universally accepted treatment for granulomatous mastitis. Treatment comprises antibiotics to treat cases with infectious etiology and steroids with/without immunosuppressive therapy in cases of suspected autoimmune etiology.^[5],[6] Other treatment option includes incision and drainage, and wide local resection. Long-standing granulomas can calcify and are even more difficult to differentiate from breast carcinoma and can lead to diagnostic dilemmas. Histopathology can provide a clue as to the etiology in many cases. Some of the important etiologies for granulomas may be summarized as follows [Table 1].

Table 1: Differential diagnosis of granulomatous lesions of the breast^[15]

Click here to view

Infections

Most commonly infections of breast are secondary to skin infections; they rarely persist almost never develop into chronic granulomatous reactions. Granulomas resulting from infections usually show central caseous necrosis as seen in tuberculosis, syphilis, histoplasmosis, cryptococcosis, and coccidioidomycosis.^[2] Tuberculous mastitis shows presence of acid-fast bacilli (AFB) in less than 25% of the cases on needle aspiration and the bacterial isolation is possible only in 25% of the cases.^[7],[8],[9] AFB positivity on histopathology is much lesser. Tuberculous mastitis was classified by McKeon into the following categories: namely (a) nodular type––most common form with small localized nodules, (b) acute military type, (c) disseminated––multiple sinuses involving the entire breast, (d) sclerosing––extensive stromal hyalinization with tissue shrinkage, clinically mimics carcinoma due to skin retraction, and (e) tuberculous mastitis obliterans––intraductal infection-causing fibrosis obliteration of ducts.^[8] In contrast, fungal granulomas are rich in neutrophils and giant cells when compared to tubercular granulomas. Often the fungal elements can be shown. Large areas of necrosis may be seen especially in immunocompromised patients.^[7],[8],[9]

Foreign body and trauma-related granulomas

Foreign material such as suture material, silicone, impacted wood, and metal shards, which cannot be broken down results in granuloma in an attempt to wall off the offending agent.^{[1],[2],[3],[4]} The foreign body can be shown on light microscopy. Traumatic granulomas are often accompanied by traumatic fat necrosis. In other cases, fat necrosis occurs superficially in breast as a result of surgery and post-radiotherapy. Incidence has increased due to increasing breast conservation surgeries. Granulomas usually show necrotic fat, surrounded by lipid-laden macrophages, giant cells, and fibrosis sealing off the necrotic debris.^[2],[3],[4]

Autoimmune diseases including plasma cell mastitis

Sjogren’s syndrome, rheumatoid arthritis, sarcoidosis are common autoimmune causes of granulomatous mastitis. The granulomas are non-caseating and comprise chronic lymphocytic infiltrate. However secondary infections may develop due to steroid therapy and can show caseation like in granulomas with infectious agents.^[10],[11] The latest addition to this category is plasma cell mastitis; many of which are now being increasingly diagnosed as a part of IgG4 related diseases.^{[10],[11],[12]}

Materials and Methods

This was a retrospective study, wherein a detailed review of demographic, clinico-radiological, and histopathology slides was done. All cases diagnosed as granulomatous mastitis or granulomatous lobular mastitis over a 5-year period (2014–2019) were included in the study.

In this hospital, patient’s presenting with breast lump are subjected to complete clinical examination, FNAC, trucut biopsy, appropriate radiology (including mammography), and lumpectomy or mastectomy as required. Same protocol had been followed for these patients as well

All core biopsy bits and/or lumpectomy specimens were formalin-fixed and paraffin embedded. Routine histopathological examination was done on H and E stained slides. Deep tissue sectioning and immunohistochemistry were done wherever needed.

Only cases with presence of granulomas were included in the study. Core biopsies with granulomas and presence of tumor (benign or malignant) and cases of acute mastitis were excluded from the study.

Results

A total of 17 cases were diagnosed as granulomatous mastitis during the study period. The age range was 22–51 years. All of them were female. Of these, two cases were excluded because of technical reasons or lack of follow-up. These cases are summarized in [Table 2]. Various representative photomicrographs are represented in [Figure 1]A–F and [Figure 2]A–E.

Table 2: Clinico-pathological summary of cases

Click here to view

Figure 1: Various histological appearances of granulomas. (A) Lobular well defined granuloma, classical intra-lobular location. (B) Dense intralobular infiltration by lymphocytes and epithelioid cells; focal epithelitis (Case 2). (C) Epithelioid cell granuloma showing numerous giant cell, lymphocytes and macrophages. (D) Necrotizing granuloma showing central neutrophilic abscess walled off by dense infiltrate of chronic inflammatory cells (Cases 4 and 6). (E) High-power view of the above necrotizing granuloma shows plasma cell rich infiltrate and a giant cell (Cases 4 and 6). (F) Loose granulomas showing edema and a large central dilated duct filled with secretions (Case 8)

Click here to view

Figure 2: Associated findings in the cases with granulomatous mastitis. (A) Apocrine change. (B) High-power view showing apocrine snouts with secretions in the duct lumen along with a few lymphocytes and macrophages. (C) Periductular hyalinization surrounded by a dense lymphoplasmacytic infiltrate. (D) Perivascular inflammation comprising of plasma cells and lymphocytes; also seen is injury to the endothelial lining and associated edema surrounding the vessel (Case 5). (E) Duct ectasia; enlarged duct associated with periductal acute inflammation. Neutrophils are also seen infiltrating the duct lumen

Click here to view

Seven of the fifteen cases (46%) showed the presence of well-formed granulomas. Few of these (2/7) had foci of caseous necrosis. The predominant cell population was lymphocytes, with numerous epithelioid cells, macrophages, and few giant cells. There was fibroblastic rimming in most of these granulomas indicating chronicity. These features are akin to tubercular granulomas seen at other sites in the body. The non-granulomatous breast parenchyma in these cases showed a non-specific periductular lymphocytic infiltrate. However, no epithelitis was seen. There were no obvious vascular changes seen.

Six out of fifteen cases (40%) showed presence of lobular mastitis with granulomatous reaction. There was dense chronic inflammation extending throughout the lobules. Five out of these six cases showed presence of numerous plasma cells in the infiltrate along with lymphocytes. Plasma cells were more numerous in these cases of lobular mastitis when compared to other granulomas in the breast parenchyma. However, these were retrospective cases and IgG4 immunostaining could not be done on these cases. None of these cases however showed obliterative arteritis or any other feature suggestive of IgG4 related disease. Two of the six cases also showed presence of superimposed acute inflammation predominantly comprising of neutrophils. Both these cases showed inspissated secretions in the large ducts (one case showed duct ectasia with neutrophilic abscesses, whereas the other showed epithelitis). There was prominent periductular fibrosis and epithelitis in one case each.

One case showed presence of sheets of plasma cells in the entire parenchyma. Plasma cells were seen in a periductular, lobular, and stromal location. There was prominent periductular hyalinization and obliterative endarteritis (vascular destruction) seen focally. There were no obvious granulomas in the main lesional area. However, periphery of the lesion at the junction of the normal breast parenchyma showed occasional granulomas. No disproportionate increase in the number of giant cells or epithelioid cells was noted. This case had a high serum IgG4 level (450 mg/dl). There were an increased number of IgG4 positive plasma cells on IHC.

Another case showed non-specific chronic mastitis with ill-formed granulomas. No specific etiology could be ascertained in this case.

Discussion

Granulomas in the breast, like at other sites are defined by the presence of microscopically identifiable circumscribed collection of lymphocytes, epithelioid cells, plasma cells, and macrophages. In addition, foreign bodies, fibrosis, organisms, and extracellular materials are few other components that may or may not be seen in variable proportion. Granuloma is still a fascinating microscopic feature for the pathologist’s eye. Their presence and the etiology behind them are of utmost importance; correct identification of the cause of granuloma is a basic requirement of therapeutic decisions.

The breast is a dynamic organ, which continues to undergo many evolutionary and involutionary changes in the reproductive cycle of a female. It is an organ that is less frequently involved by tuberculosis, the commonest cause of granulomas in the Indian subcontinent. It is rather a site of idiopathic granulomatous response.

In this study which is morphologically underlined by the presence of granulomatous response in breast, we have tried to analyze the histomorphology of these granulomas in detail. We propose that presence or predominance of certain features in contrast to others helps us to better characterize these cases.

Granulomatous mastitis is a chronic inflammation of the breast tissue which is caused due to various causes enumerated in [Table 1].^[1],[2] On histology granulomatous mastitis has varied morphology depending upon the etiology.

In the case of tuberculosis a central caseation is surrounded by macrophages which are activated and assume epithelioid morphology. These activated macrophages form giant cells in an attempt to fend off the overwhelming antigens. This focus is surrounded by a cuff of lymphocytes which in turn produces TGF-Beta to induce fibroblast recruitment. This classical morphology is observed in tuberculous infections of the breast. However, well-formed granulomas are not seen in the early stages and are affected by extent of inflammation mounted by the immune system.^[7],[8],[9] A close mimicker of tuberculosis is sarcoidosis. Sarcoid granulomas are naked granulomas without caseation and lymphocyte cuffing. Giant cells, when present have typical asteroid bodies. In our series 7 out of 15 cases showed presence of well-formed granulomas as described above, with 2 cases also showing extensive caseation.

Granulomas caused due to suture or foreign body will often show the respective material in the lesion, around which the granuloma may be centered. Foreign bodies may be seen in giant cells; usually the number of giant cells is disproportionate to the number of other constituent cells. We did not encounter any case of foreign body granulomatous response in our study.

Granulomatous lobular mastitis as the name suggests, is a granulomatous response that is centered on the lobule and comprises of a lobule centric chronic inflammation comprising of granuloma, epithelioid giant cells and lymphoplasmacytic cells.^{[12],[13],[14]} Broad terminologies such as granulomatous mastitis and idiopathic granulomatous mastitis should not be considered synonymous with granulomatous lobular mastitis.^[12] There must be morphological evidence of lobular nature of the lesion coupled with distribution of granulomas in the intra-lobular location. Presence of random granulomas for which such a morphological distribution cannot be identified should be categorized as “idiopathic granulomatous” rather than affixing “lobular” term to the same.

Granulomatous lobular mastitis has been suggested to be categorized into IgG4-related and non IgG4 related granulomatous lobular mastitis by Ogura et al.^[15] Recently IgG4-related sclerosing syndrome has been described which shows dense stromal sclerosis and lymphoplasmacytic infiltrates in various organs.^{[16],[17],[18]} The plasma cells are IgG4 + and serum IgG4 is elevated in these cases. Manifestation of this syndrome in breast is IgG4- related sclerosing mastitis which may be related to granulomatous lobular mastitis.^{[10],[11],[12]} However, presence of well-formed granulomas in these cases suggests an alternate diagnosis.^[14] Case 5 in our study showed a similar histological picture comprising of sheets of plasma cells and admixed lymphocytes obliterating lobules and showing periductular hyalinization. Few areas of focal vascular destruction were also observed [Figure 2]A–D.

As recognition of plasma cell mastitis in 1925 by Ewing and its first description in 1931 by Cheatle and Cutler very less is known about plasma cell mastitis. Adair in 1933 suggested the products of milk disintegration were the cause of primary plasma cell response^[6],[7 plasma cell mastitis is an inflammatory disease of the breast usually in non-lactating females in the reproductive age],[ although extremes of ages can be involved.^[8],[9] And few cases have been observed in males.^[10] various articles describe its incidence differently, from common to rare.^[7],[11] Plasma cell mastitis is thought to be an extreme form of periductal mastitis characterized by marked diffuse plasma cell infiltrates surrounding ducts as well as lobules. These lesions may show presence of granulomas.^[16] We noted that the presence of secretions and lobular granulomas is associated with a higher number of plasma cells.905

In our series 7 out 15 cases were of granulomatous mastitis suggestive of tubercular etiology. Six out of 15 cases showed typical morphology of granulomatous lobular mastitis. 1 case showed morphology of plasma cell mastitis/IgG4 related mastitis. These cases showed epithelitis in the ductules and ductal epithelium. Few of these cases showed secretions present in the ducts. Plasma cells were increased in these cases of granulomatous lobular mastitis. One case showed ill-formed granulomas with non-specific chronic inflammation without any significant autoimmune or any other history suggestive a diagnosis of Idiopathic granulomatous mastitis.

Follow-up

All of these cases underwent wide local excision due to the clinician suspicion or prior biopsy diagnosis of granulomatous mastitis. The patient with IgG4 related mastitis was further referred to rheumatological follow-up with tapered steroids and is well 16 months after surgery. Four of the six cases of tubercular mastitis had pulmonary tuberculosis also, and were treated with appropriate antitubercular regimens. Two of these patients were lost to follow-up after initiating therapy. There was no further management for 7 cases of granulomatous lobular mastitis; however, they are still on follow-up and doing well.

Conclusion

To conclude it is possible to categorize granulomatous diseases of the breast by observing the histomorphology of the lesion. Suggestion of the etiopathology, especially in the absence of AFB demonstration can help guide important therapeutic decisions and thus help in patient management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Dabbs DJ, Weidner N. Reactive and inflammatory conditions of the breast. In: Dabbs DJ, editor. Breast Pathology. 2nd ed. Philadelphia, PA: Elsevier; 2017. p. 29.
2.	Hicks DG, Lester SC. Diagnostic Pathology Breast. 2nd ed. Salt Lake City, UT: Elsevier; 2016. p. 620-1.
3.	Michalany J, Michalany NS. A new morphological concept and classification of granulomatous inflammation: The polar granulomas. Ann Pathol 1984;4:85-95.
4.	Illman JE, Terra SB, Clapp AJ, Hunt KN, Fazzio RT, Shah SS, et al. Granulomatous diseases of the breast and axilla: Radiological findings with pathological correlation. Insights Imaging 2018;9:59-71.
5.	Konan A, Kalyoncu U, Dogan I, Kiliç YA, Karakoç D, Akdogan A, et al. Combined long-term steroid and immunosuppressive treatment regimen in granulomatous mastitis. Breast Care (Basel) 2012;7:297-301.
6.	Kessler E, Wolloch Y. Granulomatous mastitis: A lesion clinically simulating carcinoma. Am J Clin Pathol 1972;58:642-6.
7.	Gupta D, Rajwanshi A, Gupta SK, Nijhawan R, Saran RK, Singh R. Fine needle aspiration cytology in the diagnosis of tuberculous mastitis. Acta Cytol 1999;43:191-4.
8.	Wolfrum A, Kümmel S, Theuerkauf I, Pelz E, Reinisch M. Granulomatous mastitis: A therapeutic and diagnostic challenge. Breast Care (Basel) 2018;13:413-8.
9.	Tauro LF, Martis JS, George C, Kamath A, Lobo G, Hegde BR. Tuberculous mastitis presenting as breast abscess. Oman Med J 2011;26:53-5.
10.	Cutler M. Plasma-cell mastitis: Report of a case with bilateral involvement. Br Med J 1949;1:94-6.
11.	Ming J, Meng G, Yuan Q, Zhong L, Tang P, Zhang K, et al. Clinical characteristics and surgical modality of plasma cell mastitis: Analysis of 91 cases. Am Surg 2013;79:54-60.
12.	Wang X, Han Y, Liu J, Zhang Y, Cheng K, Guo J, et al. Exosomes play an important role in the progression of plasma cell mastitis via the PI3K-akt-mtor signaling pathway. Mediators Inflamm 2019;2019:4312016.
13.	Bhaskaran CS, Prasad KR, Rao G, Kameshwari R, Saheb DA, Aruna CA. Chronic granulomatous mastitis: Review of 26 cases with special reference to chronic lobular mastitis. Indian J Pathol Microbiol 1992;35:38-43.
14.	Palmieri A, D’Orazi V, Martino G, Frusone F, Crocetti D, Amabile MI, et al. Plasma cell mastitis in men: A single-center experience and review of the literature. In Vivo 2016;30:727-32.
15.	Ogura K, Matsumoto T, Aoki Y, Kitabatake T, Fujisawa M, Kojima K. Igg4-related tumour-forming mastitis with histological appearances of granulomatous lobular mastitis: Comparison with other types of tumour-forming mastitis. Histopathology 2010;57:39-45.
16.	Bakaris S, Yuksel M, Ciragil P, Guven MA, Ezberci F, Bulbuloglu E. Granulomatous mastitis including breast tuberculosis and idiopathic lobular granulomatous mastitis. Can J Surg 2006;49:427-30.
17.	Hoda SA. Inflammatory and reactive tumors. In: Hoda SA, Brogi E, Koerner FC, Rosen PP, editors. Rosens Breast Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. p. 42.
18.	Hoda SA. Inflammatory and reactive tumors. In: Hoda SA, Brogi E, Koerner FC, Rosen PP, editors. Rosens Breast Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. p. 48.