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Granulomatous mastitis: a clinicopathological review of 26 cases
Pathology
ISSN: 0031-3025 (Print) 1465-3931 (Online) Journal homepage: http://www.tandfonline.com/loi/ipat20
Granulomatous mastitis: a clinicopathological review of 26 cases Gary M. K. Tse, Cycles S. P. Poon, Kalavathy Ramachandram, Tony K. F. Ma, Lai‐Man Pang, Bonita K. B. Law, Winnie C. W. Chu, Alice P. Y. Tang & Humairah S. Cheung To cite this article: Gary M. K. Tse, Cycles S. P. Poon, Kalavathy Ramachandram, Tony K. F. Ma, Lai‐Man Pang, Bonita K. B. Law, Winnie C. W. Chu, Alice P. Y. Tang & Humairah S. Cheung (2004) Granulomatous mastitis: a clinicopathological review of 26 cases, Pathology, 36:3, 254-257 To link to this article: http://dx.doi.org/10.1080/00313020410001692602
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Date: 30 March 2016, At: 19:40
Pathology (June 2004) 36(3), pp. 254–257
ANATOMICAL PATHOLOGY
Granulomatous mastitis: a clinicopathological review of 26 cases GARY M. K. TSE, CYCLES S. P. POON*, KALAVATHY RAMACHANDRAM{, TONY K. F. MA{, LAI-MAN PANG§, BONITA K. B. LAW||, WINNIE C. W. CHU§, ALICE P. Y. TANG} AND HUMAIRAH S. CHEUNG**
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Departments of Anatomical and Cellular Pathology, §Diagnostic Radiology and Organ Imaging, and ||Surgery, Prince of Wales Hospital, Chinese University of Hong Kong; *Department of Pathology, Pamela Youde Eastern Hospital, and Departments of {Pathology and }Radiology, Alice Ho Miu Ling Nethersole Hospital, Hong Kong; {Department of Pathology, Tengku Ampuan Afzan Hospital, Kuantan, and **Department of Radiology, International Islamic University Medical School, Kuantan, Pahang, Malaysia
Summary Aims: Twenty-six cases of granulomatous mastitis were examined to determine the common histological and clinical features and the possible association with micro-organisms. Methods: A retrospective review of the clinical and histological features of these cases was undertaken, including granuloma, inflammatory cell infiltrate, multinucleated giant cells, necrosis and lymphocytic lobulitis, as well as special stains for micro-organisms including Mycobacterium, other bacteria and fungus. PCR for Mycobacterium tuberculosis DNA was also performed in 19 cases. Results: Granulomas were present in all cases (100%) while multinucleated giant cells were seen in 17 cases (65%), background inflammatory cell infiltrate in 23 cases (88%), predominantly lymphocytes in 18 cases (69%), significant lymphocytic lobulitis in 13 of 19 cases (68%) and necrosis in three cases (11%). Special stains and cultures for microorganisms were all negative. Clinically, four cases (15%) were associated with duct ectasia, eight (31%) with abscess, and there was no such association in 14 cases (54%). Of the 19 cases with PCR for tuberculosis, one case showed Mycobacterium DNA in the sample, raising the possibility of occult tuberculosis infection. Conclusions: Granulomatous mastitis is a heterogeneous group of diseases with a diverse clinical picture and association. Most idiopathic cases are not associated with specific micro-organisms. Key words: Granuloma, mastitis, tuberculosis. Received 14 November 2003, revised 9 February, accepted 13 February 2004
INTRODUCTION Granulomatous mastitis was first described by Kessler and Woolloch.1 In the literature, only a few large series have been reported, emphasising the histological,2–6 imaging7–9 and cytological10–12 aspects, with case numbers ranging from six to 34 cases. The remaining cases are mostly single case reports. The histological features of granulomatous mastitis have been described as consisting of non-caseating granuloma formation within the breast parenchyma and
lobulitis with or without neutrophilic micro-abscess.13,14 There is considerable overlap between granulomatous mastitis and other conditions, particularly tuberculosis. In granulomatous mastitis, microbiological, histological and clinical features for tuberculosis are negative. In one recent paper,6 an association between granulomatous mastitis and Gram-positive bacilli Corynebacterium spp. was observed. In this review, the authors analysed 26 cases of granulomatous mastitis, with emphasis on the various histological features, including the characteristics of the granulomas, the presence of giant cells, and the nature of the background inflammatory cells, necrosis, lobulitis and vasculitis. The clinical findings were also reviewed, in particular, for any microbiological investigations. Ziehl Neelsen (ZN) staining for acid fast bacilli, Gram stain for other bacteria, and special stains for fungus were performed, and polymerase chain reaction (PCR) for Mycobacterium tuberculosis DNA was also carried out in the majority of these cases.
MATERIALS AND METHODS The histopathology files from three hospitals (Prince of Wales Hospital and Pamela Youde Eastern Hospital, Hong Kong, and Tengku Ampuan Afzan Hospital, Kuantan, Malaysia) were searched for granulomatous inflammation of the breast from 1987 to 2002 in one (PWH), from 1997 to 2002 in the second (PYEH) and from 2001 to 2002 in the third (TAAH). All specimens were formalin fixed and routinely processed and the 4-mm H&E slides were examined. Ziehl Neelsen (ZN) stain was also performed for all cases, and only cases that were negative by ZN were included in this study. A total of 26 cases was reviewed. All the slides were scored by three authors (GMKT, CSPP, KR) in a semi-quantitative manner. The parameters assessed included the presence of granulomas, necrosis, the presence and morphology of the giant cells, the presence and amount of inflammatory cells, the relative proportions of lymphocytes, neutrophils, and other cells, the presence of foam cells, and the presence and severity of any lobulitis and vasculitis in the adjacent breast tissue. The medical records were retrieved and examined, with emphasis on the clinical presentation, other co-existing breast diseases including abscesses, any microbiological cultures, pregnancy history, treatment offered and recurrence. In 19 of the 26 cases, lesional tissues were obtained from the paraffin
ISSN 0031-3025 printed/ISSN 1465–3931 # 2004 Royal College of Pathologists of Australasia DOI: 10.1080/00313020410001692602
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material and polymerase chain reaction was performed from the extracted DNA for the IS6100 sequence of Mycobacterium tuberculosis. All the samples were examined in triplicate, together with positive and negative controls, and they were considered positive for tuberculosis when the threshold cycle was less than 40. In cases where the paraffin materials were not exhausted after the DNA extraction for PCR, further histochemical stainings were performed with periodic acid-Schiff with diastase (PASD), Grocott methalamine silver (GMS) and Gram for fungus and bacteria.
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RESULTS The 26 patients included 25 female and one male. The age range was 25–52 years (mean 38 years). In 16 cases the lesions occurred on the right side, eight were on the left and in two cases the side was not known. In 16 cases the specimens obtained were needle core biopsies, and in 10 cases the specimens were obtained from lumpectomies. The lesion sizes ranged from 1.3 to 5.0 cm (mean 2.7 cm). All cases showed granulomas composed of epithelioid histiocytes with or without giant cells (Fig. 1). Abundant, moderate and sparse granulomas were present in six, 11 and nine cases, respectively. Necrosis occurred in three cases. For multinucleated giant cells, 17 cases showed giant cells, with scanty, moderate and abundant numbers in 10, five and two cases, respectively (Fig. 2). All the giant cells were of Langhans type, with the nuclei arranged in a horseshoe manner. In four cases some foreign body giant cells with haphazardly arranged nuclei were also seen. In the background, most (23 cases) showed abundant inflammatory cells. Lymphocytes accounted for the majority of the inflammatory cells (w65%) in 18 cases, and in seven cases lymphocytes accounted for 35–65% of the inflammatory cells. In contrast, the proportion of neutrophils was lower, and in most (20 cases) accounted for less than 35% of the inflammatory cells. Plasma cells were uncommon, and in the majority of cases (25, 96%), they accounted for less than 35% of the inflammatory cells infiltrate. For lymphocytic lobulitis, lobules were present in the specimen for assessment in 19 cases. Of these cases, five showed severe, eight showed moderate and three showed mild lymphocytic lobulitis, which was absent in three cases (Fig. 3). For vasculitis, assessment could be
Fig. 1 A granuloma composed of epithelioid histiocytes with a central necrotic area with neutrophils. No giant cells are identified (H&E, original magnification, 6100).
Fig. 2 Many multinucleated giant cells present within a loose stroma with lymphocytic infiltrate (H&E, original magnification, 6200).
made in 24 cases, with one showing moderate and 12 showing mild vasculitis, which was absent in 11 cases. Only three cases showed ectatic ducts, and 23 cases did not show any. Five cases showed the presence of foam cells, while 21 did not. In 12 cases, further materials were available for the other histochemical organism stains including PASD, GMS and Gram, and they were all negative. For the clinical features, in two remote cases the medical records could not be retrieved. Eight patients had coexisting or recent history of breast abscesses, and most of these patients were treated by incision and drainage, antibiotics and excision. None of these cases recurred. In the remaining 16 patients, 12 presented with breast lumps of recent onset (up to a few months) and four with mastalgia. Review of the medical records showed that of all these patients, five had microbiological cultures from the excised breast tissue, including two patients who had breast abscesses. All the submitted breast tissues were culture negative for acid fast bacilli, other bacteria or fungus. Treatment was by excision, antibiotics or steroid, and in two cases there were recurrences at 3- and 12month intervals. Histological features of these two groups
Fig. 3 A core of breast tissue with an intense lymphocytic infiltrate in a lobular distribution (H&E, original magnification, 6100).
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were similar, with the exception that ectatic ducts were found in three of the patients who presented with breast lumps. Of these three patients, two had a history of recent delivery, and one had a history of prolactin secreting pituitary adenoma. For the 19 cases in which PCR for tuberculosis DNA was performed, 18 were negative and one was positive. Histology of this positive case showed scanty granulomas devoid of giant cells and necrosis, with abundant lymphocytic inflammatory cells background. There was mild lobulitis, but vasculitis was not seen. The patient could not be traced as the excision was performed 14 years ago. Treatment at that time was by antibiotics.
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DISCUSSION Since the initial description of granulomatous mastitis 30 years ago, this disease entity has shown considerable overlap with infective mastitis, vasculitic lesions, plasma cell mastitis or even duct ectasia post-partum. Histology demonstrates a common theme of granuloma formation, with epithelioid cells, multinucleated giant cells, acute and chronic inflammatory cells, micro-abscess formation, lymphocytic lobulitis and vasculitis present in variable combination and severity. In areas where tuberculosis is endemic, and with the resurgence of tuberculosis in developed countries, it has become imperative to differentiate granulomatous mastitis from tuberculosis. Furthermore, there is a recent report of association of granulomatous mastitis with Gram-positive bacilli from New Zealand.6 In the analysis of this 26-case series, special emphasis was laid on the identification of micro-organisms, particularly acid fast bacilli and Gram-positive bacilli. In this series, granuloma was present in all cases histologically. The number of granulomas for all cases was variable, with similar numbers of cases showing scanty, moderate and abundant granulomas. Necrosis was uncommon, occurring only in three cases (12%). Giant cells were common, in the majority of the cases (17 cases, 65%). All the giant cells were of Langhans type, with four cases showing a mixture of Langhans and foreign body types. Moderate to heavy inflammatory infiltrate was present in 23 cases (88%). The component cells were mostly lymphocytes. In the adjacent breast tissue, lymphocytic lobulitis was common, appearing in 13 cases (48%). Lymphocytic vasculitis, on the other hand, was uncommon, with a moderate to severe degree of vasculitis only seen in one case (4%). Tuberculosis is the major differential diagnosis. In the literature, most diagnoses of granulomatous mastitis are based on ruling out tuberculosis2–5,7–12 by histochemical staining and clinical evaluation. Tuberculosis of the breast may present as nodular, disseminated or sclerosed forms,15 and histologically there is much overlap between granulomatous mastitis and tuberculosis, particularly granulomas and giant cells. The single differing histological parameter is necrosis. In a series of 13 cases of mammary tuberculosis,16 necrosis occurred in the vast majority of cases (12 cases, 92%), whereas in our series of granulomatous mastitis, only three cases showed necrosis (11%). Differentiation between granulomatous mastitis and tuberculosis based on clinical criteria is also difficult, as
Pathology (2004), 36(3), June
tuberculosis has variable lymph node involvement and systemic symptoms. In the same series,16 the disease was highly localised with ipsilateral axillary lymphadenopathy occurring in one patient (8%). Most patients (nine patients, 72%) did not have systemic symptoms, and even more (11 patients, 86%) did not have pulmonary symptoms.16 In another large series of 52 cases,17 almost half of the patients showed axillary lymphadenopathy and also half of the patients had sinuses with or without breast lumps. These amply demonstrate the high variability in the presentation of tuberculosis, as many occur as isolated breast lesions. Detection of tuberculosis bacilli DNA by real time PCR is a very sensitive method in tuberculosis detection.18 In this series, 18 cases had negative PCR while one case with negative histochemical, clinical and microbiological investigations was positive for Mycobacterium tuberculosis DNA. Review of the medical records showed the patient was well after prolonged follow-up of several years, without receiving any anti-tuberculosis treatment. This raises the possibility that there may exist a small proportion of idiopathic granulomatous mastitis that is actually sub-clinical, isolated tuberculosis infection. In the literature, only one report utilises such molecular technique19 in the diagnosis of granulomatous mastitis; further experience in this is clearly needed. The cause of granulomatous mastitis remains largely uncertain. Some authors consider granulomatous mastitis to be related to duct ectasia13 while others stress the lobulocentric distribution, and most agree infective cause is unlikely.2–4 In the current study, we have identified several associations. Firstly, four cases (15%) (including two with recent delivery and one with prolactinoma) showed duct ectasia and secretory activities, highlighting the possible role of milk secretion. Secondly, eight cases (31%) had concomitant breast abscesses with history of incision and drainage. The tissue obtained from the adjacent breast showed granulomatous inflammation. The third category, which accounted for most of the cases (14 cases, 54%) was made up of patients presenting with breast lumps (9 patients, 35%) or breast pain (4 patients, 15%). There was no definite history of recent delivery, and there was no abscess, but two patients had recurrent lesions. As no other underlying pathology was detected, this group could be labelled as idiopathic, probably reminiscent of granulomatous lobular mastitis.2,3 The interesting recent observation of association of granulomatous mastitis with Gram-positive bacilli warrants further discussion. In that report of a large series of 34 cases, corynebacteria were demonstrated in 14 cases (41%).6 In that same paper, the authors also pointed out that there was a marked geographical variation, with the bacteria-positive cases mostly being from Maori and Pacific Islander patients. Gram-positive bacilli in association with granulomatous mastitis have not been extensively reported in the literature, and in the current cases, no bacilli were found in our group of patients from Southeast Asia. The significance of these observations and whether they can be explained by geographic variation alone requires further evaluation. Antibiotics and steroids are the mainstay of treatment for granulomatous mastitis when infective causes have been excluded. The clinical course is slow resolution with transient discharging sinus formation. Recurrence may
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occur but is not common. In resistant cases, excision may be required. In this paper, the authors report a large series of granulomatous mastitis, with histological features of granuloma formation in all cases, and multinucleated giant cells of mostly Langhans type, together with some foreign body type, in the majority of cases. The density of both granulomas and giant cells is variable. Many cases also show heavy lymphocytic infiltrate and adjacent lobulitis. These features show considerable overlap with other granulomatous conditions, including tuberculosis, but the absence of necrosis favours granulomatous mastitis. Although some cases are associated with duct ectasia or abscess, most are not associated with any underlying pathology. The possibility of sub-clinical or remote tuberculosis may have to be considered, particularly in tuberculosis endemic areas, and further evaluation with more sensitive molecular techniques may be helpful. Address for correspondence: Dr G. M. Tse, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Ngan Shing Street, Shatin, NT, Hong Kong, China.. E-mail: [email protected]
References 1. Kessler E, Woolloch Y. Granulomatous mastitis: a lesion clinically simulating carcinoma. Am J Clin Pathol 1972; 58: 642–6. 2. Fletcher A, Magrath IM, Riddell RH, et al. Granulomatous mastitis: a report of seven cases. J Clin Pathol 1982; 35: 941–5. 3. Going JJ, Anderson TJ, Wilkinson S, et al. Granulomatous lobular mastitis. J Clin Pathol 1987; 40: 535–40. 4. Galea MH, Robertson JF, Ellis IO, et al. Granulomatous lobular mastitis. Aust NZ J Surg 1989; 59: 547–50. 5. Bhaskaran CS, Prasad KR, Rao G, et al. Chronic granulomatous mastitis: review of 26 cases with special reference to chronic lobular mastitis. Indian J Pathol Microbiol 1992; 35: 38–43.
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6. Taylor GB, Paviour SD, Mussad S, Jones WO, Holland DJ. A clinicopathological review of 34 cases of inflammatory breast disease showing an association between corynebacteria infection and granulomatous mastitis. Pathology 2003; 35: 109– 19. 7. Engin G, Acunas G, Acunas B. Granulomatous mastitis: gray scale and color Doppler sonographic findings. J Clin Ultrasound 1999; 27: 101–6. 8. Han BK, Choe YH, Park JM, et al. Granulomatous mastitis: mammographic and sonographic appearances. Am J Radiol 1999; 173: 317–20. 9. Yilmaz E, Lebe B, Usal C, et al. Mammographic and sonographic findings in the diagnosis of idiopathic granulomatous mastitis. Eur Radiol 2001; 11: 2236–40. 10. Tse GM, Poon CS, Law BK, et al. Fine needle aspiration cytology of granulomatous mastitis. J Clin Pathol 2003; 56: 519–21. 11. Kumarasinghe MP. Cytology of granulomatous mastitis. Acta Cytol 1997; 41: 727–30. 12. Yip CH, Jayaram G, Swain M. The value of cytology in granulomatous mastitis: a report of 16 cases from Malaysia. Aust NZ J Surg 2000; 70: 103–5. 13. Page DL, Anderson TJ. Diagnostic Histopathology of the Breast. Edinburgh: Churchill Livingstone, 1987; 64–5. 14. Symmers W St C, editor. Systemic Pathology. 3rd ed, Vol. 13. Edinburgh: Churchill Livingstone, 2000: 192–5. 15. Goksoy E, Duren M, Durgun V, et al. Tuberculosis of the breast. Eur J Surg 1995; 161: 471–3. 16. Al-Marri MR, Almosleh A, Almoslmani Y. Primary tuberculosis of the breast in Qatar: ten year experience and review of the literature. Eur J Surg 2000; 166: 687–90. 17. Khanna R, Prasanna GV, Gupta P, et al. Mammary tuberculosis: report on 52 cases. Postgrad Med J 2002; 78: 422–4. 18. Desjardin LE, Chen Y, Perkins MD, et al. Comparison of the ABI 7700 system (TaqMan) and competitive PCR for quantification of IS6110 DNA in sputum during treatment of tuberculosis. J Clin Microbiol 1998; 36: 1964–8. 19. Kobayashi TK, Sugihara H, Kato M, et al. Cytologic features of granulomatous mastitis. Report of a case with fine needle aspiration cytology and immunocytochemical findings. Acta Cytol 1998; 42: 716–20.
ISSN: 0031-3025 (Print) 1465-3931 (Online) Journal homepage: http://www.tandfonline.com/loi/ipat20
Granulomatous mastitis: a clinicopathological review of 26 cases Gary M. K. Tse, Cycles S. P. Poon, Kalavathy Ramachandram, Tony K. F. Ma, Lai‐Man Pang, Bonita K. B. Law, Winnie C. W. Chu, Alice P. Y. Tang & Humairah S. Cheung To cite this article: Gary M. K. Tse, Cycles S. P. Poon, Kalavathy Ramachandram, Tony K. F. Ma, Lai‐Man Pang, Bonita K. B. Law, Winnie C. W. Chu, Alice P. Y. Tang & Humairah S. Cheung (2004) Granulomatous mastitis: a clinicopathological review of 26 cases, Pathology, 36:3, 254-257 To link to this article: http://dx.doi.org/10.1080/00313020410001692602
Published online: 06 Jul 2009.
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Article views: 13
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipat20 Download by: [University of California, San Diego]
Date: 30 March 2016, At: 19:40
Pathology (June 2004) 36(3), pp. 254–257
ANATOMICAL PATHOLOGY
Granulomatous mastitis: a clinicopathological review of 26 cases GARY M. K. TSE, CYCLES S. P. POON*, KALAVATHY RAMACHANDRAM{, TONY K. F. MA{, LAI-MAN PANG§, BONITA K. B. LAW||, WINNIE C. W. CHU§, ALICE P. Y. TANG} AND HUMAIRAH S. CHEUNG**
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Departments of Anatomical and Cellular Pathology, §Diagnostic Radiology and Organ Imaging, and ||Surgery, Prince of Wales Hospital, Chinese University of Hong Kong; *Department of Pathology, Pamela Youde Eastern Hospital, and Departments of {Pathology and }Radiology, Alice Ho Miu Ling Nethersole Hospital, Hong Kong; {Department of Pathology, Tengku Ampuan Afzan Hospital, Kuantan, and **Department of Radiology, International Islamic University Medical School, Kuantan, Pahang, Malaysia
Summary Aims: Twenty-six cases of granulomatous mastitis were examined to determine the common histological and clinical features and the possible association with micro-organisms. Methods: A retrospective review of the clinical and histological features of these cases was undertaken, including granuloma, inflammatory cell infiltrate, multinucleated giant cells, necrosis and lymphocytic lobulitis, as well as special stains for micro-organisms including Mycobacterium, other bacteria and fungus. PCR for Mycobacterium tuberculosis DNA was also performed in 19 cases. Results: Granulomas were present in all cases (100%) while multinucleated giant cells were seen in 17 cases (65%), background inflammatory cell infiltrate in 23 cases (88%), predominantly lymphocytes in 18 cases (69%), significant lymphocytic lobulitis in 13 of 19 cases (68%) and necrosis in three cases (11%). Special stains and cultures for microorganisms were all negative. Clinically, four cases (15%) were associated with duct ectasia, eight (31%) with abscess, and there was no such association in 14 cases (54%). Of the 19 cases with PCR for tuberculosis, one case showed Mycobacterium DNA in the sample, raising the possibility of occult tuberculosis infection. Conclusions: Granulomatous mastitis is a heterogeneous group of diseases with a diverse clinical picture and association. Most idiopathic cases are not associated with specific micro-organisms. Key words: Granuloma, mastitis, tuberculosis. Received 14 November 2003, revised 9 February, accepted 13 February 2004
INTRODUCTION Granulomatous mastitis was first described by Kessler and Woolloch.1 In the literature, only a few large series have been reported, emphasising the histological,2–6 imaging7–9 and cytological10–12 aspects, with case numbers ranging from six to 34 cases. The remaining cases are mostly single case reports. The histological features of granulomatous mastitis have been described as consisting of non-caseating granuloma formation within the breast parenchyma and
lobulitis with or without neutrophilic micro-abscess.13,14 There is considerable overlap between granulomatous mastitis and other conditions, particularly tuberculosis. In granulomatous mastitis, microbiological, histological and clinical features for tuberculosis are negative. In one recent paper,6 an association between granulomatous mastitis and Gram-positive bacilli Corynebacterium spp. was observed. In this review, the authors analysed 26 cases of granulomatous mastitis, with emphasis on the various histological features, including the characteristics of the granulomas, the presence of giant cells, and the nature of the background inflammatory cells, necrosis, lobulitis and vasculitis. The clinical findings were also reviewed, in particular, for any microbiological investigations. Ziehl Neelsen (ZN) staining for acid fast bacilli, Gram stain for other bacteria, and special stains for fungus were performed, and polymerase chain reaction (PCR) for Mycobacterium tuberculosis DNA was also carried out in the majority of these cases.
MATERIALS AND METHODS The histopathology files from three hospitals (Prince of Wales Hospital and Pamela Youde Eastern Hospital, Hong Kong, and Tengku Ampuan Afzan Hospital, Kuantan, Malaysia) were searched for granulomatous inflammation of the breast from 1987 to 2002 in one (PWH), from 1997 to 2002 in the second (PYEH) and from 2001 to 2002 in the third (TAAH). All specimens were formalin fixed and routinely processed and the 4-mm H&E slides were examined. Ziehl Neelsen (ZN) stain was also performed for all cases, and only cases that were negative by ZN were included in this study. A total of 26 cases was reviewed. All the slides were scored by three authors (GMKT, CSPP, KR) in a semi-quantitative manner. The parameters assessed included the presence of granulomas, necrosis, the presence and morphology of the giant cells, the presence and amount of inflammatory cells, the relative proportions of lymphocytes, neutrophils, and other cells, the presence of foam cells, and the presence and severity of any lobulitis and vasculitis in the adjacent breast tissue. The medical records were retrieved and examined, with emphasis on the clinical presentation, other co-existing breast diseases including abscesses, any microbiological cultures, pregnancy history, treatment offered and recurrence. In 19 of the 26 cases, lesional tissues were obtained from the paraffin
ISSN 0031-3025 printed/ISSN 1465–3931 # 2004 Royal College of Pathologists of Australasia DOI: 10.1080/00313020410001692602
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material and polymerase chain reaction was performed from the extracted DNA for the IS6100 sequence of Mycobacterium tuberculosis. All the samples were examined in triplicate, together with positive and negative controls, and they were considered positive for tuberculosis when the threshold cycle was less than 40. In cases where the paraffin materials were not exhausted after the DNA extraction for PCR, further histochemical stainings were performed with periodic acid-Schiff with diastase (PASD), Grocott methalamine silver (GMS) and Gram for fungus and bacteria.
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RESULTS The 26 patients included 25 female and one male. The age range was 25–52 years (mean 38 years). In 16 cases the lesions occurred on the right side, eight were on the left and in two cases the side was not known. In 16 cases the specimens obtained were needle core biopsies, and in 10 cases the specimens were obtained from lumpectomies. The lesion sizes ranged from 1.3 to 5.0 cm (mean 2.7 cm). All cases showed granulomas composed of epithelioid histiocytes with or without giant cells (Fig. 1). Abundant, moderate and sparse granulomas were present in six, 11 and nine cases, respectively. Necrosis occurred in three cases. For multinucleated giant cells, 17 cases showed giant cells, with scanty, moderate and abundant numbers in 10, five and two cases, respectively (Fig. 2). All the giant cells were of Langhans type, with the nuclei arranged in a horseshoe manner. In four cases some foreign body giant cells with haphazardly arranged nuclei were also seen. In the background, most (23 cases) showed abundant inflammatory cells. Lymphocytes accounted for the majority of the inflammatory cells (w65%) in 18 cases, and in seven cases lymphocytes accounted for 35–65% of the inflammatory cells. In contrast, the proportion of neutrophils was lower, and in most (20 cases) accounted for less than 35% of the inflammatory cells. Plasma cells were uncommon, and in the majority of cases (25, 96%), they accounted for less than 35% of the inflammatory cells infiltrate. For lymphocytic lobulitis, lobules were present in the specimen for assessment in 19 cases. Of these cases, five showed severe, eight showed moderate and three showed mild lymphocytic lobulitis, which was absent in three cases (Fig. 3). For vasculitis, assessment could be
Fig. 1 A granuloma composed of epithelioid histiocytes with a central necrotic area with neutrophils. No giant cells are identified (H&E, original magnification, 6100).
Fig. 2 Many multinucleated giant cells present within a loose stroma with lymphocytic infiltrate (H&E, original magnification, 6200).
made in 24 cases, with one showing moderate and 12 showing mild vasculitis, which was absent in 11 cases. Only three cases showed ectatic ducts, and 23 cases did not show any. Five cases showed the presence of foam cells, while 21 did not. In 12 cases, further materials were available for the other histochemical organism stains including PASD, GMS and Gram, and they were all negative. For the clinical features, in two remote cases the medical records could not be retrieved. Eight patients had coexisting or recent history of breast abscesses, and most of these patients were treated by incision and drainage, antibiotics and excision. None of these cases recurred. In the remaining 16 patients, 12 presented with breast lumps of recent onset (up to a few months) and four with mastalgia. Review of the medical records showed that of all these patients, five had microbiological cultures from the excised breast tissue, including two patients who had breast abscesses. All the submitted breast tissues were culture negative for acid fast bacilli, other bacteria or fungus. Treatment was by excision, antibiotics or steroid, and in two cases there were recurrences at 3- and 12month intervals. Histological features of these two groups
Fig. 3 A core of breast tissue with an intense lymphocytic infiltrate in a lobular distribution (H&E, original magnification, 6100).
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were similar, with the exception that ectatic ducts were found in three of the patients who presented with breast lumps. Of these three patients, two had a history of recent delivery, and one had a history of prolactin secreting pituitary adenoma. For the 19 cases in which PCR for tuberculosis DNA was performed, 18 were negative and one was positive. Histology of this positive case showed scanty granulomas devoid of giant cells and necrosis, with abundant lymphocytic inflammatory cells background. There was mild lobulitis, but vasculitis was not seen. The patient could not be traced as the excision was performed 14 years ago. Treatment at that time was by antibiotics.
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DISCUSSION Since the initial description of granulomatous mastitis 30 years ago, this disease entity has shown considerable overlap with infective mastitis, vasculitic lesions, plasma cell mastitis or even duct ectasia post-partum. Histology demonstrates a common theme of granuloma formation, with epithelioid cells, multinucleated giant cells, acute and chronic inflammatory cells, micro-abscess formation, lymphocytic lobulitis and vasculitis present in variable combination and severity. In areas where tuberculosis is endemic, and with the resurgence of tuberculosis in developed countries, it has become imperative to differentiate granulomatous mastitis from tuberculosis. Furthermore, there is a recent report of association of granulomatous mastitis with Gram-positive bacilli from New Zealand.6 In the analysis of this 26-case series, special emphasis was laid on the identification of micro-organisms, particularly acid fast bacilli and Gram-positive bacilli. In this series, granuloma was present in all cases histologically. The number of granulomas for all cases was variable, with similar numbers of cases showing scanty, moderate and abundant granulomas. Necrosis was uncommon, occurring only in three cases (12%). Giant cells were common, in the majority of the cases (17 cases, 65%). All the giant cells were of Langhans type, with four cases showing a mixture of Langhans and foreign body types. Moderate to heavy inflammatory infiltrate was present in 23 cases (88%). The component cells were mostly lymphocytes. In the adjacent breast tissue, lymphocytic lobulitis was common, appearing in 13 cases (48%). Lymphocytic vasculitis, on the other hand, was uncommon, with a moderate to severe degree of vasculitis only seen in one case (4%). Tuberculosis is the major differential diagnosis. In the literature, most diagnoses of granulomatous mastitis are based on ruling out tuberculosis2–5,7–12 by histochemical staining and clinical evaluation. Tuberculosis of the breast may present as nodular, disseminated or sclerosed forms,15 and histologically there is much overlap between granulomatous mastitis and tuberculosis, particularly granulomas and giant cells. The single differing histological parameter is necrosis. In a series of 13 cases of mammary tuberculosis,16 necrosis occurred in the vast majority of cases (12 cases, 92%), whereas in our series of granulomatous mastitis, only three cases showed necrosis (11%). Differentiation between granulomatous mastitis and tuberculosis based on clinical criteria is also difficult, as
Pathology (2004), 36(3), June
tuberculosis has variable lymph node involvement and systemic symptoms. In the same series,16 the disease was highly localised with ipsilateral axillary lymphadenopathy occurring in one patient (8%). Most patients (nine patients, 72%) did not have systemic symptoms, and even more (11 patients, 86%) did not have pulmonary symptoms.16 In another large series of 52 cases,17 almost half of the patients showed axillary lymphadenopathy and also half of the patients had sinuses with or without breast lumps. These amply demonstrate the high variability in the presentation of tuberculosis, as many occur as isolated breast lesions. Detection of tuberculosis bacilli DNA by real time PCR is a very sensitive method in tuberculosis detection.18 In this series, 18 cases had negative PCR while one case with negative histochemical, clinical and microbiological investigations was positive for Mycobacterium tuberculosis DNA. Review of the medical records showed the patient was well after prolonged follow-up of several years, without receiving any anti-tuberculosis treatment. This raises the possibility that there may exist a small proportion of idiopathic granulomatous mastitis that is actually sub-clinical, isolated tuberculosis infection. In the literature, only one report utilises such molecular technique19 in the diagnosis of granulomatous mastitis; further experience in this is clearly needed. The cause of granulomatous mastitis remains largely uncertain. Some authors consider granulomatous mastitis to be related to duct ectasia13 while others stress the lobulocentric distribution, and most agree infective cause is unlikely.2–4 In the current study, we have identified several associations. Firstly, four cases (15%) (including two with recent delivery and one with prolactinoma) showed duct ectasia and secretory activities, highlighting the possible role of milk secretion. Secondly, eight cases (31%) had concomitant breast abscesses with history of incision and drainage. The tissue obtained from the adjacent breast showed granulomatous inflammation. The third category, which accounted for most of the cases (14 cases, 54%) was made up of patients presenting with breast lumps (9 patients, 35%) or breast pain (4 patients, 15%). There was no definite history of recent delivery, and there was no abscess, but two patients had recurrent lesions. As no other underlying pathology was detected, this group could be labelled as idiopathic, probably reminiscent of granulomatous lobular mastitis.2,3 The interesting recent observation of association of granulomatous mastitis with Gram-positive bacilli warrants further discussion. In that report of a large series of 34 cases, corynebacteria were demonstrated in 14 cases (41%).6 In that same paper, the authors also pointed out that there was a marked geographical variation, with the bacteria-positive cases mostly being from Maori and Pacific Islander patients. Gram-positive bacilli in association with granulomatous mastitis have not been extensively reported in the literature, and in the current cases, no bacilli were found in our group of patients from Southeast Asia. The significance of these observations and whether they can be explained by geographic variation alone requires further evaluation. Antibiotics and steroids are the mainstay of treatment for granulomatous mastitis when infective causes have been excluded. The clinical course is slow resolution with transient discharging sinus formation. Recurrence may
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occur but is not common. In resistant cases, excision may be required. In this paper, the authors report a large series of granulomatous mastitis, with histological features of granuloma formation in all cases, and multinucleated giant cells of mostly Langhans type, together with some foreign body type, in the majority of cases. The density of both granulomas and giant cells is variable. Many cases also show heavy lymphocytic infiltrate and adjacent lobulitis. These features show considerable overlap with other granulomatous conditions, including tuberculosis, but the absence of necrosis favours granulomatous mastitis. Although some cases are associated with duct ectasia or abscess, most are not associated with any underlying pathology. The possibility of sub-clinical or remote tuberculosis may have to be considered, particularly in tuberculosis endemic areas, and further evaluation with more sensitive molecular techniques may be helpful. Address for correspondence: Dr G. M. Tse, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Ngan Shing Street, Shatin, NT, Hong Kong, China.. E-mail: [email protected]
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