Study on the Correlation Between the Expression of Cd68 and Cd25 and the Degree of Lesion in Granulomatous Mastitis

doi:10.21203/rs.3.rs-3108389/v1

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Study on the Correlation Between the Expression of Cd68 and Cd25 and the Degree of Lesion in Granulomatous Mastitis

https://doi.org/10.21203/rs.3.rs-3108389/v1

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Objective

Study on the correlation between the expression of CD68 and CD25 and the degree of lesion in granulomatous mastitis.

Material and methods

50 female patients with Graves' disease underwent mammary and thyroid gland surgeries during the study period. Post-surgery pathology analyses confirmed their diagnoses, and all patients were married, aged between 26 to 50 years, without signs of pregnancy or lactation. The ailment duration averaged at 2.5 months.

Results

Both Groups A and B expressed these cells positively, without a significant difference. However, Group C showed a lack of positive expression that differs significantly from Groups A and B. In Group A, CD68 and IgG expression levels were compared across different stages of the disease course in Table 3. The statistical analysis revealed no differences between these indicators (P > 0.05). Yet it highlighted a substantially higher level of CD25 expression in Group A between 15 days to 9 weeks when compared to those observed be low 15 days (P < 0.05). After ninety or more days had elapsed, however, there was no statistically significant difference observed with a p-value greater than 0.05. For Group B, No statistically significant differences were detected among the four indicators at various stages during the disease's development (P > 0.05). CD68, CD25, and IgG expression remained consistently high for a lesion size above or below 4 cm within group A. However, no significant variations were noticed as the p-value exceeded > 0.05.

Conclusions

GLM and PCM are diseases related to the immune system with different pathogenesis involving various immune cells and cellular elements. M2 macrophages play a crucial role in both GLM and PCM progression by promoting tumorigenesis. Inverted nipples can help distinguish between IgG4-related and non-IgG4-related GLM.

Expression of CD68

CD25

Granulomatous mastitis

M2 macrophages. Graves' disease

In 1972, Kessler and Wolloch initially identified Granulomatous Mastitis (GM) as a benign disease. Since then, cases have been documented globally.(1) It is considered uncommon with an estimated incidence of 2.4 per 100,000 women and 0.37% in the United States. Reliable incidence and prevalence data on genetically modified organisms (GMOs) in Europe or Germany is lacking; however, available literature suggests that GM predominantly affects reproductive age women with a prior history of breastfeeding. The onset typically manifests approximately 24 months after cessation of breastfeeding with a median age of onset at 30 years old.(2) The precise origin or cause of GM remains uncertain despite several hypotheses being postulated including damage to epithelial tissue from an inflammatory autoimmune reaction but the exact etiology behind this damage remains unidentified. Breastfeeding may be associated due to extravasation of secretions from lobules elicit an inflammatory response as well as Corynebacterium kroppenstedtii has been frequently isolated from GM lesions suggesting involvement in its pathogenesis. A current topic links antipsychotic medication use to hyperprolactinemia which is known to induce ductal ectasia and milk stasis while exhibiting pro-inflammatory properties linking it to GM development alongside erythema nodosum or arthritis. Moreover, alpha-1 antitrypsin deficiency increases potential risk among individuals of Caucasian European or North American ancestry where histopathological observations reveal predominance inflammation in lobular regions observes primarily during panniculitis occurrences among patients.(4) Symptoms include distressing neoplasm involving erythema, swelling, retraction of the areola and breast mass along with skin/nipple retraction mimicking bacterial abscesses/ cancer resulting in lymphadenopathy seen up to 15%. Early diagnosis can pose challenges due to similarities with non-specific symptoms extending over several months. (5, 6)

GLM is an on-going inflammatory disorder that targets the breast and is named after tumour samples from idiopathic granulomatous mastitis. GMH mostly appear on one side of the breast, especially around the areola region or upper outer quadrant, but some cases havereported bilateral occurrences. In certain patients, multiple quadrants or even the entire mammary gland may be affected. The usual clinical presentation involves a solitary firm bump in the mammary gland with mild or no discomfort. The standard diagnostic criterion for determining GLM is histopathological examination. The lobular granulomas contain several cellular components, such as macrophages, neutrophils, lymphocytes, monocytes and non-caseating necrotic lesions. The microscopic features of granulomas are evident through Langhan's giant cells, neutrophil polymorphs and epithelioid histocytes. Additionally, microabscesses, necrosis, sinus tracts and duct ectasia can be detected as well (7). Currently, there are no established protocols to guide the management of GLM. GLM is believed to be an autoimmune disorder, with immune dysfunction varying based on age, familial status, and location of inflammatory aggregation associated with breast disease according to research (8–12). Although its correlation with M2 macrophages, natural killer cells (NK), or IgG4-positive plasmocytes has yet to be confirmed. It's challenging for healthcare professionals to differentiate between two non-malignant conditions- PCM and GLM. Managing these conditions is complicated, requiring a histopathological examination to determine which condition patients have(12–15). To differentiate between GLM, PCM, and other benign conditions, the control group consists of patients diagnosed with breast cystic hyperplasia. This prevalent non-malignant ailment exhibits a different pathogenesis in comparison to inflammatory conditions.

There are two distinct categories of macrophages. The second category, activated macrophages, sometimes referred to as M2-type macrophages, are primarily identified by the presence of CD68+ (a marker for all macrophages) and CD163+ (a marker unique to M2 macrophages). M2-type macrophages possess the ability to suppress the immune response and restrict inflammation (11). This study utilized immunohistochemical techniques to examine the expression of CD68, CD163, CD57, and IgG4 in patients with GLM, PCM, and breast cystic hyperplasia. The aim of the study on the correlation between the expression of CD68 and CD25 and the degree of lesion in granulomatous mastitis This research aimed to investigate alterations in inflammatory cells and cytokines in order to get a deeper understanding of the development of GLM. The ultimate goal was to mitigate the harm caused by breast surgery and provide a theoretical framework for future therapy of the condition.

This study was done in the department after taking the permission from the ethical committee of the institute. All the patients were divided into 3 groups.

Group A (Study Group)

Group B (Control Group 1)

During the study period, a group of 30 patients diagnosed with plasma cell mastitis (PCM) and who underwent mammary gland thyroid surgery were included in group B at our hospital. Postoperative pathology reports confirmed all diagnoses. The age range of the participants was between 20 to 40 years old.

Group C (Control Group 2)

The second control group consisted of 20 cases of breast cystic hyperplasia. The confirmation was made via postoperative pathological histology and the study participants' age range was from 25 to 45 years. The p-value greater than 0.05 indicates that there is no significant difference in the age of individuals between group A and groups B and C. Therefore, we can conclude that the ages are similar across these groups.

The experts in clinical pathology verified all specimens after examination. To ensure accuracy, it is important to retain the clinical and pathological data of each specimen and for patients to receive regular follow up. The study excluded cases involving breast tumors that were cancerous, as well as individuals with certain medical conditions including diabetes, rheumatism, autoimmune diseases such as SLE, liver or kidney disease, tuberculosis and other medical conditions. Women who were lactating six months prior to the surgical procedure or had a recent pregnancy are not eligible for inclusion in this study.

Methodology

During the study, we collected specimens and embedded them in paraffin. Immunohistochemical staining was carried out using Elivision super testing to detect CD68, CD163, CD57, and IgG4 expression in the pathological tissue samples. The relationship between clinical parameters, including age, reproductive condition, nipple retraction, and tumor size, and the expressions of CD68, CD163, CD57, and IgG4 was analyzed.. A negative control was implemented to ensure accurate results, with a preference given to using PBS instead of negative resistance. We conducted semi-quantitative observations on samples (10–12) based on participant age (baby boomers vs non-baby boomers), fertility condition (around lactation vs after lactation), and nipple depression severity (moderate, severe, or normal invagination). The nipple retraction technique was used in cases of moderate invagination while severe cases did not allow for this technique to be applied. And normal/mild depressions allowed for its application but still resulted in retracted nipples upon compression. Additionally, we accounted for various stages when characterizing inflammatory diseases: initial acute phase (lasting less than 15 days), intermediate subacute phase (lasting between 15 and 90 days), and prolonged chronic phase (lasting beyond 90 days). Finally, we performed sectionalization based on lesion size: below or above 4 cm.

Statistical analysis

The SPSS 25.0 software, developed by IBM Corporation in Armonk, NY was used for statistical analyses. The mean value (x) and standard deviation (S) were utilized to analyze score data. For one-way ANOVA pairwise comparisons, Fisher's Least Significant Difference (LSD) test was used when the variance was homogeneous. However, when homogeneity of variance wasn't met, Kruskal-Wallis H test served as its nonparametric alternative for multiple groups. Inspection level α was either set at 0.05 or α' at 0.0083 for bilateral or one-sided testing respectively.

The cytoplasm contained M2 macrophages and IgG-positive plasma cells, and CD25-positive NK cells were detected in the cell membranes. Both Group A and B showed positive expression of these cells with no significant difference. In contrast, Group C exhibited a lack of positive expression that was significantly different from Groups A and B (Table 1, Figs. 1 and 2).

Table 1

Comparison of expression among groups
	Group A = 50		Group B = 30		Group C = 20		P value
CD25	Number	%	Number	%	Number	%	0.001
Low expression	18	36	6	20	20	100
Average expression	30	60	21	70	0	0
High expression	2	4	3	10	0	0
CD68							0.001
Low expression	5	10	2	6.67	20	100
Average expression	30	60	20	66.67	0	0
High expression	15	30	8	26.66	0	0
IgG							0.03
Low expression	30	60	20	66.67	20	100
Average expression	15	30	9	30	0	0
High expression	5	10	1	3.33	0	0

The study uncovered significant inflammation in both Group A and Groups B or C. This was proven by the increased presence of CD68-positive M2 macrophages, CD25 positive NK cells, and IgG positive plasma cells (P < 0.05). According to Table 2, there was no substantial difference between the expression levels of Group A and Group B. Nonetheless, both groups possessed higher levels than Group C (P < 0.05).

Table 2

Comparison between the quantities
	Group A = 50		Group B = 30		Group C = 20		P value
	Mean	Sd	Mean	Sd	Mean	Sd
CD25	29.87	4.85	41.37	4.66	6.45	1.11	0.001
CD68	5.47	0.58	5.63	0.49	2.36	0.12	0.001
IgG	7.15	0.99	9.74	0.87	4.36	0.34	0.001

The expression levels of CD68 and IgG were compared in Group A across different disease stages, but no significant differences were found (P > 0.05). However, CD25 had significantly higher expression levels in Group A from 15 days up until 9 weeks than those observed below 15 days (p < 0.05). No statistically significant difference was observed after a period of 90 days or more (P > 0.05). For Group B, none of the four indicators showed any statistically significant difference at various stages of the disease course (P > 0.05) (Table 3 and Fig. 3).

Table 3

Comparison between the expressions of CD25, CD68 and IgG of Group A and group B
	Below 15 days		15–90 days		Above 90 days		P value
Group A	Mean	Sd	Mean	Sd	Mean	Sd
CD25	18.69	3.66	41.77	5.85	25.88	3.69	0.39
CD68	5.11	0.66	5.77	0.79	4.39	0.26	0.55
IgG	5.55	0.79	10.15	1.36	7.88	1.19	0.15
Group B
CD25	41.96	5.85	37.88	4.69	45.58	4.78	0.36
CD68	5.11	0.88	6.04	0.94	6.04	0.96	0.22
IgG	5.11	0.77	3.33	0.19	13.47	1.38	0.27

During the acute phase of less than 15 days and chronic phase of more than 90 days, we observed lower levels of natural killer (NK) cells in group A compared to group B, indicating a significant difference between the two groups. Meanwhile, in group B, the expression of IgG gradually increased during the chronic phase after 90 days and widened the gap.

The study compared the expression of various cell types in baby boomers and non-baby boomers from Group A and B, to identify any generational differences. However, the results, shown in Table 4, indicate that there was no significant variation seen in CD68 positive M2 macrophages, CD25 positive NK cells, and IgG-positive plasma cells with a p-value greater than 0.05. Hence there is no noticeable difference found between generations regarding the analyzed cell types (Fig. 4).

Table 4

The expressions of CD68 and CD25 and IgG in baby boomers and non-baby boomers
	Baby boomers		Non baby boomers		P value
CD68 Group A and IgG( Group A and B)	Mean	Sd	Mean	Sd
CD68 Group A	5.11	0.87	5.36	0.79	0.37
IgG Group A	7.44	1.11	7.12	1.34	0.19
IgG Group B	9.22	1.22	9.01	1.87	0.44
CD68 Group B and CD25 Group A and B)
CD25 Group A	31.29	3.69	24.25	3.57	0.25
CD68 Group B	5.59	0.48	6.69	0.79	0.16
CD25 Group B	40.98	5.55	42.88	5.98	0.33

The study aimed to evaluate the levels of CD68 and IgG expression in Group A and B pre and post three years after childbirth. The results suggest that there are no significant differences in the expressions of CD68 and IgG between Group A and B (P > 0.05). However, individuals who developed onset symptoms of more than three years postpartum had a significant increase in CD25 expression as compared to those with onset within three years after childbirth (P < 0.05).

The comparison of CD68 and CD25 expression levels between patients with and without nipple retraction in Group A and B was performed using Table 5. The findings show no significant discrepancy in the expression levels of CD68 and CD25 in either group (P > 0.05). However, IgG expression among patients without nipple retraction in Group A was substantially higher, which established a statistically significant difference (P < 0.05).

Table 5

The expressions of CD68 and CD25 and IgG in present or absent nipple retraction
	Nipple retraction Present		Nipple retraction Absent		P value
CD68 Group A and IgG( Group A and B)	Mean	Sd	Mean	Sd
CD68 Group A	5.44	0.98	6.48	0.85	0.41
IgG Group A	6.89	1.22	13.67	1.79	0.23
IgG Group B	7.39	1.49	9.44	1.93	0.23
CD68 Group B and CD25 (Group A and B)
CD25 Group A	27.81	4.11	37.84	4.96	0.19
CD68 Group B	5.11	0.41	6.16	0.72	0.27
CD25 Group B	42.11	5.69	43.58	5.11	0.11

CD68, CD25, and IgG expression demonstrated consistency in group A regardless of the lesion's size (above or below 4 cm). However, no significant differences were observed as the p-value exceeded 0.05 (Table 6 and Fig. 5).

Table 6

The expressions of CD68 and CD25 and IgG in in patients with different lesion ranges
	Below 4		Above 4		P value
	Mean	Sd	Mean	Sd
CD68 Group A	5.11	0.55	4.88	0.39	0.21
CD25 Group A	24.85	2.42	29.98	3.09	0.11
CD68 Group B	6.11	1.11	6.45	1.21	0.31
CD25 Group B	50.59	5.51	40.78	5.56	0.21
IgG Group A	14.47	1.52	4.11	1.72	0.14

Non-lactational mastitis refers to a group of conditions, including GLM, PCM, subareolar abscess, and lymphocytic sclerosing lobular mastitis. Previously regarded as an infrequent non-cancerous inflammatory disease in mammary glands during the non-lactational phase, GLM's prevalence has significantly increased globally. Reports from European and American countries suggest that non-lactational mastitis accounts for 3% of benign breast diseases (16–20). However, at our hospital, we found that non-lactational mastitis constituted approximately 10% of all surgeries performed for benign breast diseases. Among them, the most frequent procedures were GLM and PCM. In recent years, reports confirmed the increasing rates of GLM among Asian and Hispanic women in the Asia-Pacific region (21), highlighting its significance in these geographical areas. Misdiagnosis rate associated with GLM was found to be as high as 40%, emphasizing the importance of distinguishing it from other conditions such as inflammatory breast cancer or lactating mastitis (22–25). GLM presents symptoms such as primary breast pain, nipple discharge, pull invagination in breasts without breastfeeding periods and centripetal developing scleroderma alongside abscesses which can develop into a "orange peel" appearance on skin along with swelling and enlarged axillary lymph nodes. Although clinical staging holds significant value in surgery because it directly impacts surgical approach techniques used postoperative cosmetic outcomes patient psychological rehabilitation; several scholars argue that granulomatous mastitis types should be classified by molecular expressions similar to those observed in breast cancer expressing inflammatory factors rather than clinical stages with varying progression levels resulting treatment differences along with prognosis based on uniformity not guaranteed(25–27).

In 1972, Kesler first documented the disease as being self-limiting (28). However, Cohen (17) suggested that it could be an autoimmune origin focal lesion. Domestic studies have validated varying levels of immune dysfunction in non-lactational mastitis patients. Chen et al. (18) observed an increase in the percentage of CD3 and CD4/CD8 T cell subgroups as well as elevated levels of IgG, IGLM, and IgA with a decrease in complement C3 but an elevation in C4 levels. Meanwhile, Xia et al. suggest about half of the patients showed reduction in quantity across multiple T lymphocyte subsets; this was accompanied by varied degrees of increase in immunoglobulin and decreased C4 level when analyzed for possible complement disorder issues (29–31). The underlying factors contributing to inconsistent results could vary with discrepancies amidst specimens utilized or fluctuations amidst GLM, PCM, Zuska disease composition ratios or even discrepant stages the disease progresses through. Analysis had shown both cellular immunity and humoral immunity were involved within the presented case reports detailing diagnosis support via pathological examination endorsed by certain experts drug administration like glucocorticoid along with surgery intervention described to bring positive clinical effects on treating related symptoms Moreover anti-tuberculosis intervention was recognized centrally into comprehensive treatment paradigms advocated by prominent scholars who endorses a multidisciplinary approach focusing on complementary traditional Chinese medicine interventions alongside aforementioned tools to improve patient prognosis overall (31–36).

There are two main types of macrophages (37). The first one, known as M1 macrophages or classically activated macrophages, help eliminate microbes and cancerous cells by triggering the immune response. However, they also produce harmful byproducts and present antigens to T-cells. M1 macrophages play a protective role against pathogenic infections and possess anti-tumor properties. On the other hand, the second type named M2 or activated macrophages produce a variety of cytokines that activate an anti-inflammatory response aiming at cease inflammatory reactions in tissues for quicker repairment(38). Therefore, maintaining internal body balance is possible via balancing pro-inflammatory response with its counterpart: Anti-inflammatory reaction.

CD68 is a molecule found on the surface of macrophages. Chronic inflammation often involves an increase in macrophage activity, leading to more macrophages showing up in patient samples from those having granulomatous mastitis (GLM). For early stage GLM patients, cortisol may be an effective treatment option and could reduce the need for surgery. Chronic stress has been shown to suppress immune function, complicating treatments geared towards increasing extended cortisol use (39–40).

A recent study revealed that both plasmacyte mastitis and granulomatous mastitis contain M2-type macrophages which suggests they share a common immune pathway causing tumorigenesis. There was no significant difference of observed levels of macrophage expression between acute or chronic stages indicating low doses of glucocorticoids during initial phases are a viable therapeutic approach. During the chronic phase, inhibition or suppression of tumor promotion by M1 to M2 transition pathway can lead to better outcomes with post-operative complications. For GLM patients, some are treated with three anti-tuberculosis drugs which have proven useful in specific instances alongside early glucocorticoid coverage; however this method's long-term effectiveness is still unproven pending further research due to lack of medical evidence supporting it conclusively. It is believed that certain substances can heighten the function capacity for processes such as clearance and secretion undertaken by these cells.(41)

NK cells area significant part of the body's defence system and specifically target ubiquitin to eliminate harmful pathogens. These cells possess anti-tumor and anti-viral properties while also regulating the immune system. However, their improper functioning can lead to autoimmune diseases. The maturation of CD25 + NK cells could help in reducing chronic illnesses associated with immunosenescence. NK cells have an important role in the early natural immune response as well as acquired immunity by releasing both stimulatory and inhibitory cytokines, connecting the two types of immunity together (37–40). Liang and his team hypothesized that specific TAAS expression patterns are associated with better tumor differentiation, smaller tumor size, and an increased presence of CD25-positive natural killer cells.

They explored the possibility that inflammatory factors' expression levels could indicate the progression of GLM tumors. The results suggest that CD25-positive NK cell levels may differentiate between GLM from non GLM cases. During GLM development, these cells become upregulated peaking within 15 to 90 days after disease onset. Conversely, in non-GLM cases, CD25 expression remained unchanged. The findings suggest that NK cells and their cytokines play a crucial role in clinical outcomes for patients with GLM. The study also identified a potential link between pregnancy or lactation and PCM onset as evidenced by increases in NK cell expression among patients diagnosed two years post-delivery. Shifting immune responses from Th2 during pregnancy to Th1 postpartum have been linked to numerous autoimmune flare-ups (40–41). Therefore it is essential to monitor immune indices during mastitis patients for at least two years post-delivery regardless of whether they were lactating or not. IgG, a type of globulin that relies on Th2 cells, has a section known as Fc which can attach itself to mast cells.

This process contributes to the body's allergic reactions (38). Autoimmune disorders associated with IgG have been linked to various inflammatory conditions like autoimmune pancreatitis, retroperitoneal fibrosis, sclerosing cholangitis, and inflammatory pseudotumors (33–36). Cases of breast inflammatory pseudotumors have been reported as being related to IgG (37). Immunohistochemical staining showed positive results of numerous plasma cells that had an increased concentration of serum IgG in affected patients. Measuring serum IgG can serve as an effective biomarker for inflammatory pseudotumors in the mammary gland and hormone therapy could be an advantageous treatment option. Clinicopathological characteristics indicate similarities between breast inflammatory pseudotumors and GLM which could potentially be connected to IgG. Granulomatous mastitis is classified into two categories: IgG-related and non-IgG-related. The former occurs during pregnancy, while the latter is linked to autoimmune disorders. Steroid hormone therapy has proven effective in treating non-IgG granulomatous lobular mastitis, reducing the risk of postoperative mammary gland damage and aiding patients' psychological convalescence. This intervention has been studied by Ogura, Cheuk et al. (32–38).

IgG-SM is a type of inflammation that affects the mammary gland. Researchers have been investigating whether granulomatous lobular mastitis can be classified as IgG-SM. A study (38) reports that none of the nine cases of lymphocytic mastitis showed any infiltration of IgG4-positive plasma cells, while six out of seven cases of granulomatous lobular mastitis had no infiltration of IgG-positive plasma cells. Although the study's sample size was limited and conclusive evidence linking granulomatous mastitis with IgG-related sclerosing mastitis remains elusive, it reveals low levels of IgG expression in both GLM and PCM, with consistent patterns. Furthermore, the expression level varies depending on different combinations involving nipple depression features in GLM patients. These findings suggest distinct clinical subtypes exist between the two conditions and may have different underlying causes. The study suggests that there's a significant difference in expression level between patients having inverted vs. non-inverted nipples, likely due to blockage of milk ducts, damage to skin cells lining the ducts, and immune response from exposure to autoantigens all leading to increased IgG levels. This aligns with the notion of bifurcating GLM into either IgG-correlated or non-IgG-correlated categories. However, no notable association was found between fertility condition, duration since lactation cycle completion & manifestation of IgG among individuals. The GLM can be divided into two categories: IgG-correlated and non-IgG4-correlated. The former is associated with nipple depression, while the latter shows no relation to this condition. It's worth noting that the deficient IgG4 expression in GLM or PCM doesn't satisfy the diagnostic standards for IgG-related conditions and isn't classified as such. Consequently, the IgG expression level cannot serve as a basis for immunosuppressive therapy applications.

GLM and PCM are immunological disorders characterized by distinct etiology that involves a variety of immune cells and cellular components. M2 macrophages have a significant impact on the course of both GLM and PCM by stimulating the development of tumors. Inverted nipples may be used to differentiate between IgG4-related and non-IgG4-related granulomatous mastitis (GLM). These diseases may have distinct etiology and immunological mechanisms, necessitating specialized treatment methods. Currently, comprehensive surgery is mostly used to treat GLM and PCM. However, the research demonstrates that some clinical GLM patients may get advantages from immunosuppressive therapies as an alternative to surgical intervention. Additional investigation is required to validate the development of non-lactational mastitis, particularly the role of GLM.

Ethical Approval: The study was carried out following relevant ethical guidelines and regulations. The heads of each health facility gave their permission. Prior to interviewing, information regarding the aim of the study, the right of respondents and the absence of any potential risk for participating in the survey was provided.

Competing interests

The authors declare that they have no competing interests.

Consent to Publish

All authors have showed consent to publish this manuscript.

Consent to Participate

All authors have equally participate in research work.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request

Funding information

No funding information is available.

Conflict of Interest
The authors declare that they have no conflict of interest.

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Study on the Correlation Between the Expression of Cd68 and Cd25 and the Degree of Lesion in Granulomatous Mastitis

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Introduction

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Group A (Study Group)

Group B (Control Group 1)

Group C (Control Group 2)

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