Current perspectives on diagnosis and management of primary and secondary breast endometriosis and potential risk of breast cancer

Abstract

Breast endometriosis represents an exceptionally rare extragenital manifestation of ectopic endometrial tissue, with only a few histologically confirmed breast cases reported worldwide. There appears to be a potential relationship between endometriosis and an increased risk of developing breast cancer. The proposed mechanisms include chronic inflammation, oxidative stress, hormonal dysregulation, and genetic factors such as mutations in the GATA binding protein 2, phosphatase and tensin homolog, Kirsten rat sarcoma viral oncogene homolog, and AT-rich interactive domain-containing protein 1A genes, as well as alterations in circulating microRNAs, primarily miR-199a and the let-7 family of miRNAs. However, the molecular mechanisms underlying this association are not yet fully understood. A structured literature search revealed a small number of primary and secondary breast cases, all of which were confirmed by histopathology. Primary lesions occurred spontaneously, whereas secondary cases were associated with prior breast surgery, suggesting possible implantation of endometrial tissue during surgical manipulation. Morphologic diagnosis relies on identifying endometrial glands and stroma, supported by immunoreactivity for CD10 and paired box gene 8 and negativity for GATA binding protein 2. Clinically, lesions may present as palpable nodules or painful masses, often mimicking malignancy or fat necrosis, particularly in patients with a history of reconstructive or reduction surgery. Complete surgical excision was curative in all reported cases, with no recurrence or malignant transformation documented during follow-up. Although exceedingly rare, recognition of this entity is essential to avoid misdiagnosis and to enhance the understanding of the mechanisms underlying ectopic endometrial implantation in extrapelvic sites such as the breast.

Key Words: Endometriosis; Mammary endometriosis; Rare breast lesions; Genomic profile of endometriosis; Ectopic extrapelvic location; Palpable nodules; Painful masses; Malignant transformation risk

Core Tip: Breast endometriosis constitutes an exceedingly uncommon extragenital presentation of ectopic endometrial tissue, with only a limited number of histologically verified cases documented globally. Endometriosis is associated with increased risks of breast, endometrial, ovarian, and thyroid cancers; melanoma; and non-Hodgkin lymphoma. Given its potential for clinical and radiologic mimicry of malignancy and its implications for surgical management, breast endometriosis warrants awareness among pathologists and breast surgeons. Current genomic research has opened new horizons in both diagnosis and therapy. Surgical excision is the method of choice, offering a permanent cure and no recurrence.

INTRODUCTION

Endometriosis is a common, chronic, histologically benign, yet biologically aggressive, estrogen-dependent inflammatory gynecological condition characterized by the presence of endometrial glands and stroma outside the uterine cavity, primarily within the pelvis. It affects mainly women of reproductive age but can also affect those who are postmenopausal. Several genes, including the GATA2 gene, play a role in the development of endometriosis[1,2]. Endometriosis, a complex disease, affects 5%-10% of women of reproductive age[3], with more than 176 million cases reported worldwide annually[4]. The diagnosis of endometriosis is often delayed, usually 8 years to 10 years, because of nonspecific manifestations[2,5].

Ectopic deposits of endometrial tissue retain hormonal responsiveness, resembling that of the normal endometrium. Thus, under the influence of estrogen and progesterone, this ectopic tissue undergoes cyclical proliferation, bleeding and inflammation[6,7]. This kind of repeated tissue injury and repair process generates chronic inflammation, oxidative stress, fibrosis and adhesion, resulting in chronic pain and distortion of the pelvic anatomy. Endometriosis invades local tissues, induces angiogenesis, and is characterized by hormonal and inflammatory dysregulation, similar to neoplastic processes. The pelvis is the most common site of involvement. Nevertheless, endometrial foci have been identified in other organ systems, including the lung, urinary tract, bowel, diaphragm, and even the central nervous system. These unusual localizations are collectively termed extrapelvic or extragenital endometriosis[2,5].

Symptoms such as painful menstruation (dysmenorrhea), pelvic pain, dyspareunia and infertility significantly reduce quality of life, causing psychological distress[2,5]. Progestogens are the primary treatment option and have been shown to effectively manage pain and lower recurrence rates[8].

Epidemiological studies indicate a possible link between endometriosis and an increased risk of cancer[9-11]. In premenopausal women, endometriosis or its treatment may cause premature or early menopause. Therefore, it is crucial for health care providers to be well trained in managing endometriosis during menopause and beyond. Surgery is the preferred treatment for symptomatic endometriosis after menopause, as it can alleviate pain, provide an accurate diagnosis, and reduce the risk of malignancy[12]. Laparoscopic surgery, which utilizes advanced technological resources, has become the predominant method of surgical intervention[13]. Endometriosis is also associated with a higher risk of cardiovascular disease; ovarian, breast, and thyroid cancers; and osteoporosis[12].

There is a potential connection between endometriosis and an elevated risk of breast cancer[4,9,12,14]. Breast endometriosis, where ectopic endometrial tissue is found in the breast, is extremely rare, with only a few histopathologically confirmed cases reported worldwide[4,12]. The first histologically proven case of mammary endometriosis was described by Moloshok and Ivan'ko[15] in 1984. Since then, very few cases have been documented - primary or iatrogenic. Proposed mechanisms include lymphovascular spread, coelomic metaplasia of pluripotent stromal cells, and iatrogenic transplantation of occult endometrial tissue during reconstructive procedures such as transverse rectus abdominis myocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flap surgery[16,17]. Because of its extreme rarity and histologic similarity to inflammatory or neoplastic lesions, accurate diagnosis requires a high index of suspicion and confirmation by immunohistochemistry[18]. All published, histopathologically confirmed cases of mammary endometriosis are shown in Table 1.

Table 1 Published, histopathologically confirmed cases of mammary endometriosis.

Ref.	Age (years)	Location	Classification	Clinical presentation	Imaging findings	Histopathology/immunohistochemistry	Proposed pathogenesis	Outcome
Moloshok and Ivan'ko[15]	35	Subareolar breast parenchyma	Primary mammary endometriosis	Painful subareolar nodule, clinically interpreted as fibroadenoma	Not reported	Endometrial glands and stroma embedded in breast tissue with hemosiderin deposition	Lymphovascular dissemination	Complete remission after excision
McArthur et al[17]	35	Reconstructed breast (DIEP flap)	Iatrogenic mammary endometriosis	Painless breast lump 1-year post-reconstruction	Not specific	Endometrial-type glands and stroma within adipose tissue of transferred flap, focal hemorrhage	Iatrogenic transplantation from abdominal donor site	No recurrence after excision
Al-Wageeh et al[52]	16	Retroareolar breast parenchyma	Primary mammary endometriosis	Painful retroareolar swelling, initially suspected abscess	Poorly circumscribed cystic-solid lesion on ultrasound	Endometrial glands and stroma with hemosiderin-laden macrophages; stromal CD10(+), glandular ER/PR(+)	De novo mammary localization	No recurrence at 1-year follow-up
De la Riva-Morales et al[16]	49	Interface between DIEP flap and native breast	Iatrogenic mammary endometriosis	Firm breast nodule 1-year post-reconstruction	Mimicked fat necrosis	Well-formed endometrial glands and stroma with hemosiderin; PAX8(+), CD10(+), GATA3(-)	Iatrogenic implantation	Complete remission after excision
Reza et al[51]	24	1Skin between breasts (cutaneous)	Cutaneous endometriosis (non-mammary)	Painful swollen mass with periodical abscess discharge	Not specific fluid findings	Excision biopsy Endometrial glands and stroma with hemosiderin within skin	Lymphovascular dissemination	Excision

¹This case is included for anatomical comparison only and does not represent true mammary parenchymal involvement. Mammary cutaneous endometriosis represents a diagnostic challenge owing to its infrequent occurrence and its clinical presentation, which often resembles other breast disorders. Nonetheless, it is an established condition characterized by the presence of ectopic endometrial tissue within the skin of the breast, leading to cyclical symptomatology. DIEP: Deep inferior epigastric perforator; CD10: Cluster differentiation, antigen; PAX8: Pair boxed, antigen; GATA3: GATA binding protein 3, transcription factor; ER: Endoplasmatic reticulum; PR: Progesterone receptors.

While extremely rare, mammary endometriosis falls within a broader spectrum of heterotopic or metaplastic lesions reported in breast tissue, including thyroid tissue, cutaneous adnexal elements, melanocytic nevi, and Mullerian-type cysts. These phenomena reinforce the biological plausibility of endometrial implantation or metaplasia within the mammary microenvironment[19,20].

Endometriosis is linked to an increased risk of several cancers, including ovarian, endometrial, and breast cancer; melanoma; and non-Hodgkin lymphoma[9,21]. Genetic mutations in the AT-rich interactive domain-containing protein 1A, phosphatase and tensin homolog, GATA2, and Kirsten rat sarcoma viral oncogene homolog genes have been implicated in both endometriosis and certain cancers, suggesting that these genetic changes may be key factors in the development of both conditions[9,22].

Many circulating microRNAs (miRNAs) have been studied in the plasma or serum of patients with endometriosis to develop noninvasive diagnostic biomarkers for early detection. Among these, the roles of miR-199a and the let-7 family of miRNAs in regulating cell proliferation, invasion, apoptosis, and epithelial-mesenchymal transition are notable. Further research and strategic development targeting these miRNAs could provide effective therapeutic options for managing endometriosis[23].

This minireview synthesizes and critically examines all reported cases localized within the breast parenchyma, highlighting the associated clinical and diagnostic complexities. Furthermore, it delineates the clinicopathological, immunohistochemical, and pathogenetic characteristics of both primary and secondary variants.

PATHOGENETIC MECHANISM

The pathogenetic mechanism of endometriosis remains unknown. Several theories have been proposed to explain the ectopic implantation of endometrial tissue, none of which alone account for all observed patterns[24,25].

Anatomic or implantation theories

The classical and most widely accepted model, proposed by Sampson[26] in 1927, is that of retrograde menstruation, whereby viable endometrial cells reflux through the fallopian tubes into the peritoneal cavity, adhere to serosal surfaces, and proliferate. However, this mechanism alone cannot explain extrapelvic localizations.

Complementary to Sampson’s theory[26] is lymphatic and hematogenous dissemination (Halban’s theory), which accounts for distant extrapelvic localizations, such as pulmonary, cerebral, and mammary endometriosis, through the embolic spread of endometrial fragments. Together, these mechanisms explain both local implantation and distant metastasis-like behavior[27].

Metaplastic theories

The hypothesis of coelomic metaplasia, originally proposed in 1942, provides a biologically plausible explanation for the occurrence of endometriosis in locations not accessible by retrograde menstruation (unrelated to the Mullerian tract, such as the pleura or breast) and in the absence of a functioning uterus (among women with Mullerian duct defects, postmenopausal women, or premenarchal girls). This theory proposes that stem cells can transform into endometrial-type epithelium and stroma under hormonal, inflammatory, or genetic influences[26].

Molecular and stem-cell-based theories

Recent evidence highlights the contribution of bone marrow-derived cells and endometrial stem cells capable of systemic migration and differentiation into ectopic endometrial tissue. At the molecular level, endometriotic lesions are characterized by estrogen receptor (ER) β overexpression, local aromatase activity, and resistance to progesterone-mediated apoptosis, which together promote autonomous growth outside the uterus. These endocrine and epigenetic alterations establish a permissive microenvironment for cell survival, angiogenesis, and invasion mechanisms that likely underpin extrapelvic dissemination. Dysregulated immune responses and increased oxidative stress further sustain the survival and invasiveness of ectopic endometrial cells[28]. Together, these mechanisms support the view of endometriosis as a multifactorial, systemic, and stem-cell-driven disorder rather than a purely retrograde implantation disease[29].

More precisely, the pathogenesis of endometriosis is complex and involves a range of mechanisms, such as retrograde menstruation, coelomic metaplasia, immune dysregulation, environmental factors, and, notably, genetic susceptibility. Among genetic contributors, chromosome 10q26 has been significantly linked to endometriosis, mainly in patients with familial conditions. Furthermore, recent genome-wide association studies have identified additional locations, including 7p15.2, reinforcing the hypothesis that hereditary factors play a critical role in disease pathophysiology. Endometriosis is associated with various factors, including inflammation, oxidative stress, stem cell activity, hormonal influences, genetic predisposition, immune dysfunction, and the upregulation of antiapoptotic molecules. The genetic architecture underlying endometriosis encompasses a broad array of gene variants and polymorphisms that modulate diverse biological pathways, such as inflammation, immune regulation, steroid hormone signaling, angiogenesis, and tissue remodeling. Notably, these genes are not exclusively related to endometriosis but are also involved in other chronic inflammatory and hormone-related disorders, suggesting a shared molecular framework. A key pathogenic mechanism of endometriosis involves the dysregulation of estrogen and progesterone receptor signaling, which alters gene transcription and cellular behavior in ectopic endometrial tissues. Following the discovery of a stem cell population within the endometrium, recent research has increasingly focused on the hypothesis that the dissemination of these cells via the bloodstream, lymphatic circulation, or retrograde menstruation may contribute to the initiation of endometriotic lesions. The observation that endometriotic lesions may originate from clonal populations, via stem cells shed during menstruation, supports the notion that endometrial stem cells are instrumental in lesion formation. Recent advances in single-cell transcriptomic analyses have revealed stem-like epithelial cells characterized by leucine-rich repeat-containing G-protein coupled receptor 5 and SRY-box transcription factor 9 expression, as well as stromal cell populations, which collectively establish proinflammatory and profibrotic microenvironments conducive to disease progression[30,31].

Extrapelvic endometriosis, which accounts for less than 1% of cases, involves diverse sites, such as the lung, diaphragm, urinary bladder, bowel, abdominal wall, and even the brain. These distant manifestations support the view of endometriosis as a systemic, metastasis-like disorder capable of lymphovascular spread. Among all reported extrapelvic localizations, the breast represents one of the rarest and least intuitive sites. Its ectodermal embryologic origin and lack of continuity with Mullerian-derived structures make the occurrence of endometrial tissue in the mammary stroma biologically intriguing. The precise mechanism of mammary involvement remains unclear. In primary cases, the most plausible explanations include lymphatic or hematogenous dissemination and coelomic metaplasia. Endometrial cells have been shown to disseminate via pelvic lymphatics and blood vessels, explaining the presence of distant lesions such as those in the lung or brain. Similar embolic spread could theoretically seed breast tissue, which has a rich lymphovascular network. Alternatively, coelomic metaplasia of pluripotent stromal cells within the mammary environment might result in the production of endometrial-type epithelium under hormonal or inflammatory stimuli. In iatrogenic cases following reconstructive surgery, direct transplantation of microscopic endometrial foci from abdominal donor sites provides the most convincing mechanism, especially in patients with prior DIEP or TRAM flaps. The recognition of both primary and iatrogenic forms supports the notion that mammary endometriosis is not a single pathological entity but rather a final phenotype arising from multiple pathways[32].

GENOMIC PROFILE

Endometriosis is linked to a high risk of several cancers, including ovarian, endometrial, and breast cancer; melanoma; and non-Hodgkin lymphoma[9,21]. Genetic mutations in genes such as the AT-rich interactive domain-containing protein 1A, phosphatase and tensin homolog, and Kirsten rat sarcoma viral oncogene homolog are involved in both endometriosis and certain cancers, indicating that these mutations may play crucial roles in the development of both conditions[9].

The genomic profiles of endometriosis[33,34] and cancer include mutations in cancer-related genes such as Kirsten rat sarcoma viral oncogene homolog, PIK3CA, FBXW7, PPP2R1A, and PIK3R1. However, these mutations alone are insufficient to cause malignant transformation of endometriosis. Identifying the factors that lead to this transformation remains challenging[35]. Hormonal imbalances combined with oxidative stress within the endometriosis microenvironment may be key contributors to both infertility and cancer development. Oxidative stress promotes angiogenesis, proliferation of endometriotic tissue, and selective iron-induced DNA damage, resulting in oncogene mutations in genes such as TP53, Kirsten rat sarcoma viral oncogene homolog, phosphatase and tensin homolog, PIK3CA, and AT-rich interactive domain-containing protein 1A[21]. Furthermore, exposure to environmental endocrine-disrupting chemicals, such as those found in plastics, may also induce gene mutations[36].

A total of 26 shared differentially expressed genes were identified, with insulin-like growth factor 1 (IGF-1), CREBBP, EP300, and PIAS1 recognized as key hub genes. Increased expression of the IGF-1 gene was significantly associated with poor survival outcomes in patients with endometrial cancer. Genetic connections exist among endometrial cancer, endometriosis, and obesity, highlighting high IGF-1 gene expression as a potential prognostic indicator for endometrial cancer and recurrent changes in hub genes as promising therapeutic targets[37].

An association between endometriosis and the PGR-B, SF-1, RASSF1A, HOXA10, COX-2, IL-12B, and GATA6 genes has been described[38]. Epigenetic regulation is crucial for controlling immunity and inflammation in endometriosis. Genes related to m6A regulators, such as METTL3, CBLL1, and YTHDF2, could serve as valuable biomarkers for endometriosis in ectopic endometrial tissue. Targeting m6A regulators presents a promising potential therapeutic strategy for treating endometriosis[39].

The expression of the VEGF, IGF1, IGF2, and H19 LncRNA genes, along with epigenetic changes in the former gene, plays a dynamic role in the development of endometriosis. In particular, hypomethylation of H19-DMR region II may contribute to the dysregulation of IGF2 in endometriosis[40].

Transfer RNA fragments (tRFs) are differentially expressed in various cancers and have emerged as new noninvasive biomarkers. PANDORA-seq, a sequencing technique, offers strong potential for early diagnosis and treatment through the detection of tRFs. Using PANDORA-seq, both eutopic and ectopic endometrial tissues were analyzed. Eleven differentially expressed tRF target genes were found to be significantly involved in endometriosis-related signaling pathways, including p53, Ras, mitogen-activated protein kinase, and mitophagy. These differentially expressed tRFs may contribute to the development of endometriosis by regulating target genes within the mitogen-activated protein kinase and autophagy signaling pathways. Therefore, differentially expressed tRFs hold promise as new noninvasive biomarkers for endometriosis[41].

miRNAs are delivered to recipient cells via exosomes, where they influence cellular functions. Exosomal miRNAs play important roles in various pathological processes in endometriosis, including angiogenesis, ectopic lesion growth, cell migration, and immune system activation. Among these, miR-199a and the let-7 family are particularly significant. Their involvement in multiple mechanisms related to endometriosis makes them promising noninvasive biomarkers that warrant further research[23].

Recent studies have demonstrated that noncoding RNAs, such as long noncoding RNAs and miRNAs, may play a role in the development of endometriosis[42]. Measuring free circulating DNA and analyzing the differential methylation patterns of specific genes have recently been suggested as promising new noninvasive diagnostic biomarkers for detecting endometriosis[43,44].

IMPORTANT CONSIDERATIONS REGARDING ENDOMETRIOSIS AND BREAST CANCER

Endometriosis and breast cancer represent significant global health issues affecting women. Endometriosis has garnered significant interest, yet its cause remains unknown. However, it appears to involve several contributing factors[45]. This condition is characterized by the growth of endometrial tissue outside the uterus, leading to symptoms such as pelvic pain, painful menstruation, and infertility or subfertility[46]. These symptoms affect 50%-80% of women who experience pelvic pain and up to half of those who face fertility problems[4]. Endometriosis a polymorphic, multisite disease for which no cures or methods of prevention currently exist[4,47]. The pelvic cavity represents the predominant site for endometriosis and frequently involves the ovaries, vagina, retrocervical region, bladder dome, rectosigmoid colon, and round ligaments. In contrast, atypical endometriosis is an uncommon condition that poses significant diagnostic challenges. The urinary tract, gastrointestinal tract, breast, lungs, inguinal region, pelvic nerves and umbilicus constitute the most frequently reported atypical locations for endometriotic lesions[47]. Diagnosis usually involves pelvic exams and ultrasound imaging, but laparoscopy with histopathological confirmation remains the definitive method despite risks such as tissue damage, adhesion formation, and potential effects on fertility. The biomarker cancer antigen 125 is elevated in advanced stages but is not sensitive enough for early detection.

Breast cancer accounted for 11.7% of all cancer cases globally in 2020, with approximately 2.3 million new cases, making it a leading cause of death among women. Risk factors include older age, genetic predisposition, a history of benign breast conditions, hormone exposure, fertility issues, obesity, and radiation exposure. Both endometriosis and breast cancer share key features and risk factors, such as a dependence on estrogen, progressive growth, invasion, recurrence, and the potential to metastasize. Elevated estrogen levels are found in the ectopic lesions of endometriosis patients[4].

Breast cancer risk in patients with endometriosis

Two functional single-nucleotide polymorphisms, rs2046210 and rs9383590, previously linked to breast cancer risk, along with rs9340799, are associated with implantation defects and infertility and were investigated for their potential relationships with endometriosis susceptibility, disease progression, and regulation of the ESR1 gene in patients with endometriosis. Evidence suggests that rs2046210 may represent a functional genetic variant contributing to the development and progression of endometriosis[48].

A retrospective cohort study conducted in Germany reported no significant association between endometriosis and an elevated risk of subsequent breast cancer[49]. In contrast, a comprehensive cohort study from China, which included 14 studies, indicated that endometriosis may increase the risk of both endometrial and breast cancers. Consequently, it has been recommended that women with endometriosis undergo routine screening as part of their long-term clinical management[50].

DIAGNOSIS

The diagnostic approach in order of priority is shown schematically in Figure 1.

Figure 1 Scheme of diagnostic approach in order of priority for mammary endometriosis. MRI: Magnetic resonance imaging; CD10: Cluster differentiation, antigen; PAX8: Pair boxed, antigen; GATA3: GATA binding protein 3, transcription factor; ER: Endoplasmatic reticulum; PR: Progesterone receptors.

Clinical presentation

The majority of reported patients present with localized breast pain or a palpable mass. Symptoms are sometimes cyclic and correlated with menstruation, although this feature has been inconsistently reported. In postoperative cases (TRAM/DIEP), the latency between surgery and lesion detection range from months to one year. Breast endometriotic lesions can clinically manifest as palpable nodules or painful lumps, frequently resembling malignancies or fat necrosis, particularly in individuals with a prior history of reconstructive or reduction mammoplasty. In adolescents or women without prior surgery, lesions are frequently misdiagnosed as inflammatory or cystic processes. Definitive diagnosis is achieved only after surgical excision and histopathological evaluation[15-17,51,52].

Imaging modalities

Imaging methods are considered the gold standard for diagnosing endometriosis, with transvaginal ultrasound and magnetic resonance imaging (MRI)providing the greatest benefit during the diagnostic process[53]; for suspected breast endometriosis, mammography, ultrasound, MRI and stereotactic image-guided fine-needle core biopsy of the breast are indicated[54], either alone or with the support the novel artificial intelligence-based tools[55].

Imaging was nonspecific across all reported cases of breast endometriosis[56,57]. Mammography and ultrasound typically revealed circumscribed or irregular hypoechoic nodules, often classified as BI-RADS 4 and interpreted as fat necrosis, abscess, or complex cysts. MRI was not routinely performed, but by analogy with extrapelvic endometriosis, lesions may show T1 hyperintensity due to subacute hemorrhage and variable enhancement[57].

MRI[58] is advised when transvaginal or breast ultrasound results are inconclusive or negative in symptomatic patients prior to surgery or an interventional procedure, or following surgery if symptoms continue. The European Society of Urogenital Radiology guidelines emphasize the importance of standardized MRI reporting, which should incorporate the use of MRI classification[59]. Recommended preimaging procedures include fasting, the administration of antiperistaltic agents, moderate bladder filling, and bowel preparation. A thorough MRI protocol should include multiplanar T2-weighted sequences, T1-weighted sequences, and coverage of the kidneys. Superficial endometriosis should be identified on T1-weighted fat-suppressed images as areas of high signal intensity on the peritoneal surface. Endometriomas should be detailed regarding their number, signal intensity, central or peripheral position, bilaterality, and MRI classification[60].

Histopathology

Histologic diagnosis requires the presence of at least two of three elements: Endometrial glands, endometrial stroma, and hemosiderin-laden macrophages (evidence of prior hemorrhage). This classical triad, originally proposed for pelvic disease, was consistently applied to mammary cases. Some lesions display predominantly stromal elements, necessitating immunohistochemical confirmation[18,61].

Immunohistochemistry

The diagnostic panel includes the following: CD10, a sensitive marker of endometrial stroma[18]. Paired box gene 8 (PAX8), a nuclear marker of Mullerian epithelium, preserved in extragenital endometriosis[62]. GATA3, a marker of mammary differentiation, typically negative in reported cases[61]. ER and progesterone receptor, may be expressed but lack diagnostic specificity in breast tissue[62,63].

Mammary endometriosis represents one of the rarest and least understood localizations of extrapelvic endometriosis. Since the first description, only a handful of histologically verified cases have been published, emphasizing the exceptional rarity of this entity. While endometriosis commonly affects the pelvis, its presence within the breast parenchyma challenges existing pathogenetic models and underscores the systemic potential of the disease. The immunohistochemical profile is shown in Table 2.

Table 2 Immunohistochemical profile.

Marker	Expected result	Diagnostic significance
CD10	Positive (stromal cells)	Sensitive marker of endometrial stroma. Useful when glands are scant
PAX8	Positive (glandular epithelium)	Confirms Mullerian epithelial origin
GATA3	Negative	Excludes breast epithelial origin
ER/PR	Often positive	Hormonal responsiveness, nonspecific within breast tissue

CD10: Cluster differentiation, antigen; PAX8: Pair boxed, antigen; GATA3: GATA binding protein 3, transcription factor; ER: Endoplasmatic reticulum; PR: Progesterone receptors.

Hormonal context

The hormonal milieu of the breast, which is rich in estrogen and progesterone receptors, may facilitate the survival of ectopic endometrial tissue. Endometriotic implants are known to overexpress aromatase and ER while showing progesterone resistance, leading to local hyperestrogenism and inflammation. This hormonal microenvironment could explain why transplanted or disseminated endometrial cells can survive and proliferate within the mammary stroma[6,7]. Furthermore, cyclic hormonal stimulation may produce recurrent microhemorrhage, accounting for the hemosiderin deposition observed histologically[18,61]. Although endometriosis is associated with an increased risk of certain malignancies, particularly clear-cell and endometrioid ovarian carcinoma, there is no evidence to date linking mammary endometriosis with breast cancer. Nevertheless, its ability to mimic carcinoma both radiologically[58] and histologically makes diagnostic vigilance essential[6,7].

Diagnostic pitfalls

Mammary endometriosis often presents as a palpable mass or focal pain and may simulate abscesses or fat necrosis on imaging. Differential diagnoses may also include fibroadenoma and ductal carcinoma when the lesion represents a Mullerian metastasis. Radiologic findings are usually nonspecific. Therefore, histopathology remains the cornerstone of diagnosis. The characteristic triad - endometrial glands, stroma, and hemosiderin-laden macrophages - is diagnostic when present. However, stroma-predominant lesions can be misinterpreted as fibrosis or scar tissue, highlighting the role of immunohistochemistry. CD10-positive stroma and PAX8-positive glandular epithelium, coupled with GATA3 negativity, confirm a Mullerian origin and exclude primary mammary pathology[18,61]. Because ER/progesterone receptor can be expressed in both the mammary and endometrial epithelium, they serve as supportive rather than discriminatory markers[6,7].

MANAGEMENT

With respect to endometriosis-related infertility, new treatments, such as antioxidant molecules and stem cell therapy, require further research to confirm their effectiveness[52]. Drugs aimed at key genes that cause abnormal gene expression in the eutopic endometrium may aid in treating infertility in women with endometriosis[64]. For endometriosis affecting the fallopian tubes, evaluation includes assessing how salpingectomy can alleviate disease-related symptoms and identifying patients who might benefit from risk-reducing salpingectomy based on their likelihood of developing ovarian cancer[65].

All patients with breast location underwent local excision. No adjuvant hormonal therapy was required, and no recurrences have been documented to date. For iatrogenic cases, recognition of donor-site origin (TRAM/DIEP) was emphasized to prevent misdiagnosis as flap necrosis or recurrent malignancy. Given the absence of systemic disease, surgery alone appears curative for isolated mammary endometriosis[15-17,52].

Hormonal therapy may offer symptomatic benefit but is not definitive for localized mammary lesions. Even if concurrent pelvic disease is present, systemic hormonal therapy is generally unnecessary for extrapelvic endometriosis. The key clinical message is that awareness of this entity prevents unnecessary radical surgery or misdiagnosis as malignancy, particularly in postreconstruction settings[66].

Broader implications

Beyond its rarity, mammary endometriosis provides valuable insights into the systemic behavior of endometriosis as a disseminated, hormonally responsive condition. The presence of lesions in a non-Mullerian organ such as the breast supports theories of hematogenous spread and stem-cell plasticity, reinforcing the need to view endometriosis as a multisystemic disorder rather than a purely pelvic disease. Mammary endometriosis, although exceedingly rare, exemplifies the migratory potential of endometrial tissue and underscores the diagnostic value of immunohistochemistry in distinguishing. Mullerian from mammary lesions. Future research should focus on molecular characterization of such ectopic tissue and on assessing whether local microenvironmental factors in the breast stroma facilitate endometrial cell survival. Nevertheless, the pathogenesis of breast endometriosis remains unclear. For primary lesions, lymphatic or hematogenous dissemination of endometrial cells, analogous to benign metastasis, has been proposed. Evidence of lymph node involvement and lymphangiogenesis in deep endometriosis supports this mechanism. Alternatively, coelomic metaplasia or stem cell differentiation may account for de novo Mullerian-type epithelium within the breast stroma. In iatrogenic cases, inadvertent transplantation of occult endometrial foci during abdominal flap reconstruction is the most plausible mechanism. No malignant transformation has been reported in any breast cases, although it can occur in long-standing ovarian or peritoneal endometriosis. The link between endometriosis and breast cancer risk remains inconclusive[66-68].

While the majority of research predominantly concentrates on women of reproductive age, the guidelines additionally consider endometriosis in both adolescent and postmenopausal populations. It delineates the diagnostic approach to endometriosis, critically evaluating the roles of laparoscopy and histological examination as the definitive diagnostic standards. Therapeutic strategies for alleviating endometriosis-related pain symptoms, including the use of analgesics, pharmacological interventions, and surgical procedures, are comprehensively reviewed. Furthermore, nonpharmacological treatment modalities are also examined. In addressing endometriosis-associated infertility, the guidelines identify surgical intervention and reproductive technologies as viable management options[61].

CONCLUSION

Pelvic endometriosis is a common gynecological condition with an unknown cause, and currently, there is no reliable noninvasive biomarker for its diagnosis. It is advised that women diagnosed with endometriosis undergo regular screening as an integral component of their long-term follow-up. Despite the extreme rarity of breast endometriosis, whether primary or iatrogenic, accurate identification by MRI is crucial for preventing misdiagnosis and advancing the understanding of the pathophysiological mechanisms involved in ectopic endometrial implantation at extrapelvic locations, including the breast. Diagnosis requires a high index of suspicion and confirmation by immunohistochemistry. Recognition of the characteristic immunoprofile - CD10 and PAX8 positivity with GATA3 negativity - is crucial to prevent overtreatment. Definitive treatment can be achieved through complete surgical excision; however, consistent postoperative monitoring is advised to detect potential recurrence or malignant transformation.