The role of steroid receptors, peptides and growth factors in the aetiopathogenesis of idiopathic gynecomastia.

Idiopathic gynecomastia is a diagnosis of exclusion. We aimed to evaluate the role of steroids, peptides and growth factors in these patients. Those with bilateral idiopathic gynecomastia (n = 29) (Simon's grade IIb or III) who underwent gland excision were evaluated by immunohistochemical techniques using semi-quantitative grading for oestrogen receptor (ER), progesterone receptor (PR), aromatase, androgen receptor (AR), peptides (IGF-1, IGF-2, HER-2, parathyroid-hormone related peptide [PTHrP]) and growth factors (EGFR, TGFß). The cohort comprised 29 patients, with a mean age of 25.3 ± 5.1 years and a mean body mass index of 27.2 ± 2.3 kg/m2 . Grade IIb gynecomastia was present in 79.1% and moderate-to-severe insulin resistance (HOMA-IR >3) in 53.7% of patients. ER expression was positive in 100% samples, followed by AR (96.5%), aromatase (96.5%) and PR (93.1%). IGF-1 was expressed in 86.2% of the cohort, IGF2 in 27.5% and HER-2 in only two samples, with both showing weak immunoexpression. None of the patients had positive expression of EGFR, TGF-ß or PTHrP. There was no association between immunoexpression and gynecomastia grade. This study demonstrates the predominant role of oestrogen, aromatase and insulin resistance in the aetiopathogenesis of idiopathic gynecomastia and implicates the paracrine hyperestrogenic milieu in its causation as circulating hormones were normal.

[Gynaecomastia and adipomastia on black skin: Clinical and surgical particularity]. / Gynécomastie et adipomastie sur peau noire : particularités clinique et chirurgicale.

AIM: Analyze the management of gynecomastia and adipomastia; and identify the peculiarities in black people in a general surgery department of the CHU Sylvanus Olympio in Lomé (Togo). PATIENT AND METHOD: Descriptive retrospective study included 43 cases of gynecomastia and 5 cases of adipomastia (January 2014 to December 2020). The data taken into account were: epidemiological, clinical, paraclinical and the treatment (surgery and medical). The administration of hydrocortisone (solumedrol 120mg/day) for 3days immediately after surgery and the application of shea butter on the scar were performed. RESULT: Patients consult for aesthetic discomfort, especially with bilateral lesions and fear of breast cancer for unilateral lesions. Morpho-types 3 and 4 are therefore the most frequent in 75% of cases. Age was over 30years in 87% of patients. We noted retro-areolar fibrosis. The etiology was dominated by idiopathic causes. The surgery was performed in 85% of the cases. The morbidities were 5 cases of hypertrophic scars without keloid. CONCLUSION: Surgical difficulties on black skin are not only technical, but also scarring: hypertrophy and keloids. A delay in surgical management after 30years, and the prevention of unsightly scars would be a track for improving the aesthetic result.

Isoniazid-induced gynaecomastia: report of a paediatric case and review of literature.

BACKGROUND: Gynaecomastia is a fairly common condition in puberty but is rare in prepubertal boys. While it is necessary to exclude possible endocrinopathay in prepubertal gynaecomastia, medication is an important and potentially reversible cause to consider in new onset gynaecomastia. Isoniazid-induced gynaecomastia has been reported in adult males, but none was reported in the paediatric population and general paediatricians may not be aware of this uncommon side effect. CASE PRESENTATION: We hereby report a 11-year-old prepubertal boy who developed gynaecomastia while taking anti-tuberculosis drugs. Investigations excluded endocrinopathies. Gynaecomastia subsided 8 weeks after stopping isoniazid. CONCLUSION: This case is the first paediatric case report describing the association of gynaecomastia with isoniazid use. It is important for general paediatricians to recognize this entity, as prompt diagnosis and cessation of the offending drug can lead to resolution of the problem.

Atypical ductal hyperplasia in men with gynecomastia: what is their breast cancer risk?

PURPOSE: Atypical ductal hyperplasia (ADH) significantly increases the risk of breast cancer in women. However, little is known about the implications of ADH in men. METHODS: Review of 932 males with breast pathology was performed to identify cases of ADH. Patients were excluded if ADH was upgraded to cancer on excision, or if they had contralateral breast cancer. Cases were reviewed to determine whether any male with ADH developed breast cancer. RESULTS: Nineteen males were diagnosed with ADH from June 2003 to September 2018. All had gynecomastia. Surgical procedure was mastectomy in 8 patients and excision/reduction in 11. One patient had their nipple areola complex removed, and 1 required a free nipple graft. Median patient age at ADH diagnosis was 25 years (range 18-72 years). Of the 14 patients with bilateral gynecomastia, 10 had bilateral ADH and 4 had unilateral. Five cases of ADH were described as severe, bordering on ductal carcinoma in situ. No patient reported a family history of breast cancer. No patient took tamoxifen. At a mean follow-up of 75 months (range 4-185 months), no patient developed breast cancer. CONCLUSION: Our study is the first to provide follow-up information for males with ADH. With 6 years of mean follow-up, no male in our series has developed breast cancer. This suggests that either ADH in men does not pose the same risk as ADH in women or that surgical excision of symptomatic gynecomastia in men effectively reduces the risk of breast cancer.

Developmental disorders and malformations of the breast.

Developmental abnormalities and malformations of the breast are rare and encompass a variety of genetic, syndromic, acquired and sporadic conditions. Abnormalities in development may include irregularities in the nipple areolar complex and/or the underlying glandular tissue, resulting in under or overdevelopment of breasts. Age of presentation and clinical severity is dependent on the underlying biologic cause. Abnormalities may involve the entirety of unilateral or bilateral breasts, particularly in association with syndromic conditions or endocrine abnormalities. Disordered development may also be focal, resulting in tumor-like lesions such as hamartomas, pseudoangiomatous stromal hyperplasia and gynecomastia. In this review, we discuss the disorders of breast development including etiologies, clinical presentations and corresponding histopathologic features.

Trends in Imaging Workup of the Male Breast: Experience from a Single Center.

BACKGROUND: Male breast cancer (MBC) is a rare disease representing less than 1% of breast cancers. In the absence of a screening program, such as for females, the diagnostic workup is critical for early detection of MBC. OBJECTIVES: To summarize our institutional experience in the workup of male patients referred for breast imaging, emphasizing the clinical, imaging, and histopathological characteristics of the MBC cohort. METHODS: All male patients who underwent breast imaging between 2011 and 2016 in our institution were retrospectively reviewed. Clinical, radiological, and histopathological data were collected and statistically evaluated. All images were reviewed using the American College of Radiology Breast Imaging Reporting and Data System. RESULTS: 178 male patients (average age 61 years, median age 64), underwent breast imaging in our institution. The most common indication for referral was palpable mass (49%) followed by gynecomastia (16%). Imaging included mostly mammography or ultrasound. Biopsies were performed on 56 patients, 38 (68%) were benign and 18 (32%) were malignant. In all, 13 patients had primary breast cancer and 5 had metastatic disease to the breast. Palpable mass at presentation was strongly associated with malignancy (P = 0.007). CONCLUSIONS: Mammography and ultrasound remain the leading modalities in breast imaging among males for diagnostic workup of palpable mass, with gynecomastia being the predominant diagnosis. However, presentation with palpable mass was also associated with malignancy. Despite a notable MBC rate in our cohort, the likelihood of cancer is low in young patients and in cases of gynecomastia.

3D Mammometric Changes in the Treatment of Idiopathic Gynecomastia.

BACKGROUND: Three-dimensional surface imaging (3DSI) has shown promise for plastic surgeons to objectively assess changes in body contour and breast volume. OBJECTIVES: To assess the surgical outcome after bilateral subcutaneous mastectomy (BSM) and water jet-assisted liposuction (WAL) as treatment for idiopathic gynecomastia, using 3DSI to document changes regarding nipple-areolar complex (NAC) and breast volume. METHODS: Thirty male patients (Simon II A to B) receiving BSM and WAL were enrolled. Eight subjects received additional mastopexy and NAC reduction. Use of a Vectra 3D Imaging System® before and 6 months after surgery provided data regarding changes of NAC placement and NAC and breast dimensions. The sum volume of intraoperatively approximated lipoaspirate before and after centrifugation and mastectomy specimens quantified using water displacement were compared with 3D-assessed differences in volume. RESULTS: When compared to the NAC dimensions defined during surgery, patients receiving NAC reductions showed nonsignificant postoperative changes in NAC dimensions. Patients without additional mastopexy showed a significant (p < 0.001) vertical (15.7 ± 14.3%) and horizontal (17.1 ± 15.0%) reduction in NAC diameter. 3D volume changes (92.8 ± 26.4 mL) showed significant differences (p < 0.001) 6 months after surgery compared to the intraoperatively measured lipoaspirate before (182 ± 54.5 mL) and after (120 ± 34.6 mL) centrifugation. CONCLUSION: Although it is clear that patient satisfaction must remain the prime focus of surgical body contouring, 3DSI has proven valuable to objectively demonstrate both the anticipated outcome and further findings regarding treatment of idiopathic gynecomastia. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Correction of Tuberous Nipple Areolar Complex Deformity in Gynecomastia: The Deformity That Can Get Forgotten.

The desired end point of surgical reduction of gynecomastia is a masculine breast appearance and symmetry. This article concentrates on the tuberous deformity of the nipple areolar complex (NAC) that can present in gynecomastia and is sometimes overlooked at surgical correction.This deformity can be corrected at primary surgery if it is recognized preoperatively. If missed, or not adequately corrected, the postoperative result of primary reduction may be deemed incomplete by the patient and they will request revision.The deformity involves overprojection of the NAC in an anteroposterior direction, yet the base diameter may be close to normal. Correction involves reduction of the herniated breast bud, excision of excess areolar tissue, and careful radial scoring to flatten the NAC to a normal level of projection.For the NAC to have a masculine appearance, the areolae need to be symmetrical, of normal male size, and slightly oval in a transverse direction. The projection of both areola and nipple needs to be low, but present: not flattened. This article presents an operative technique to address primary or residual tuberous NAC deformity in the treatment of gynecomastia.

Long-Term Follow-up of Recurrence and Patient Satisfaction After Surgical Treatment of Gynecomastia.

BACKGROUND: "Gynecomastia" is an enlargement of the male breast. Our study aims to assess patient satisfaction as well as evaluate differences in recurrence rates in lipomatous and glandular gynecomastia 10-19 years postoperatively. METHODS: Forty-one gynecomastia patients undergoing surgical treatment from 1997 to 2005 were invited for a follow-up examination 10-19 years postoperatively. Of these, 16 patients presented for a clinical examination. Patient satisfaction was measured with a validated questionnaire [consultation satisfaction questionnaire (CSQ)-9]. Furthermore, photo-material and patient charts were evaluated concerning preoperative macroscopical type of gynecomastia, BMI, and operative technique. RESULTS: Mean follow-up time was 13.8 years (range: 10.5-19 years). Eight patients (50%) had presented with lipomatous and eight patients (50%) with glandular gynecomastia prior to surgery. One of the patients with glandular gynecomastia (12.5%) presented with recurrence at the time of follow-up, while five of the eight patients showing lipomatous gynecomastia (62.5%) presented with recurrence. Interestingly, younger patient groups tend to be more satisfied with the operative treatment of gynecomastia than older patient groups, especially regarding the improvement of self-esteem. CONCLUSIONS: Long-term follow-up results showed that recurrence rates are significantly higher in patients with lipomatous gynecomastia than in patients with glandular gynecomastia, with BMI increase in patients with glandular and lipomatous gynecomastia showing no statistically significant differences. Furthermore, general patient satisfaction and improvement of self-esteem was higher in younger patient groups than older patient groups. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . CLINICAL TRIAL REGISTRATION NUMBER: DRKS00009630.

Prepubertal Gynecomastia Due to Indirect Exposure to Nonformulary Bioidentical Hormonal Replacement Therapy: A Case Report.

BACKGROUND: Gynecomastia is a disorder of the endocrine system characterized by an abnormal presence of a palpable unilateral or bilateral enlargement and proliferation of glandular ductal benign breast tissue in male individuals. This case discusses the medical implications of an unregulated, indirect exposure to nonformulary, bioidentical hormone replacement therapy in male children. CASE: An 8-year-old boy presented with prepubertal gynecomastia secondary to estrogen exposure from maternal use of bioidentical hormonal replacement therapy (the Wiley protocol). We review the literature on prepubertal gynecomastia secondary to exogenous estrogen exposure, evaluation, clinical surveillance of the pubertal development, and relevant short- and long-term implications. CONCLUSION: Indirect exposure to nonformulary hormonal replacement in our case report was an etiologic factor in the development of prepubertal gynecomastia. This novel estrogen exposure source has important implications in the differential diagnosis of prepubertal gynecomastia and potential adverse effects secondary to precocious hormonal exposure.

Adverse drug reactions associated with antiretroviral therapy in South Africa.

South Africa has one of the highest prevalences of HIV and AIDS in the world. HIV/AIDS patients face countless challenges, one of which is the risk of adverse drug reactions (ADRs). This study aimed to describe the ADRs reported in South Africa with reference to the type of ADRs, antiretrovirals (ARVs) implicated, seriousness of the ADRs and patient demographics associated with specific ADRs. A retrospective quantitative study was carried out using ADR reports submitted to the National Department of Health (NDoH) from 1 January 2010 to 31 December 2014. A descriptive and inferential analysis was carried out to determine the strength of the relationships between different variables. A total of 2 489 reports were analysed. This study found evidence of ADRs among patients on regimens based on stavudine (n = 1 256, 50.46%), efavirenz (n = 572, 22.98%), zidovudine (n = 209, 8.40%), tenofovir (n = 203, 8.16%) and nevirapine (n = 153, 6.15%). The 10 most common ADRs reported with the use of ARVs were peripheral neuropathy (n = 472, 19%), lipodystrophy (n = 471, 18.9%), serious skin reactions (n = 266, 10.7%), gynaecomastia (n = 219, 8.8%), renal failure (n = 140, 5.6%), dizziness (n = 133, 5.3%), hyperlactatemia (n = 118, 4.7%), psychosis/hallucinations (n = 47, 1.9%), sleep disturbances (n = 44, 1.8%) and vomiting (n = 44, 1.8%). Female patients were more likely to experience peripheral neuropathy, lipodystrophy, skin rash, anaemia and hyperlactatemia, while male patients were more prone to experience gynaecomastia and peripheral neuropathy. In addition, patients aged 30-44 years reported the most ADRs. Most reactions resulted from the use of stavudine, efavirenz, zidovudine, nevirapine and tenofovir in the population groups identified in this study.

Elucidating encounters of atypical ductal hyperplasia arising in gynaecomastia.

AIMS: Atypical ductal hyperplasia (ADH) rarely arises in gynaecomastia. We set out to understand more clearly the clinical, histological and immunohistochemical features of ADH in this setting. METHODS AND RESULTS: Twenty-five cases of ADH arising in gynaecomastia, nine cases of ductal carcinoma in situ (DCIS) and 36 cases of gynaecomastia with usual ductal hyperplasia (UDH) were studied. Reviews of clinical, morphological and immunohistochemical findings were performed. The extent of cytokeratin 5/6 (CK5/6) luminal epithelial cell staining was assessed (0% = 0, < 10% = 1, 10-50% = 2 and > 50% = 3). Oestrogen receptor (ER) was evaluated using the H-scoring system. The average age of ADH patients was 35 years (range 14-78). ADH was bilateral in 20% and less frequent in active gynaecomastia (24%). ADH often showed a cribriform pattern (72%), with less nuclear variation/size and similar frequency of mitoses than UDH cells. CK5/6 luminal epithelial staining was decreased in ADH (68%) versus UDH (11%). ADH showed high ER expression compared to UDH (H score > 270 in 88% and 14%, respectively). CONCLUSIONS: ADH in gynaecomastia can be distinguished from UDH by morphological and immunohistochemical features. We also identified a subset of young patients (< 25 years) with extensive bilateral ADH. More studies are needed to characterize this patient subset more clearly.

Intratubular Large Cell Hyalinizing Sertoli Cell Tumor of the Testes in a 4-Year-Old Male With Peutz-Jeghers Syndrome.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder that typically displays familial inheritance. Gastrointestinal polyposis and cutaneous pigmentation is a classic presentation of this syndrome. The reported lifetime cumulative cancer risk in PJS patients is >76% when compared with the general public with females affected more often than males. The prepubertal testicular tumor registry found Sertoli cell tumors (SCTs) to compose approximately 1% of all pediatric solid tumors. Prepubertal testicular masses are relatively rare. Only a small number of SCT cases have been reported in the first decade of life. The concurrence of PJS and feminizing SCTs of the testes is an increasingly recognized cause of prepubertal gynecomastia. The testicular lesions observed in patients with PJS primarily represent multifocal intratubular large cell hyalinizing SCTs with a distinct morphology that differs from large cell calcifying SCTs and sex cord tumors with annular tubules. Here, we describe the diagnosis and treatment course of a 4-year-old male with a SCT of the testes and diagnosis of PJS.

Overuse of imaging the male breast-findings in 557 patients.

Gynecomastia is the most common abnormality of the male breast. However, breast cancer may occur, albeit with a significantly lower incidence than in females. Imaging is often used as part of the diagnosis. The aim of this study was to assess the utilization and outcome of imaging with mammography or ultrasound of the male breast in a university hospital's department of radiology. A retrospective study assessing the imaging of the male breast in 557 patients over a 10-year period. Referral was done mainly by general surgeons and general practitioners. The most common indication was enlargement of the breast, described as gynecomastia or swelling in 74% of patients, followed by pain in 24% and "lumps" in 10%. The modalities used were mammography in 65%, ultrasound in 51% and both in 26%. Most examinations, 519, were BI-RADS 1 or 2, and 38 were BI-RADS 3 or higher. Altogether 160 patients had additional fine-needle aspiration or biopsy. Malignancies were diagnosed in five patients (0.89%). Imaging had a sensitivity of 80% and a specificity of 99%. The positive predictive value was 44% and the negative predictive value 99.8%. Malignancies are rare in the male breast. The probability of finding cancer when performing imaging of clinically benign findings in the male breast is negligible. Imaging is not warranted unless there are suspicious abnormalities. Routine imaging of gynecomastia should be discouraged.

Bilateral pseudoangiomatous stromal hyperplasia tumors in axillary male gynecomastia: report of a case.

Pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferation of breast stromal cells with a complex pattern of interanastomosing spaces lined by myofibroblasts. The exact etiology is still unknown, but a proliferative response of myofibroblasts to hormonal stimuli has been postulated. PASH is a relatively common incidental finding in breast tissue removed for other reasons and rarely manifests as a localized mass. Fewer than 150 cases of tumoral PASH have been reported since it was first described in 1986. Although PASH tends to grow over time, most lesions are cured by surgical excision and the prognosis is excellent. We report an unusual case of bilateral axillary tumoral PASH in a 44-year-old man. Awareness of this disease is important when considering the differential diagnosis of axillary masses. To our knowledge, only one other case of unilateral axillary tumoral PASH in a male patient has been described in English and this is the first case of PASH occurring in male bilateral axillary gynecomastia.

Pathological findings in gynecomastia: analysis of 5113 breasts.

OBJECTIVE: This study aimed to analyze the histopathology results of surgically excised breast specimens with the diagnosis of gynecomastia (GM). SUMMARY BACKGROUND DATA: Gynecomastia is a term used to describe benign hypertrophy of the breast in men; it is a common, mostly transient, phenomenon in adolescents, but may also be seen in older men. Breast enlargement can lead to psychological problems; if it persists it can be surgically corrected. The obtained breast tissue specimens are routinely submitted for pathological examination. We performed this study to assess the prevalence of pathological findings after surgical management of GM. METHODS: Pathology reports were obtained from the nationwide network and registry of histopathology and cytopathology in the Netherlands (PALGA). The reports of 5113 breasts were analyzed for the prevalence of pathologies in different age groups. RESULTS: The average age of the patients was 35.3 ± 18.3 years (range, 1-88 years). The most common finding was GM followed by pseudo-GM. The overall prevalence of invasive carcinomas was 0.11% and of in situ carcinomas was 0.18%. The youngest patient with invasive cancer was 65 years old and the youngest patient with carcinoma in situ was 24 years old. The overall prevalence of atypical ductal hyperplasia was 0.4%; in patients younger than 20 years, it was 0.23%. The youngest patient with atypical ductal hyperplasia was 16 years old. Pathological findings were found more often in unilateral procedures. CONCLUSIONS: The prevalence of malignancies in GM resection specimens is low; however, it increases with patient age. Unilateral cases have a statistically nonsignificant higher prevalence of pathologies. LEVEL OF EVIDENCE: Prognostic/risk II.

Do columnar cell lesions exist in the male breast?

AIMS: In females, columnar cell lesions (CCLs) have been recognized as putative precursor lesions of low-grade breast cancer, but their role in male breast carcinogenesis is as yet unclear. METHODS AND RESULTS: We reviewed surgical resections from males with breast cancer (n = 89), gynaecomastia (n = 20) and normal breast specimens from autopsies (n = 5) for the presence of CCL. In addition, we performed immunohistochemistry for cytokeratin 5/6 (CK5/6), CK14 and oestrogen receptor alpha (ER). In 19 of 89 resections (two DCIS cases and 17 invasive carcinoma), some individual ducts were found to contain cells with snouts on the luminal border but lacking further typical columnar cell lesion features. We mainly found three-layered ductal epithelium, characteristic for gynaecomastia and confirmed by immunohistochemistry. Moreover, we found a few ducts in male breast cancer sections that were clonally negative for basal cytokeratins. CONCLUSION: We found no lesions with convincing CCL morphology at the periphery of invasive male breast cancers, in gynaecomastia or in normal male breast specimens. Although we cannot completely exclude the existence of CCLs in the male breast, these lesions seem to be very uncommon and are therefore unlikely to play a major role in male breast carcinogenesis.

Deciphering the molecular landscape: evolutionary progression from gynecomastia to aggressive male breast cancer.

BACKGROUND: Gynecomastia denotes the benign proliferation of glandular breast tissue and stands as a recognized risk factor for male breast cancer. Nonetheless, the underlying carcinogenic mechanisms orchestrating the progression from gynecomastia to cancer remain poorly understood. METHODS: This study employed single-cell RNA sequencing (scRNA-seq) to meticulously dissect the cellular landscape of gynecomastia and unravel potential associations with male breast cancer at a single-cell resolution. Pseudotime and evolutionary analyses were executed to delineate the distinct features characterizing gynecomastia and male breast cancer. The TCGA database, along with cell-cell communication analysis and immunohistochemistry staining, was harnessed to validate differential gene expression, specifically focusing on CD13. RESULT: From the copy number variation profiles and evolutionary tree, we inferred shared mutation characteristics (18p+ and 18q+) underpinning both conditions. The developmental trajectory unveiled an intriguing overlap between gynecomastia and malignant epithelial cells. Moreover, the differential gene CD13 emerged as a common denominator in both gynecomastia and male breast cancer when compared with normal mammary tissue. Cell-cell interaction analysis and communication dynamics within the tumor microenvironment spotlighted distinctions between CD13+ and CD13- subsets, with the former exhibiting elevated expression of FGFR1-FGF7. CONCLUSIONS: Our investigation provides novel insights into the evolutionary progression from gynecomastia to male breast cancer, shedding light on the pivotal role of CD13 in driving this transition. The identification of CD13 as a potential therapeutic target suggests the feasibility of CD13-targeted interventions, specifically tailored for male breast cancer treatment.