Fibroadenoma of the vulva with pseudoangiomatous stromal hyperplasia: A common neoplasm in uncommon site.

Mammary-type tissue in the vulva was first described in 1872 but has been rarely reported in the literature. This tissue was previously considered as ectopic breast tissue that occurs as a result of incomplete regression of the milk line. Similar to native breast tissue, ectopic mammary tissue is hormone-sensitive and can develop benign changes, such as fibroadenoma, as well as malignant changes. A more recent theory suggests that these benign and malignant mammary-type entities arise from mammary-like anogenital glands, which constitute normal vulvar components. We report a case of a 41-year-old woman who presented with a chronic asymptomatic cyst on the left vulva that eventually became uncomfortable, especially on standing. The cyst was located on the labium minus, measuring 1.0 × 0.5 cm, with no identified erythema or other skin abnormalities. Excision of the lesion and subsequent microscopic examination showed a circumscribed mass with a nodular overgrowth of epithelial and stromal components, resembling a mammary fibroadenoma with pseudoangiomatous stromal hyperplasia. We bring to attention this rare diagnosis and the importance of considering it in the presence of a vulvar lesion. The malignant and recurrence potential of mammary-type tissue necessitates excision with clear margins and close monitoring of these patients.

Infra-areolar subcutaneous mastectomy in the surgical treatment of adolescent gynecomastia.

BACKGROUND: Despite being a common condition in puberty, only 5-10% of pubertal gynecomastia need surgical treatment. Here the authors present their experiences with infra-areolar subcutaneous mastectomy in the surgical treatment of adolescent gynecomastia. METHODS: The records of patients who underwent infra-areolar subcutaneous mastectomy for adolescent gynecomastia between January 2004 and December 2021 were reviewed retrospectively. The patients' demographic data, complaints and clinical presentation, physical examination, laboratory and radiological findings, surgical management, and postoperative follow-ups were evaluated. The patients were evaluated according to the localization of the gynecomastia (unilateral/bilateral) and according to the patients' body mass index (BMI) (normal/overweight). RESULTS: A total of 21 boys with a mean age of 15 ± 1.4 years were operated by the senior author and infra-areolar subcutaneous mastectomy by a semilunar incision was performed for adolescent gynecomastia. The mean duration of the complaint was 24.2 ± 10.9 months. Gynecomastia was bilateral in 15 (71.5%) and unilateral in 6 (28.5%) of the patients. Sixteen patients (76.2%) were normal weight, 5 (23.8%) were overweight. Chromosomal anomaly and hypogonadism were detected in two patients. Pseudoangiomatous stromal hyperplasia was detected in the pathology of one patient. The mean follow-up time was 2.7 ± 1 years, seroma developed in 2 patients at the early postoperative period. Their long-term follow-up was uneventful without complication. CONCLUSIONS: The results of infra-areolar subcutaneous mastectomy are very promising in pubertal gynecomastia due to good skin elasticity and without obesity in the adolescent age group. We believe that this method provides an almost invisible incision and a natural pectoral appearance for adolescent patients who have experienced serious emotional problems related to their body images.

Giant juvenile fibroadenomas with and without prominent pseudoangiomatous stromal hyperplasia (PASH)-like change: clinicopathological and molecular characteristics.

AIMS: Juvenile fibroadenomas (JFA) are biphasic fibroepithelial lesions (FEL) usually occurring in adolescent female patients. Giant (G) JFA, like other FEL, may exhibit prominent pseudoangiomatous stromal hyperplasia (PASH)-like change. We sought to determine clinicopathological and molecular characteristics of GJFA with and without PASH. METHODS AND RESULTS: Archives were searched for cases of GJFA (1985-2020). All were stained for androgen receptor (AR), beta-catenin, CD34 and progesterone receptor (PR). Cases were sequenced using a custom 16-gene panel - MED12 (exons 1 and 2), TERT promoter (-124C>T and -146Ctable>T), SETD2, KMT2D, RARA (exons 5-9), FLNA, NF1, PIK3CA (exons 10, 11 and 21), EGFR, RB1, BCOR, TP53, PTEN, ERBB4, IGF1R and MAP3K1. Twenty-seven GJFA from 21 female patients aged 10.1-25.2 years were identified. Size ranged from 5.2 to 21 cm. Two patients had multiple, bilateral and later recurrent GJFA. Thirteen (48%) cases showed prominent PASH-like stroma. All were positive for stromal CD34, negative for AR and beta-catenin and one case showed focal PR expression. Sequencing showed MAP3K1 and SETD2 mutations in 17 samples, with KMT2D, TP53 and BCOR aberrations in 10 (45%), 10 (45%) and seven (32%) cases, respectively. Tumours with a PASH-like pattern had higher prevalence of SETD2 (P = 0.004) and TP53 (P = 0.029) mutations, while those without PASH had more RB1 mutations (P = 0.043). MED12 mutation was identified in one case. TERT promoter mutation was observed in four (18%), including two recurrences. CONCLUSIONS: Gene mutations along more advanced phases of the proposed FEL pathogenetic pathway in GJFA are unusual, and suggest a mechanism for more aggressive growth in these tumours.

A reciprocal perspective on the differential associations between personality traits and multiple indicators of academic achievement.

OBJECTIVE: This study aims to explore the reciprocal associations between personality traits (conscientiousness and openness to experience) and academic achievement in adolescents, using the Personality Achievement Saturation Hypothesis (PASH). BACKGROUND: Personality traits, especially conscientiousness, and openness, have been identified as strong predictors of academic achievement. The PASH provides a framework for understanding these relationships but has mainly been studied from a unidirectional perspective. This study extends the PASH to examine reciprocal associations and how they vary with different achievement indicators. METHODS: Using large-scale panel data (N = 6482) of secondary school students in Germany, we applied cross-lagged panel models and latent change score models to examine the differential reciprocal associations between personality traits (conscientiousness/openness) and academic achievement (school grades/achievement test scores) in language and math over two years from grades 7 to 9. RESULTS: In line with the PASH, initial levels of conscientiousness were more strongly associated with school grades than with achievement test scores over two years. Simultaneously, prior school grades were more strongly associated with conscientiousness over two years. However, initial levels of openness did not show differential associations with either school grades or achievement test scores over two years. Similarly, prior school grades and achievement test scores were also not differentially associated with openness over two years. CONCLUSIONS: Our findings introduce an innovative lens through which we observe how the PASH can be leveraged to explain the differential reciprocal associations between conscientiousness and academic achievement. Further research is needed to examine if PASH could be similarly extended to disentangle the associations between openness and academic achievement.

Breast hamartoma: reassessment of an under-recognised breast lesion.

AIMS: Breast hamartomas are an under-recognised lesion because they lack a distinctive microscopic appearance. Microscopic diagnosis can often conclude 'no significant lesion' or 'normal breast tissue', leading to repeated biopsies and diagnostic delay. We describe the histological, immunohistochemical and radiological features of breast hamartomas with the aim of identifying specific signs to facilitate their diagnosis and to differentiate them from normal breast and fibroepithelial lesions. METHODS AND RESULTS: Forty-seven breast hamartomas were reassessed (histological diagnosis and imaging features). An immunohistochemical study [oestrogen receptor (ER), progesterone receptor (PR), CD34, high-mobility group A2 (HMGA2)] was performed. On breast imaging, hamartomas most often presented as probably benign solid masses with circumscribed margins and variable densities. Histologically, breast hamartomas resembled normal breast, although their stromal component was predominant, separating randomly scattered epithelial elements with areas of pure collagenous stroma. Pseudoangiomatous stromal hyperplasia (PASH) was present in 93.6% of cases and CD34 antibody highlighted intralobular, perilobular and interlobular distribution of CD34-positive fibroblasts. By comparison, CD34 was mainly expressed in the intralobular normal breast tissue stroma. Hamartoma stromal cells expressed HMGA2, ER and PR in 79%, 66% and 76.3% of our cases, respectively, compared to 7.7%, 23% and 19% in normal breast tissue, respectively (P < 0.0001; P = 0.0005; P < 0.0001). CONCLUSIONS: After ascertaining that core needle biopsy is effectively intralesional, breast hamartomas can be diagnosed with confidence by taking into account the presence of stromal changes, PASH, interlobular distribution of CD34-positive fibroblasts, HMGA2 and hormonal receptor stromal expression.

Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis.

The challenge of unravelling the molecular basis of multifactorial disorders nowadays cannot rely just on association studies searching for potential causative variants shared by groups of patients and not present in healthy individuals; indeed, association studies have as a main limitation the lack of information on the interactions between the disease-causing variants. Thus, new genomic analysis tools focusing on disrupted pathways rather than associated gene variants are required to better understand the complexity of a disease. Therefore, we developed the Variant Enrichment Analysis (VEA) workflow, a tool applicable for whole exome sequencing data, able to find differences between the numbers of genetic variants in a given pathway in comparison with a reference dataset. In this study, we applied VEA to discover novel pathways altered in patients with complex autoinflammatory skin disorders, namely PASH (n = 9), 3 of whom are overlapping with SAPHO) and PAPASH (n = 3). With this approach we have been able to identify pathways related to neutrophil and endothelial cells homeostasis/activations, as disrupted in our patients. We hypothesized that unregulated neutrophil transendothelial migration could elicit increased neutrophil infiltration and tissue damage. Based on our findings, VEA, in our experimental dataset, allowed us to predict novel pathways impaired in subjects with autoinflammatory skin disorders.

MRI features of pseudoangiomatous stromal hyperplasia with histopathological correlation.

Pseudoangiomatous stromal hyperplasia (PASH), a rare, noncancerous lesion, is often an incidental finding on magnetic resonance imaging (MRI)-guided biopsy analysis of other breast lesions. We sought to describe the characteristics of PASH on MRI and identify the extent to which these characteristics are correlated with the amount of PASH in the pathology specimens. We identified 69 patients who underwent MRI-guided biopsies yielding a final pathological diagnosis of PASH between 2008 and 2015. We analyzed pre-biopsy MRI scans to document the appearance of the lesions of interest. All biopsy samples were classified as having ≤50% PASH or ≥51% PASH present on the pathological specimen. On MRI, 9 lesions (13%) appeared as foci, 19 (28%) appeared as masses with either washout or persistent kinetics, and 41 (59%) appeared as regions of nonmass enhancement. Of this latter group, 33 lesions (80%) showed persistent kinetic features. Masses, foci, and regions of nonmass enhancement did not significantly correlate with the percentage of PASH present in the biopsy specimens (P ≥ .05). Our findings suggest that PASH has a wide-ranging appearance on MRI but most commonly appears as a region of nonmass enhancement with persistent kinetic features. Our finding that most specimens had ≤50% PASH supports the notion that PASH is usually an incidental finding. We did not identify a definitive imaging characteristic that reliably identifies PASH.

Atypical pseudoangiomatous stromal hyperplasia showing rapid growth of the breast: Report of a case.

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign lesion manifesting as myofibroblastic proliferation and anastomosing slit-like spaces. Atypical PASH is an extremely rare lesion characterized by cytological alteration of myofibroblast, presenting as myofibroblastic sarcoma arising from PASH. To our knowledge, only one other case has been reported since the first report of Rosen. We present a case of atypical PASH. A 39-year-old female presented with a round, elastic hard, painless mass in the left breast. Mammography and ultrasonography revealed no definitive sign of malignancy. Core needle biopsy report was suggestive of atypical PASH. Five months later, the mass had grown rapidly with pain. Considering the clinicopathological features, excision was performed. Pathological examination revealed the spindle cells proliferation in collagenous stroma. The spindle cell involved the adipose tissue and lobules and lined peudoangiomatous spaces. These cells exhibited marked cytological atypia and mitotic activity. Immunohistochemically, these spindle cells were positive for SMA, CD10, and bcl-2, and negative for podoplanin, p63, CD31, ERG and cytokeratins. The final diagnosis was atypical PASH. She is tumor-free on 12 months follow-up. The nature of atypical PASH remains unknown. Further studies are required for a clear definition, a new histological entity and diagnostic criteria.

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.

Treating inflammation by blocking interleukin-1 in humans.

IL-1 is a master cytokine of local and systemic inflammation. With the availability of specific IL-1 targeting therapies, a broadening list of diseases has revealed the pathologic role of IL-1-mediated inflammation. Although IL-1, either IL-1α or IL-1ß, was administered to patients in order to improve bone marrow function or increase host immune responses to cancer, these patients experienced unacceptable toxicity with fever, anorexia, myalgias, arthralgias, fatigue, gastrointestinal upset and sleep disturbances; frank hypotension occurred. Thus it was not unexpected that specific pharmacological blockade of IL-1 activity in inflammatory diseases would be beneficial. Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity. In common conditions such as heart failure and gout arthritis, IL-1 blockade can be effective therapy. Three IL-1blockers have been approved: the IL-1 receptor antagonist, anakinra, blocks the IL-1 receptor and therefore reduces the activity of IL-1α and IL-1ß. A soluble decoy receptor, rilonacept, and a neutralizing monoclonal anti-interleukin-1ß antibody, canakinumab, are also approved. A monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α are in clinical trials. By specifically blocking IL-1, we have learned a great deal about the role of this cytokine in inflammation but equally important, reducing IL-1 activity has lifted the burden of disease for many patients.