Microbes, Histology, Blood Analysis, Enterotoxins, and Cytokines: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 3.

BACKGROUND: There has been an increasing need to acquire rigorous scientific data to answer the concerns of physicians, patients, and the FDA regarding the self-reported illness identified as breast implant illness (BII). There are no diagnostic tests or specific laboratory values to explain the reported systemic symptoms described by these patients. OBJECTIVES: The aim of this study was to determine if there are quantifiable laboratory findings that can be identified in blood, capsule tissue pathology, or microbes that differentiate women with systemic symptoms they attribute to their implants from 2 control groups. METHODS: A prospective blinded study enrolled 150 subjects into 3 cohorts: (A) women with systemic symptoms they attribute to implants who requested implant removal; (B) women with breast implants requesting removal or exchange who did not have symptoms attributed to implants; and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue underwent detailed analysis and blood was sent from all 3 cohorts to evaluate for markers of inflammation. RESULTS: No significant histologic differences were identified between the cohorts, except there were more capsules with synovial metaplasia in the non-BII cohort. There was no statistical difference in thyroid-stimulating hormone, vitamin D levels, or complete blood count with differential between the cohorts. Next-generation sequencing revealed no statistically significant difference in positivity between Cohort A and B. Of the 12 cytokines measured, 3 cytokines, interleukin (IL)-17A, IL-13, and IL-22, were found to be significantly more often elevated in sera of subjects in Cohort A than in Cohorts B or C. The enterotoxin data demonstrated an elevation in immunoglobulin G (IgG) anti-Staphylococcus aureus enterotoxin A in Cohort A. There was no correlation between the presence of IgE or IgG anti-Staphylococcal antibody and a positive next-generation sequencing result. CONCLUSIONS: This study adds to the current literature by demonstrating few identifiable biomedical markers to explain the systemic symptoms self-reported by patients with BII.

Longevity of Post-Explantation Systemic Symptom Improvement and Potential Etiologies: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 4.

BACKGROUND: Breast Implant Illness (BII) describes a variety of symptoms reported by patients with breast implants. Biospecimens data revealed minimal statistical differences between BII and non-BII cohorts. Baseline analysis of PROMIS data demonstrated significant differences between the BII cohort and the 2 control cohorts. OBJECTIVES: This study was designed to determine if patients in the BII cohort obtained any symptom improvement after explantation, whether symptom improvement was related to the type of capsulectomy, and which symptoms improved. METHODS: A prospective blinded study enrolled 150 consecutive patients divided equally into 3 cohorts. Baseline demographic data and a systemic symptoms survey, including PROMIS validated questionnaires, were obtained at baseline, 3 to 6 weeks, 6 months, and 1 year. RESULTS: A total of 150 patients were enrolled between 2019 and 2021. Follow-up at 1 year included 94% of the BII cohort and 77% of non-BII and mastopexy cohorts. At 1 year, 88% of patients showed at least partial symptom improvement, with a reduction of 2 to 20 symptoms. The PROMIS score in the BII cohort decreased at 1 year for anxiety, sleep disturbances, and fatigue. Systemic symptom improvement was noted out to 1 year in the BII cohort regardless of the type of capsulectomy performed. CONCLUSIONS: Parts 1-3 in this series concluded that there were no consistent differences in biospecimen results between the cohorts. Unlike the data observed in the biospecimen analysis, BII patients had heightened symptoms and poorer PROMIS scores at baseline compared to the control cohorts. The reduction of negative expectations and a potential nocebo effect could contribute to this improvement.

Descriptive study comparing outcomes of classic and nonclassic lobular carcinoma in situ (florid and pleomorphic) initially diagnosed on core needle biopsy.

The lobular carcinoma in situ (LCIS) subtypes include classic (CLCIS), pleomorphic (PLCIS), and florid LCIS (FLCIS). The CLCIS is considered a breast cancer risk factor, but clinical significance and natural history of other LCIS subtypes are unclear. The outcome data on PLCIS and FLCIS is limited. The aim of current study is to compare excision and follow-up findings of CLCIS and nonclassic LCIS (NCLCIS). The breast needle biopsies (NBs) with LCIS during 01/2007-12/2017 were identified. The imaging, clinical findings, and outcome were compared between CLCIS and NCLCIS. A total of 36 NBs from 32 patients with NCLCIS (14 PLCIS & 22 FLCIS) and 73 NBs from 68 patients with CLCIS were identified. The NCLCIS patients were older (57 vs 52 years; P = .02) and presented more often with calcifications (78% vs 44%; P = .01). Seven (19%) PLCIS were initially diagnosed as ductal carcinoma in situ (DCIS). The microscopic invasion was frequent with NCLCIS (25%). No invasion was identified in NBs with CLCIS. A separate concurrent NBs with a carcinoma (29% vs 6%; P = .018) or ductal atypia (12% vs 3%; P = .1) was more frequent with CLCIS. The upgrade rate (invasion or DCIS) was higher with NCLCIS (25% vs 4%). Four NCLCIS developed ipsilateral recurrences: 2 NCLCIS, 1 IDC, and 1 ILC (50; 10-96 months). No breast event was reported in 24 pure CLCIS (60; 8-144 months). Invasive carcinoma with NCLCIS, unlike CLCIS, is always lobular type. Recurrences following NCLCIS are ipsilateral lobular tumors. NCLCIS subtypes are nonobligate precursors to invasive lobular carcinoma.

Relationship of histologic grade and histologic subtype with oncotype Dx recurrence score; retrospective review of 863 breast cancer oncotype Dx results.

PURPOSE: Oncotype Dx (ODx) is a multigene assay that is prognostic and predictive in estrogen receptor (ER) positive early breast cancer. ODx recurrence score (RS) is reported to be histologic grade dependent. Relationship of RS with breast cancer histologic subtypes is unknown. This study was designed to assess the relationship of histologic subtype with RS. Histologic grade dependence of RS was also investigated. METHODS: Results of consecutive ODx tests (1/2007-7/2016) from two institutions were reviewed. Histologic subtypes (in: Lakhani et al., WHO classification, IARC Press, Lyon, 2012), combined Nottingham histologic grade, age and tumor size were recorded from pathology reports. Univariate and multivariate analysis was performed to investigate the relationship between RS and ODx risk categories and histologic subtypes, grade, age and tumor size. RESULTS: RS was grade dependent. RS of grade 1 and grade 2 tumors were significantly lower than grade 3 tumors. There was no high-risk grade 1 tumor. In favorable histologic subtypes there was no high-risk tumor. Mean RS of grade 1 lobular tumors was significantly higher than grade 1 ductal tumors. Using newer ODx cut-offs, 5 grade 1 tumors were reclassified as high risk (RS > 25) and grade 3 lobular tumors showed significantly higher rate of reclassification as high-risk than grade 3 ductal tumors. In a multivariate analysis, only grade showed a significant positive correlation with RS. Adding dichotomous histologic subtyping (favorable vs. non-favorable) to grade further improved correlation with RS. CONCLUSIONS: The Oncotype Dx result is impacted by histologic grade and histologic subtype. Tumors with favorable histologic subtypes and histologic grade 1 tumors do not have high-risk RS. High RS in a grade 1 tumor or in a tumor with favorable histology is unusual that warrants further investigation. Invasive lobular carcinomas rarely show high-risk RS. Histologic grade and histologic subtype should be considered while ordering ODx testing.

Endometrial Adenocarcinomas With Significant Mucinous Differentiation: A Characterization of Intratumoral Heterogeneity of KRAS Mutations in Mucinous and Endometrioid Histologic Components.

OBJECTIVE: KRAS mutations are frequently seen in malignancies with mucinous morphology. In our previous study, mucinous endometrial carcinomas were associated with a significantly higher frequency of KRAS mutations as compared with matched conventional endometrioid carcinomas. This study expands our previous report by exploring possible intratumoral heterogeneity for KRAS gene mutations in the mucinous components of mucinous carcinomas (MCs) and endometrioid carcinomas with significant mucinous differentiation (ECSMD) versus their associated "usual" endometrioid components. MATERIALS AND METHODS: KRAS-positive cases from our previous report were studied, including 10 MCs and 10 ECSMDs. The specimens were microscopically dissected to separately isolate morphologically mucinous and endometrioid components. Direct DNA sequencing for KRAS mutations at codons 12 and 13 using capillary electrophoresis were performed. RESULTS: KRAS mutations were detected in the endometrioid components of 8 (80%) of 10 MCs and 3 (30%) of 10 ECSMDs. The endometrioid component of the ECSMD group was less frequently associated with KRAS mutation than the endometrioid component of the MC group, even when the mucinous component of the same tumor contained a mutation; the difference is statistically significant (P < 0.05). CONCLUSIONS: Our current study shows that intratumoral heterogeneity for KRAS gene mutation was associated with ECSMD, but less frequently with MC. It is possible that when the mucinous component predominates, qualifying for an MC, KRAS mutations appear to be widespread, irrespective of the mucinous or nonmucinous differentiation of the tumor cells. The findings suggest that multiple samples for KRAS tests may be useful, especially in endometrioid carcinoma with significant mucinous differentiation.

Testosterone-induced "Virilization" of Mesonephric Duct Remnants and Cervical Squamous Epithelium in Female-to-Male Transgenders: A Report of 3 Cases.

Mesonephric ducts regress in genotypic females, leaving behind few remnants. These vestigial structures are often recognized in the mesosalpinx and paracervical regions. We report here 3 cases of female-to-male transgenders who underwent hysterectomy following testosterone treatment. Both female and male genital structures were identified on histologic examination. Although the morphologic appearances of the specimens were unremarkable, histologically 1 case revealed a well-formed fallopian tube as well as an epididymis and 2 cases showed prostate glands to be present in the cervical squamous epithelium.

Perinatal Mortality Associated with Positive Postmortem Cultures for Common Oral Flora.

Introduction. To investigate whether maternal oral flora might be involved in intrauterine infection and subsequent stillbirth or neonatal death and could therefore be detected in fetal and neonatal postmortem bacterial cultures. Methods. This retrospective study of postmortem examinations from 1/1/2000 to 12/31/2010 was searched for bacterial cultures positive for common oral flora from heart blood or lung tissue. Maternal age, gestational age, age at neonatal death, and placental and fetal/neonatal histopathological findings were collected. Results. During the study period 1197 postmortem examinations (861 stillbirths and 336 neonatal deaths) were performed in our hospital with gestational ages ranging from 13 to 40+ weeks. Cultures positive for oral flora were identified in 24 autopsies including 20 pure and 8 mixed growths (26/227, 11.5%), found in 16 stillbirths and 8 neonates. Microscopic examinations of these 16 stillbirths revealed 8 with features of infection and inflammation in fetus and placenta. The 7 neonatal deaths within 72 hours after birth grew 6 pure isolates and 1 mixed, and 6 correlated with fetal and placental inflammation. Conclusions. Pure isolates of oral flora with histological evidence of inflammation/infection in the placenta and fetus or infant suggest a strong association between maternal periodontal conditions and perinatal death.

Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers.

For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell). The HER2/CEP17 equivocal category is eliminated. The aim of this study is to assess the impact of 2013 HER2 FISH testing guideline recommendations update on the assignment of HER2 status with dual probe HER2 FISH assay. Dual probe HER2 FISH assay results on breast cancers from 09/2009 to 07/2015 that underwent reflex HER2 FISH testing after equivocal HER2 (2+) immunohistochemistry (IHC) were reviewed. HER2 copy number, CEP17 signals, and HER2/CEP ratios were noted. HER2 status was assigned as HER2 negative (HER2-), HER2 equivocal (HER2e), and HER2 amplified (HER2+) by applying both 2007 and 2013 CAP/ASCO HER2 FISH guideline recommendations and results were compared. New guidelines reclassified HER2 FISH status in a significant proportion of cases (8.3 %, 69/836; p = .021). There were 22 (2.6 %) more HER2+, 17 (2.1 %) more HER2e, and 39 (4.1 %) fewer HER2- tumors. Change of HER2 status correlated significantly with ≥3 CEP17 signals (38 vs. 2 %; p < .001). The 2013 CAP/ASCO guideline recommendations for HER2 FISH testing by dual probe assay increased the HER2 amplified and HER2 equivocal tumors. Increase in HER2 equivocal tumors would potentially increase the frequency of repeat HER2 testing. Tumors with ≥3 CEP17 signals, so-called chromosome 17 polysomy, are more likely to be impacted and classified as HER2 equivocal.

Evaluation of anal cytology and dysplasia in women with a history of lower genital tract dysplasia and malignancy.

OBJECTIVE: To compare the prevalence of abnormal anal cytology, high-risk anal HPV and biopsy proven anal dysplasia among women with a history of lower genital tract malignancy compared to those with dysplasia. METHODS: A prospective cohort study was performed from December 2012 to February 2014 at outpatient clinics at an academic medical center. Women with a history of high-grade cervical, vulvar, or vaginal dysplasia, or malignancy were recruited. Anal cytology and HPV genotyping were performed. All women with abnormal anal cytology were referred for high-resolution anoscopy and biopsy. RESULTS: Sixty-seven women had a lower genital tract malignancy and 123 had a history of genital dysplasia. Average age in the malignancy group was 52.6years (range 27-86) versus 43.5years (range 21-81) in the dysplasia group (p<0.0002). Similar rates of anal dysplasia were seen in both groups, 12.99% (10 cases) in the malignancy group, versus 12.20% (15) in the dysplasia group (p=1.0). Six women in the malignancy group had anal intraepithelial neoplasia (AIN2+) compared to 2 in the dysplasia group (p=0.03). CONCLUSIONS: We found high rates of abnormal anal cytology and HPV in women with lower genital tract dysplasia and malignancy. We also found high rates of anal dysplasia in both groups with a trend towards increased rate in those women with history of genital malignancy. Since precancerous anal lesions are detectable and treatable, anal cancer screening may be potentially useful in both of these higher risk groups.

The clinical significance of K-ras mutation in endometrial "surface epithelial changes" and their associated endometrial adenocarcinoma.

OBJECTIVES: The entity of 'surface epithelial changes' (SECs) was first described in 1995 [1]. Morphologically, SECs usually arise from malignant glands at the superficial aspect of well differentiated (WD) endometrioid carcinomas (ECs) and impart the appearance of a 'maturational' phenomenon at the surface of the cancer. Exhibiting a paradoxically bland histologic appearance, SECs typically show morphologic features that mimic benign entities, particularly endocervical microglandular hyperplasia (MGH). SECs have been associated with approximately half of WD endometrioid carcinomas many of which showed focal mucinous differentiation. Despite their morphologically benign histology, some have questioned whether the presence of SECs represents a 'marker' for an underlying malignancy, especially in postmenopausal women with endocervical or MGH-type SECs in their endometrial sampling. Since the biologic nature of SECs is unknown, we aimed to study the prevalence of KRAS gene mutations in SECs and the underlying WD endometrioid adenocarcinomas (EC) from which they directly arise. METHODS: 24 cases with biopsy proven SECs and ECs in their subsequent hysterectomy were retrieved. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue. PCR amplification for KRAS codons 12 and 13 was performed, followed by sequencing using capillary electrophoresis. RESULTS: KRAS codons 12 and 13 mutations were detected in 19 of 24 (79%) SECs, and 19 of 24 (79%) ECs. All SECs had the same KRAS mutation as the underlying EC. CONCLUSIONS: Our results suggest that SECs are of neoplastic origin and that KRAS mutations play an important role in the tumorigenesis of ECs and SECs.

Pathology of endometrial ablation failures: a clinicopathologic study of 164 cases.

Endometrial ablation is a minimally invasive alternative to hysterectomy for abnormal uterine bleeding. Although the failure rate is low, continued bleeding or development of pelvic pain after ablation does occur. We analyzed the clinicopathologic features of 164 hysterectomy specimens after endometrial ablation, 19 of which were performed for indications other than failed ablation (control cases). Pathologic findings included: dense fibrosis and hyalinization of the endometrial surface ablative necrosis within the uterine cavity and adherent to the endometrial surface, persistent months after ablation; uterine cavity lined by superficial, large, congested, patent blood vessels with atherosis; ablation changes present only in the lower uterine segment; and residual endometrium present in the cornual regions. Patients with ablative necrosis underwent subsequent hysterectomy sooner than those without such debris (median of 5 vs. 23 mo, respectively). Patients with superficial abnormal vessels were also more likely to have a shorter ablation-hysterectomy interval than those without (median of 2 vs. 18 mo, respectively). Patients with associated adenomyosis or prior tubal ligation were significantly more likely to have continued bleeding. Possible sources of continued abnormal bleeding or pelvic pain include: the presence of ablative necrosis or superficial abnormal blood vessels, although the association did not reach statistical significance in this study; incomplete ablation, affecting only the lower uterine segment or sparing the cornual region; tubal endometriosis after ligation; and endometrial regeneration via adenomyosis.

Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone.

OBJECTIVE: The objective of this study was to examine SLN evaluation alone in women with squamous cell carcinoma (SCC) of the vulva and evaluate the inguinal recurrence and complication rates. METHODS: An IRB approved prospective study enrolled patients with SCC of the vulva. Peritumoral injection of Tc-99 sulfur colloid and blue dye was used to identify SLNs intraoperatively. Patients with negative SLN for metastasis were followed clinically without further treatment. Patients with metastasis to a SLN underwent full groin node dissection followed by standard treatment protocols. RESULTS: A total of 73 women were enrolled onto protocol with 69 patients undergoing SLN dissection. Mean age was 66.9years (range: 29-91) with 47 stage I, 12 stage II, 9 stage III, 2 stage IV and 3 unstaged patients. SLN dissections were successful in 63 patients. Of the 111 groins evaluated with a SLN dissection 93% had a SLN identified with an average of 2 SLN per groin. There were 92 groins with negative SLN and 11 groins with positive SLN. 57 patients had negative SLN and underwent conservative management with the median follow-up of 58.3months. Three patients experienced groin recurrences (2 unilateral, 1 bilateral) for a recurrence rate of 5.2% (3/57). The complication rate for the inguinal incisions was 17.5% (1 cellulitis, 1 abscess, 2 lymphoceles, 5 lymphedema and leg pain). CONCLUSIONS: Isolated SLN dissection alone has a low inguinal recurrence rate with decreased complications and should be considered as an option for women with SCC of the vulva.

Synchronous Epidermodysplasia Verruciformis and Intraepithelial Lesion of the Vulva Is Caused by Coinfection With Alpha-Human Papillomavirus and Beta-Human Papillomavirus Genotypes and Facilitated by Mutations in Cell-Mediated Immunity Genes.

CONTEXT.­: There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature. OBJECTIVES.­: To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with α and ß human papillomavirus (α-HPV and ß-HPV) genotypes, and describe relevant underlying genetic mutations. DESIGN.­: Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed. RESULTS.­: Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both α-HPVs and ß-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found. CONCLUSIONS.­: We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with α-HPV and ß-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status.

Immunohistochemical findings and clinicopathological features of breast cancers with pathogenic germline mutations in Non-BRCA genes.

Deleterious germline mutations in multiple genes confer an increased breast cancer (BC) risk. Immunohistochemical (IHC) expression of protein products of mutated high-risk genes has not been investigated in BC. We hypothesized that pathogenic mutations may lead to an abnormal IHC expression pattern in the tumor cells. BCs with deleterious germline mutations in CHEK2, ATM, PALB2 & PTEN were identified. Immunohistochemistry was performed using Dako staining platform on formalin fixed paraffin embedded tumor tissue. Primary antibodies for PALB2 (ab202970), ATM [2C1(1A10)}, CHK2 (EPR4325), and PTEN (138G6) proteins were used for BCs with respective deleterious mutations. IHC expression was assessed in tumor and adjacent benign breast tissue. Total 27 BCs with 10 CHEK2, 9 ATM, 6 PALB2 & 2 PTEN deleterious germline mutations were identified. IHC staining was performed on 8 CHEK2, 7 ATM, 6 PALB2 & 2 PTEN cases. Abnormal CHEK2 IHC staining was identified in 7/8(88%) BCs. Three distinct CHK2 IHC patterns were noted: 1) Strong diffuse nuclear positivity (5 BC), 2) Null-pattern (2 BC), & 3) Normal breast-like staining in 1 BC Four of 5 (80%) strong CHK2 staining BC had missense CHEK2 mutations. Null-pattern was present with a missense & a frameshift mutation. Normal breast-like CHEK2 IHC staining pattern was present in 1 BC with CHEK2 frameshift mutation. Loss of nuclear/cytoplasmic PTEN IHC expression was noted in 2 in-situ carcinomas. Abnormal PTEN and CHK2 IHC were present in atypical ductal hyperplasia and flat epithelial atypia. ATM and PALB2 IHC expression patterns were similar in tumor cells and benign breast epithelium: mild to moderate intensity nuclear and cytoplasmic staining. We report abnormal CHEK2 IHC expression in 88% of BCs with pathogenic CHEK2 mutations. With PTEN and CHEK2 pathogenic mutations, abnormal IHC patterns are seen in early atypical proliferative lesions. IHC may be applied to identify CHEK2 & PTEN mutated BCs and precursor lesions.

Endometrial endometrioid adenocarcinoma with a malignant squamous component: is the unusual metastatic pattern unique of these tumors?

The FIGO scheme is currently applied for tumor grading of endometrioid adenocarcinoma. The current report presents a series of ten cases of endometrioid carcinomas that when applying the FIGO grading does not fully convey the true biological nature of the disease. The squamous component of these tumors is malignant; it constitutes the predominant invasive component, and it often metastasizes to unconventional sites. Half of the cohort developed distant disease recurrence within 2 years, even those with early-stage disease. Somatic mutations were analyzed, targeting 101 genes in all ten cases, and mutations in PTEN, MMR, PIK3CA, ATM, RB1, and TP53 genes were detected, often multiple mutations in the same case. None of the cases revealed unique molecular signatures or previously unreported gene mutations. Immunohistochemical staining for beta-catenin showed aberrant nuclear staining in eight of ten cases and remaining two showed cytoplasmic and membranous staining. Aggressive behavior and unusual sites of metastases are observed in this series even in low-grade tumor. The FIGO grading on smaller samples may be deceptive for these cases. Even if FIGO is applied, the pathology report should emphasize the malignant squamous component and its potential significance so that the gynecologic oncology team can formulate appropriate adjuvant treatment upfront. This case series argues that this histology should be regarded as a high-grade endometrioid carcinoma and can show unusual metastatic patterns. Further research is needed with more cases within this histologic subtype to guide recommendations on adjuvant therapies for this aggressive tumor type.

Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.

OBJECTIVES: K-ras gene product in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway is critical in the development of certain types of malignancies. K-ras mutation-associated pancreatic and ovarian carcinomas often display mucinous differentiation. Previous studies have shown that k-ras mutation is found in 10% to 30% of endometrial carcinomas. We investigated k-ras mutations in several morphologic subtypes of endometrial carcinomas with particular emphasis on various degrees of mucinous differentiation. METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections. Polymerase chain reaction amplification for k-ras codons 12 and 13 were performed, followed by sequencing using capillary electrophoresis. The Fisher exact test is used to compare the prevalent difference of k-ras mutation among the groups. P < 0.05 was considered significant. RESULTS: K-ras mutations were detected in 8 (80%) of 10 mucinous carcinomas, 12 (67%) of 18 endometrioid carcinomas (ECs) with significant mucinous differentiation (ECMD), 4 (25%) of 16 ECs, and 1 (9%) of 11 serous carcinomas. The differences were statistically significant between mucinous carcinomas versus EC (P < 0.01) and ECMD versus EC (P < 0.05). CONCLUSION: The findings suggest that mucinous carcinoma and endometrioid carcinoma with significant mucinous component are more likely to be associated with k-ras mutation. Potential clinical implications of k-ras mutation lies in the management of recurrent or higher-stage endometrial mucinous tumors, which would not be responsive to treatment protocols containing epidermal growth factor receptor inhibitors.

Benign Biphasic Tumors of the Mullerian Tract - a Mimic of Phyllodes Tumor. A Clinical-Pathologic Description of 21 Cases.

OBJECTIVE: A review of the clinical-pathologic characteristics and outcomes of biphasic polyps occurring in the female genital tract, not meeting the diagnostic criteria of Mullerian Adenosarcoma (MA). METHODS: An archival database search was run, after IRB approval, between 2001 and 2019, using terminology such as "Mullerian adenofibroma," "atypical Mullerian adenofibroma," "polypoid adenofibroma," and "atypical polyp with increased stromal cellularity." Two pathologists (JW and MRQ) reviewed all the retrieved cases and documented the morphologic features with particular emphasis on the presence of any features of Mullerian adenosarcoma. Follow-up data were also abstracted. RESULTS: Twenty-one cases, 12 cervical and 9 endometrial lesions, constituted the study cohort. Patients ranged from 26 to 64 years (median 49 years). On review, 20 of 21 of those cases showed Phyllodes-like architectural patterns. However, only one case showed all four features of MA, all of which were focal and inconspicuous. Follow-up (median duration of 5 years) did not document any recurrences in any of the 21 cases after excision. CONCLUSION: This series adds to the growing body of literature affirming the existence of benign biphasic Mullerian polyps encountered in the endometrium and cervix that fall short of the Mullerian adenosarcoma diagnosis.

Mammary stromal-epithelial lesions with myofibroblastic stroma and HMGA2 overexpression linked smooth muscle differentiation, a case series from single institution.

Fibroadenoma and phyllodes tumor are the prototypical mammary fibroepithelial lesions (FELs). Recently, a subset of FELs, identified as stromal-epithelial lesion (SEL) with myofibroblastic stroma have been labelled as myofibroepithelial nodule (MFN). The MFN stromal cells are diffusely positive for SMA immunostaining and frequently show unusual histological features including irregular borders. There is limited literature on FELs with myofibroblastic or smooth muscle stroma. The etiology of the variation in the FEL stromal histology and its clinical significance is unknown. In this short report we describe clinicopathologic features of six FELs with myofibroblastic and/or smooth muscle stroma. We also report immunohistochemical overexpression of HMGA2 in 2 FELs that contained stromal smooth muscle differentiation suggesting a link to mammary myoid hamartoma. On limited follow up all the 6 FELs with myofibroblastic or smooth muscle stroma had benign outcome. The HMGA2 overexpressing FEL with smooth muscle stroma and myoid hamartoma of the breast show overlapping etiology, and histological features.

Simultaneous p53 and KRAS mutation in a high-grade serous carcinoma with deceptive appearance of a low-grade carcinoma. A case report.

Low-grade and high-grade serous carcinomas have unique clinical, morphological, underlying molecular alterations, and vastly different biologic behavior (Prat et al., 2018, Vang et al., 2009). The differentiation into high and low-grade serous carcinoma is important for clinical management and prognosis and is easily recognized by practicing pathologists. High-grade serous carcinoma is characterized by marked nuclear atypia and pleomorphism, frequent, often atypical mitosis with papillary or three-dimensional clusters, p53 mutation, and block-like p16 staining. In contrast, low-grade serous carcinomas have a different morphologic appearance with micropapillary formation, small nests of tumor cells having low to intermediate grade nuclei, and absence of significant mitosis. Low-grade serous carcinoma is often associated with micropapillary variant of ovarian serous borderline tumor. The low-grade serous carcinoma shows wild type p53 expression, patchy p16 staining, and often K-RAS, N-RAS, and/or B-RAF mutation. Here we report a case of mullerian high grade serous with a deceptive morphology resembling low-grade serous carcinoma with micropapillary features and moderate nuclear atypia. However, the tumor is simultaneously p53 and K-RAS mutated. This case illustrates three critical issues; a) potential to be mistaken as a low-grade serous carcinoma because of morphologic appearance and relative uniform cytologic feature. b). raise the question of true progression of low-grade to high-grade serous carcinoma, a rare phenomenon as described in the literature, and c). whether the biologic behavior and/or response to therapy would differ from the classic forms.

Malignant Mixed Mullerian Tumor Arising from Endometriosis in the Groin: A Case Report and Literature Review.

This was a 57-year-old woman who presented with mild discomfort in the right groin. Physical examination revealed a mass in the right groin, and by ultrasound, the mass was hypoechoic and solid with some internal vascularity. The clinical differential diagnosis included lymphoma and others. The mass was excised for pathologic evaluation. Gross examination of the specimen revealed a 3 × 2.4 × 2 cm, solid and cystic mass. Microscopically, it was a biphasic tumor consisting of carcinomatous and sarcomatous components. The tumor was seen contiguous with endometriosis and atypical endometrioid hyperplasia. The histologic findings were consistent with malignant mixed Mullerian tumor (MMMT) arising from endometriosis in the right groin. The tumor involved the resection margin. Subsequent chest/abdominal/pelvic computed tomography did not reveal evidence of tumors, and diagnostic peritoneal/pelvic laparoscopy did not show diseases. Postoperatively, the patient received 6 cycles of chemotherapy consisting of carboplatin and paclitaxel, followed by radiation in the right groin. Malignant transformation from endometriosis occurs in less than 1% of endometriosis cases, and about 80% of the transformed tumors occur in the ovaries. The most commonly transformed malignant tumors are endometrioid and clear cell carcinomas, with rare adenosarcoma and endometrial stromal sarcoma reported. To our knowledge, we are reporting the first case of MMMT arising from endometriosis in the groin.