Navigating HER2-Low Testing in Invasive Breast Cancer: Update Recommendations for Pathologists.

The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.

Ductal carcinoma in situ within a fibroadenoma: A case report and review of literature.

BACKGROUND: Fibroadenoma (FA) is the most common tumor found in young women, although it can occur in any age group. Ductal carcinoma in situ (DCIS) that is confined in a FA is rare; it is most frequently reported as an incidental finding. CASE SUMMARY: We report a case of DCIS within a FA in a 46-year-old female without cancer-related personal and family histories. The patient was diagnosed with a breast conglomerate of nodules and was followed for 1 year. In the current control image study, we found suspicious microcalcification, as a new finding, within one of the nodules. Consequently, a core biopsy of the tumor, which appeared hypoechoic, oval, and circumscribed, was performed. The pathological diagnosis was ductal carcinoma in situ within a fibroepithelial lesion. The patient underwent breast-conserving surgery and received radiotherapy as well as endocrine therapy (tamoxifen). CONCLUSION: We recommend a multidisciplinary approach for adequate treatment and follow-up.

Comparing fine needle biopsy techniques in solid pancreatic lesions: A prospective randomized study.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle biopsies (EUS-FNB) are the best technique for sampling solid pancreatic lesions. However, the most appropriate biopsy technique has not been standardized using Fine Needle Biopsy (FNB) needles. The aim of this work was to identify the best biopsy technique to achieve the best tissue integrity and cause the least blood contamination. MATERIAL AND METHODS: Patients ≥18 years of age with solid pancreatic lesions who underwent EUS-FNB at our institution from January 2020 to May 2021 were consecutively selected. Three passes were performed with each of the threee techniques to obtain tissue: suction with 10 ml of vacuum, capillary, and wet. An independent pathologist evaluated the received tissue integrity and the degree of blood contamination of each sample according to scales. RESULTS: Seventy-five patients were recruited for our study. A superior tissue integrity was observed using the wet-suction technique in lesions located in the body and/or tail of the pancreas, and an average score of 4.40 (p = 0.027) was assigned for this technique. Regarding the contamination of the sample in the whole cohort, the simple-suction technique shown a higher contamination, 1.55 (p < 0.001). There was no statistically significant difference among the techniques when evaluating tissue integrity or contamination in lesions larger or smaller than 3 cm. CONCLUSION: When performing EUS-FNB for solid pancreatic lesions located in the head/uncinated process, the three methods provided similar diagnostic yields. The wet-suction technique had a higher score in tissue integrity when lesions were located in the body and/or tail of the pancreas.

NUSAP1 and PCLAF (KIA0101) Downregulation by Neoadjuvant Therapy is Associated with Better Therapeutic Outcomes and Survival in Breast Cancer.

Purpose: To evaluate whether changes in genomic expression that occur beginning with breast cancer (BC) diagnosis and through to tumor resection after neoadjuvant chemotherapy (NCT) reveal biomarkers that can help predict therapeutic response and survival. Materials and Methods: We determined gene expression profiles based on microarrays in tumor samples from 39 BC patients who showed pathologic complete response (pCR) or therapeutic failure (non-pCR) after NCT (cyclophosphamide-doxorubicin/epirubicin). Based on unsupervised clustering of gene expression, together with functional enrichment analyses of differentially expressed genes, we selected NUSAP1, PCLAF, MME, and DST. We evaluated the NCT response and the expression of these four genes in BC histologic subtypes. In addition, we study the presence of tumor-infiltrating lymphocytes. Finally, we analyze the correlation between NUSAP1 and PCLAF against disease-free survival (DFS) and overall survival (OS). Results: A signature of 43 differentially expressed genes discriminated pCR from non-pCR patients (|fold change >2|, false discovery rate <0.05) only in biopsies taken after surgery. Patients achieving pCR showed downregulation of NUSAP1 and PCLAF in tumor tissues and increased DFS and OS, while overexpression of these genes correlated with poor therapeutic response and OS. These genes are involved in the regulation of mitotic division. Conclusions: The downregulation of NUSAP1 and PCLAF after NCT is associated with the tumor response to chemotherapy and patient survival.

Immunotyping of tumor-infiltrating lymphocytes in triple-negative breast cancer and genetic characterization.

Tumor-infiltrating lymphocytes (TILs) reflect the host immune response against cancer cells. Immunomodulators have been recently suggested as a novel therapeutic strategy against triple-negative breast cancer (TNBC). However, the TIL profile in TNBC has not been thoroughly investigated. In the present study, the percentage, immunophenotype and genetic profiles of TILs in pre-surgical tumor samples of patients with TNBC were evaluated prior to neoadjuvant chemotherapy (NAC). Patients diagnosed with breast cancer at Hospital San José TecSalud were consecutively and prospectively enrolled in the present study between August 2011 and August 2015. The pathological response to NAC was evaluated using the de Miller-Payne and MD Anderson Cancer Center system. TIL percentage (low, intermediate, and high) was evaluated using special hematoxylin-eosin staining on the core needle biopsies. The immunophenotype of TILs was assessed by immunohistochemistry (IHC) for CD3+, CD4+ and CD8+. In addition, the gene expression profile of CD3, CD4, CD8, CD20, CD45, forkhead box P3, interleukin 6, programmed cell death 1 and CD274 molecule was assessed in all patients. A total of 26 samples from patients with TNBC prior to NAC were included in the present study. TILs were low in 30.7%, intermediate in 38.4% and elevated in 30.7% of tumors. CD3+ and CD4+ counts were associated with the pathological response to NAC (P=0.04). Finally, an overexpression pattern of CD3, CD4, CD8, CD45 and CD20 genes was observed in patients with a partial or complete pathological response. The present results demonstrated that TILs may predict the pathological response to NAC in patients with TNBC. Furthermore, a more accurate association was identified between the high expression levels of CD3, CD4, CD8, CD45 and CD20 genes and partial and complete pathological response, compared with the association between high expression and IHC alone.

Comparison of characteristics in Mexican women with breast cancer according to healthcare coverage.

OBJECTIVE: To compare the sociodemographic, diagnostic, clinical, and treatment-related characteristics and outcomes of patients with breast cancer in two hospitals in Mexico according to type of healthcare coverage. METHODS: A retrospective cohort study of women with breast cancer according to public or private healthcare coverage in two hospitals was done. Patients were treated by the same group of physicians and healthcare infrastructure. Groups were compared using the chi-square test for categorical variables, Mann-Whitney U-test and Student's t-test for quantitative variables, and Kaplan-Meier estimator and log-rank test for time dependent outcomes (including recurrence-free and overall survival). A value of p < 0.05 was considered statistically significant. RESULTS: A total of 282 women were included. Mean age at diagnosis was 52 years. Women with public healthcare coverage were diagnosed more frequently with self-detected tumors (82.8% vs 47.9%, p < 0.001) and advanced clinical stage (III and IV) (31.1% vs 17.8%, p = 0.014). More women with public healthcare insurance underwent initial systemic treatment (41.1% vs 17.8%, p < 0.001) and mastectomy (70.1% vs 54.9%, p = 0.020), and received more chemotherapy (79.4% vs 43.8%, p < 0.001) and adjuvant radiotherapy (68.9% vs 53.4%, p = 0.017). Overall, no differences were found in survival outcomes according to healthcare coverage. Trends suggesting worse recurrence-free and overall survival were observed in patients with public coverage at 3 years follow-up in stage III (85.7% vs 67.3% and 100% vs 84.6%, respectively) and triple negative disease (83.3% vs 74.5% and 100% vs 74.1%, respectively). CONCLUSION: Strategies to promote preventive medicine, diagnostic mammograms, and prompt diagnosis of breast cancer in Mexican women with public health coverage are needed. Access to the main treatment modalities by Seguro Popular and good quality care by an experienced group of physicians likely explains the similar outcomes between patients with private and public healthcare coverage. However, trends suggesting worse survival for patients with public medical coverage with stage III and triple-negative disease should encourage close follow-up.

Non-syndromic bilateral ovarian sex cord stromal tumor with annular tubules in a postmenopausal elderly woman as an incidental finding.

INTRODUCTION: Sex cord tumors with annular tubules (SCTAT) are very rare neoplasms comprising less than 1% of sex cord ovarian tumors. They usually occur in women of reproductive age and tend to be associated with Peutz Jeghers Syndrome (PJS), be bilateral, multifocal, and small. When diagnosed in older patients they are often described as sporadic, unilateral, predominantly cystic and bigger. CASE PRESENTATION: A bilateral hysterosalpingo-oophorectomy was performed in a seventy-one year-old-woman with postmenopausal bleeding showing no features of PJS. A bilateral SCTAT was diagnosed, associated with a focus of Leydig cell hyperplasia, an endometrial polyp and endomethroid intraepithelial neoplasia. DISCUSSION: SCTAT is a very rare histological variant in postmenopausal women. The case we present is special, different to what has been reported in the literature regarding these tumors. CONCLUSION: It is important to be aware that SCTATs can also be present in older women, they can be bilateral despite not being related to PJS syndrome and must be considered as a differential diagnosis in ovarian tumors.

Cardiac Tamponade as an Initial Manifestation of Cervical Cancer.

Cervical cancer is the second most common malignancy worldwide in women and the third most common cause of cancer death in developing countries. This type of cancer spreads mainly to the lung, the bone, and the brain; however, the pericardium is an unusual site of invasion, which is associated with a poor prognosis. We present a case of a 35-year-old woman with six months of leg edema and abnormal uterine bleeding. During the initial evaluation, cardiac tamponade and a bilateral pleural effusion were found. A left supraclavicular lymphadenopathy was identified on physical examination, while gynecological examination and MRI were irrelevant. Initial cytology of the pericardial fluid showed a poorly differentiated carcinoma, and a cervical biopsy revealed a squamous cell invasive carcinoma. Chemotherapy was started with carboplatin and paclitaxel, but no clinical improvement was noted and the patient died 46 days after arrival. Cardiac tamponade in a young female patient is a harbinger to widen the differential diagnosis to include not only infectious, cardiac, or metabolic etiology but also oncological causes since this will allow appropriate treatment.

A solitary presentation of panniculitis in a patient with a history of breast cancer.

INTRODUCTION: Panniculits presents as an inflammation of the subcutaneous adipose tissue of the skin. In breast, panniculitis is very rare and is usually a manifestation of underlying inflammatory conditions. The typical presentation is palpable tender nodules, which in cases of breast panniculitis, triggers an extensive work up to exclude a malignancy. Herein we present a case of septal and lobar panniculitis in a female with clinical history of invasive ductal carcinoma. PRESENTATION OF THE CASE: A 52-year old female with past medical history of invasive breast carcinoma 5 years prior to the presentation. The patient's chief complaint was a 1-year history of a subcutaneous nodular lesion on her left breast. A core biopsy of the firm nodule showed marked inflammation of the breast. A second skin biopsy showed an abundant chronic inflammatory infiltrate, with lymphocytic vasculitis and neuritis, suggestive of an underlying autoimmune process. DISCUSSION: Subcutaneous panniculitis with or without vasculitis is a rare condition when presenting in the breast. Panniculitis can mimic malignancy and thus, it is important to differentially diagnose it from breast carcinoma. Histologically, it is classified in lobular and septal lymphocytic panniculitis depending on specific diagnostic characteristics. CONCLUSION: Panniculitis of the breast is a rare condition that needs to be included in the differential diagnosis of subcutaneous breast masses. In all cases, but specifically in females with history of breast cancer, panniculitis still should be thought of as a possibility, and imaging as well as other diagnostic techniques can aid in making the correct diagnosis.

Pure mucinous breast carcinoma in a 25-year-old female, a case report.

INTRODUCTION: Mucinous carcinoma is a variant of invasive breast carcinomas representing 2% of them. These tumors frequently develop in postmenopausal females; it is a rare histological variant in young patients. CASE PRESENTATION: A 25-year-old female refers a slow growth mass of 2 years of evolution. Excisional biopsy reveals a pure mucinous carcinoma with positive hormone receptors and negative HER2. She was treated with hormone therapy and surgical resection. DISCUSSION: Mucinous carcinoma is a rare variant reported in young patients. Many series report that is frequently found in postmenopausal patients. We present a case of a pure mucinous carcinoma in a 25-year-old female with the importance of being a low-frequency malignancy in young patients. CONCLUSION: Due to its benign course, it is important to know that this lesion can also present in young patients. The importance underlies in the multidisciplinary management at the right time in a proper way.

Overexpression of the matrix metalloproteinase 11 gene is a potential biomarker for type 1 endometrial cancer.

Metalloproteinase matrix 11 (MMP11) is a member of the matrix metalloproteinase family, which are able to degrade extracellular matrix components, and may serve a central function in the enhancement of tumor-induced angiogenesis, cell migration, proliferation, apoptosis and connective tissue degradation. In the present study, MMP11 gene expression was investigated using the reverse transcription-polymerase chain reaction in 68 cases of type I endometrial carcinoma, and all data were analyzed in association with clinical characteristics. Overexpression of MMP11 was demonstrated in 75%, and sub-expression was demonstrated in 25%, of endometrial cancer cases. Sub-expression cases were associated with good histological parameters, including low histological grade (G1 and G2), early pathological stage, and absence of vascular invasion, metastasis and recurrence. In total, 76.4% of endometrial cancer cases with sub-expression were identified as early stage 1A and B; however, 23.6% of cases were identified as stage 2, with vascular invasion present in 29.4% of cases. On the other hand, cases which demonstrated overexpression with high ranges (>10 times more than control) were associated with adverse histopathological characteristics, including high grade tumor (G3) and vascular invasion. In conclusion, the increased expression of MMP11 may be used as a prognostic biomarker in patients with type 1 endometrial cancer.

Description of Genetic Variants in BRCA Genes in Mexican Patients with Ovarian Cancer: A First Step towards Implementing Personalized Medicine.

Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe BRCA1 and BRCA2 gene variants in Mexican patients with ovarian cancer. Sequencing of BRCA1 and BRCA2 genes from tumors of 50 Mexican patients with ovarian cancer was made in a retrospective, non-randomized, and exploratory study. We found genetic variants in 48 of 50 cases. A total of 76 polymorphic variants were found in BRCA1, of which 50 (66%) had not been previously reported. Furthermore, 104 polymorphic variants were found in BRCA2, of which 63 (60%) had not been reported previously. Of these polymorphisms, 5/76 (6.6%) and 4/104 (3.8%) were classified as pathogenic in BRCA1 and BRCA2, respectively. We have described the genetic variants in BRCA1 and BRCA2 of tumors from Northeast Mexican patients with sporadic ovarian cancers. Our results showed that the use of genetic testing helps recognize patients that carry pathogenic variants which could be beneficial for personalized medicine treatments.

Understanding the HPV integration and its progression to cervical cancer.

Cervical cancer is one of the main causes of female cancer death worldwide, and human papilloma virus (HPV) its causal agent. To investigate viral oncogenesis several studies have focused on the effects of HPV oncoproteins E6 and E7 and the mechanisms by which these proteins stimulate the cellular transformation process. However, phenomena such as the physical state of the viral genome (episomal or integrated) and the effects of this integration on cell proliferation contribute new clues to understand how HPV infection causes carcinogenesis. New molecular technologies are currently facilitating these discoveries. This paper reviews the tumor development process initiated by HPV, recent findings on the process of viral integration into the host genome, new methods to detect HPV integration, and derived associated effects.

Her-2 positive mucinous carcinoma breast cancer, case report.

INTRODUCTION: Mucinous carcinoma is a variant of invasive breast carcinomas that accounts for 2% of them and has a better prognosis in contrast to the non-specific invasive carcinoma. They regularly are positive for estrogen and progesterone receptors and, generally, they do not overexpress HER2. When HER2 is positive, the first line treatment is trastuzumab; although the resistance is 52-89% for the non-specific carcinoma, it has been described just once in mucinous carcinoma. CASE SUMMARY: A 48-year-old female presented with a lump in her right breast and after a biopsy, it was diagnosed as mucinous carcinoma in the core biopsy and surgical resection, with positive hormone receptors and HER2 positive (3+) in 100% of the tumor cells. She was treated with neoadjuvant chemotherapy based on trastuzumab and pertuzumab with no pathological response. DISCUSSION: There are few pure mucinous carcinomas positive for HER2. Mucinous carcinomas are positive for HER2 account for less than 5% of invasive ductal carcinoma. Furthermore, our case was resistance to chemotherapy. Most mucinous carcinomas test negative for HER2, so they usually would not be treated with trastuzumab, in this case because the expression of HER2 in the biopsies we initiated it. CONCLUSION: It's important to know that cases of mucinous carcinoma positive for HER2 exist and to be aware of the clinical problems that they may present: resistance to trastuzumab. Also, we need to understand the responsible mechanisms of this resistance and use immunohistochemistry for MUC which may predict it.

Aspergillus in liquid-based cervicovaginal cytology in a postmenopausal patient: A case report.

Aspergillus is an opportunistic fungus present in humid environments, whose natural environment is in soil, hay and compost. It is a frequent contaminant in the clinical laboratory. Because of this, the fungus is often inhaled, affecting those with an underlying pulmonary disease or immune deficiency. Fungal genitourinary tract infections are relatively common. A rare Aspergillus spp cervical infection diagnosed via liquid-based cytology is presented in the current study. The 57-year-old woman attended her annual check-up without any relevant medical history. The result of a gynecological examination by Papanicolaou smear was normal and routine liquid-based cytology was performed. The specimen exhibited fungal organisms characterized by septate hyphae branching at acute angles, most consistent with the Aspergillus species. Subsequent cytology demonstrated the same results. Antifungal treatment was initiated and a second post-treatment smear only exhibited atrophy. The cytomorphological features of Aspergillus spp. are discussed in the current study and a brief review of the few reported cases of a primary cervical infection in the literature is provided. In addition, the liquid-based cytology was established as a tool to diagnose the rare Aspergillus infection.

Cytological diagnosis of Rosai-Dorfman disease: A case report and revision of the literature.

Rosai-Dorfman disease also known as sinus histiocytosis with massive lymphadenopathy (SHML) is characterized by distorted lymph node architecture with marked dilation of lymphatic sinuses occupied by numerous lymphocytes, as well as histiocytes with vesicular nucleus and abundant clear cytoplasm with phagocytized lymphocytes or plasma cells, also known as 'emperipolesis'. This disease of unknown etiology progresses with a benign prognosis strictly and only when an early diagnosis and treatment is made. A late diagnosis and a generalized lymph node involvement contribute to a poor prognosis. In this study, we focussed on the cytological characteristics of the Rosai-Dorfman disease and differential diagnoses. We reported a case of a 61-year-old Mexican male with a 9-month history of painless bilateral cervical masses and low-grade fever with the final diagnosis of Rosai-Dorfman disease. The final diagnosis was made by fine needle aspiration (FNA) biopsy of parotid gland and cervical lymph node. In conclusion, FNA biopsy can be enough to make the diagnosis in most cases due to the distinct cytological features of SHML, thereby avoiding more invasive approaches that potentially are unnecessary.

CDX-2, MUC-2 and B-catenin as intestinal markers in pure mucinous carcinoma of the breast.

BACKGROUND: Pure mucinous adenocarcinoma of the breast is a rare entity characterized by the production of variable amounts of mucin comprising 1% to 6% of breast carcinomas. Some mucinous adenocarcinomas have shown expression of intestinal differentiation markers such as MUC-2. This study examines the expression of intestinal differentiation markers in this type of breast carcinoma. RESULTS: Twenty-two cases of pure mucinous adenocarcinoma of the breast were assessed. Immunochemistry was performed for beta-catenin, CDX-2 and MUC-2. All cases were positive for B-catenin. MUC-2 positivity was observed in all cases; 63. 6% were 3 plus positive. All cases were negative for CDX-2. CONCLUSIONS: These results suggest that mucinous breast carcinomas express some markers of intestinal differentiation, such as MUC-2 and beta-catenin; however, future studies with a larger series of cases and using molecular techniques that help affirm these results are needed.

Landscape of genomic alterations in cervical carcinomas.

Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

Osteoclastic giant cell rich squamous cell carcinoma of the uterine cervix: a case report and review of the literature.

Cervical carcinoma is the most common malignancy of the female genital tract and represents the second most common malignancy in women worldwide. Histologically 85 to 90% of cervical cancers are squamous cell carcinoma. Osteoclastic giant cell rich squamous cell carcinoma is an unusual histological variant of which only 4 cases have been reported. We present the case of a 49-year-old woman with a 6-month history of irregular vaginal bleeding. Examination revealed a 2.7 cm polypoid mass in the anterior lip of the uterine cervix. The patient underwent hysterectomy with bilateral salpingo-oophorectomy. Microscopically the tumor was composed of infiltrative nests of poorly differentiated nonkeratinizing squamous cell carcinoma. Interspersed in between these tumor cells were numerous osteoclastic giant cells with abundant eosinophilic cytoplasm devoid of nuclear atypia, hyperchromatism, or mitotic activity. Immunohistochemistry was performed; CK and P63 were strongly positive in the squamous component and negative in the osteoclastic giant cells, while CD68 and Vimentin were strongly positive in the giant cell population and negative in the squamous component. The patient received chemo- and radiotherapy for recurrent disease identified 3 months later on a follow-up CT scan; 7 months after the surgical procedure the patient is clinically and radiologically disease-free.

CDX-2, MUC-2 and B-catenin as intestinal markers in pure mucinous carcinoma of the breast

BACKGROUND: Pure mucinous adenocarcinoma of the breast is a rare entity characterized by the production of variable amounts of mucin comprising 1% to 6% of breast carcinomas. Some mucinous adenocarcinomas have shown expression of intestinal differentiation markers such as MUC-2. This study examines the expression of intestinal differentiation markers in this type of breast carcinoma. RESULTS: Twenty-two cases of pure mucinous adenocarcinoma of the breast were assessed. Immunochemistry was performed for beta-catenin, CDX-2 and MUC-2. All cases were positive for B-catenin. MUC-2 positivity was observed in all cases; 63. 6% were 3 plus positive. All cases were negative for CDX-2. CONCLUSIONS: These results suggest that mucinous breast carcinomas express some markers of intestinal differentiation, such as MUC-2 and beta-catenin; however, future studies with a larger series of cases and using molecular techniques that help affirm these results are needed.