Gábor Cserni

Invasive lobular carcinomas may demonstrate tubule formation both at the primary and at metastatic sites. A series of 135 invasive lobular carcinomas scrutinously screened for tubular elements were used, and tumours with axillary lymph node metastases were selected for review. Two observers blinded to the histology of the primary tumours independently and then together looked at all slides from lymph node metastases of 50/52 cases having nodal involvement searching for tubular structures. Altogether 4 lymph nodes from 4 tumours were identified as harbouring tubules, 1 from a primary with tubular elements, and 3 from carcinomas without tubular elements identified in the primary. Tubule formation was generally focal (< 10%) in most primaries (including the one with similar metastasis), therefore, by chance identification and sampling bias may be contributory factors to the discrepant primary and metastatic tubular elements, but microenvironment related factors may also be involved in a site dependent development of tubules in lobular carcinomas. Identifying tubules in a metastasis associated with a non-tubule-forming primary lobular carcinoma should not obviously mandate the search for a similar tubule-forming primary tumour.

Ki67 immunohistochemistry is widely used in clinical settings to assess tumour proliferation in breast cancer, yet the temporal changes in Ki67 labelling index following neoadjuvant chemotherapy (NACT) are underexplored. Matched core biopsy and surgical excision specimens of invasive breast cancers were collected, and the Ki67 immunostained slides were examined. Ki67 labelling index was determined and statistically evaluated based on the time elapsed between the last cycle of NACT and surgery. Subgroup analyses were carried out based on surrogate molecular subtypes, Residual Cancer Burden (RCB), and European Working Group for Breast Screening Pathology tumour regression (TR) categories. The study included 54 paired breast cancer cases post-NACT. Most tumours were RCB-II ( n = 39) and TR2b ( n = 20). The average time from NACT completion to surgery was 40.3 days. Of three methods (including image-analysis and sample-counting), eye-balling estimation provided the best linear regression fit ( p = 0.003, R ² = 0.1548). Subgroup analysis showed reduced proliferation suppression over time in HER2-positive, triple-negative, and luminal B-like tumours, as well as RCB-II, RCB-III, TR2b, TR2c, and TR3 tumour regression categories. Conversely, luminal A-like tumours, RCB-I, and TR2a categories showed an opposite trend, though limited by small sample size. Multiple studies highlight the prognostic value of Ki67 labelling index post-NACT, with pre- and post-treatment values and change between them serving as independent prognosticators, but our data suggest that the latter two may be time-dependent after the completion of NACT. The proliferation-reducing effect of NACT diminishes over time, particularly in non-luminal A-like tumours and those with poorer treatment responses.

Of breast cancers, the triple-negative subtype (TNBC) is characterized by aggressive behavior, poor prognosis and limited treatment options due to its high molecular heterogeneity. Since insufficient programmed cell death response is a major hallmark of cancer, here we searched for apoptosis-related biomarkers of prognostic potential in TNBC. The expression of the pro-apoptotic caspase 8, cytochrome c, caspase 3, the anti-apoptotic BCL2 and the caspase-independent mediator, apoptosis-inducing factor-1 (AIF1; gene AIFM1) was tested in TNBC both in silico at transcript and protein level using KM-Plotter, and in situ in our clinical TNBC cohort of 103 cases using immunohistochemistry. Expression data were correlated with overall survival (OS), recurrence-free survival (RFS) and distant metastasis-free survival (DMFS). We found that elevated expression of the executioner apoptotic factors AIF1 and caspase 3, and of BCL2, grants significant OS advantage within TNBC, both at the mRNA and protein level, particularly for chemotherapy-treated vs untreated patients. The dominantly cytoplasmic localization of AIF1 and cleaved-caspase 3 proteins in primary TNBC suggests that chemotherapy may recruit them from the cytoplasmic/mitochondrial stocks to contribute to improved patient survival in proportion to their expression. Our results suggest that testing for the expression of AIF1, caspase 3 and BCL2 may identify partly overlapping TNBC subgroups with favorable prognosis, warranting further research into the potential relevance of apoptosis-targeting treatment strategies.

Introduction: Primary cervical cancer with synchronous ovarian metastasis is a rare clinical entity; it is more common in cervical adenocarcinoma than squamous cell carcinoma. Case Presentation: We discuss the case of a 38-year-old female who presented in 2012 with a 15-cm-large cyst of the right ovary, with negative cervical smear cytology. Right adnexectomy was performed laparoscopically, and metastatic cystic squamous cell carcinoma probably originating from the endocervix was reported. One month later, radical hysterectomy (Piver type I) and left adnexectomy were performed; a 15-mm-large high endocervical papillary squamous cell carcinoma was diagnosed. There is no evidence of local recurrence or distant metastasis to date. Conclusion: This case shows that these kind of (primary) cervical and (secondary) ovarian tumors are almost always discontinuous, without any evidence of direct invasion from cervix to ovary, and it also supports the notion that in cases of cervical cancer originating from the endocervix or cervical canal and protruding into or involving the isthmus, the prevalence of ovarian metastasis is higher. This unique case is a good example of unintentionally—and fortunately—diagnosed squamous cell carcinoma of endocervical origin with unilateral ovarian metastasis.

Following a wide interdisciplinary consultation, the present recommendations have been finalized after their public discussion at the 5th Hungarian Consensus Conference on Breast Cancer. The recommendations cover non-operative, intraoperative and postoperative diagnostics, the determination of prognostic and predictive markers and the content of the cytology and histology reports. Furthermore, it touches some special issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement. The most important changes include the integration of the ASCO/CAP HER2 assessment guidelines from 2023, the reformulation of the role of cytology in breast cancer diagnostics, diagnostic categories of non-operative lymph node assessment, and the revision of PD-L1 assessment related information. The recommendations include the core and non-core elements of the ICCR (International Collaboration on Cancer Reporting) breast cancer related datasets.

Phyllodes tumours (PTs) of the breast present diagnostic challenges due to their complex histological features and potential for malignant behaviour. The World Health Organisation (WHO) classification requires the presence of five adverse histological criteria to categorise PTs as malignant, aiming to avoid overdiagnosis and improve diagnostic consistency. However, emerging evidence suggests that these strict criteria may underdiagnose tumours with metastatic potential and histological features that would otherwise be considered malignant in soft tissue tumours, leading to significant implications for prognosis and treatment. Recent studies have highlighted cases where tumours classified as borderline PT by WHO criteria exhibited metastatic behaviour, emphasising the need to refine the diagnostic framework. Microscopic criteria used to classify PT also vary among reporting pathologists, resulting in suboptimal reproducibility. This review examines the histological parameters utilised in the classification of malignant PT, highlights existing evidence gaps and analyses international breast pathologist survey data to propose a pragmatic diagnostic approach. We recommend redefining malignant PTs to include cases meeting four of the five WHO criteria, supplemented by comprehensive sampling and clinical context. This approach balances the risk of underdiagnosis with the need for standardised, reproducible diagnostic practices. Future collaborative efforts should focus upon developing evidence‐based, biologically relevant classification systems and leveraging technological advancements to enhance diagnostic precision. These efforts aim to refine classification, improve prognostic accuracy and optimise patient management strategies.

Uremic cardiomyopathy, characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis, is a common cardiovascular complication of chronic kidney disease (CKD). Men are at a higher risk for cardiovascular and renal diseases, compared to age-matched, pre-menopausal women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy through the characterization of functional and molecular indices of myocardial remodeling in a rat model. CKD was induced by a 5/6 nephrectomy in 9-week-old male and female Wistar rats. Serum and urine tests, transthoracic echocardiography, left ventricular (LV) histology, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed at week 8 or 9. Moreover, LV alterations were also tested in permeabilized cardiomyocytes (CMs) by force measurements and Western immunoblotting. CKD resulted in the development of a more severe uremic cardiomyopathy in male rats—including LVH, LV diastolic dysfunction, and fibrosis—than in female rats, where only LVH was observed. A uremic cardiomyopathy was also associated with a decrease in maximal Ca²⁺-activated force (F_max) in CMs of male rats. Additionally, increases in CM Ca²⁺-independent passive stiffness (F_passive) and decreases in cardiac myosin-binding protein C (cMyBP-C) phosphorylation levels were significantly larger in male than female rats. In conclusion, a uremic cardiomyopathy involved cardiac remodeling in both sexes. Nevertheless, male rats exhibited more pronounced signs of macroscopic and microscopic alterations than their female counterparts, illustrating a sex-dependent component of uremic cardiomyopathy.

Invasive lobular carcinoma of the breast is the most common special type breast cancer. It has been defined using morphological features, has a characteristic immunophenotype associated with the loss of E-cadherin mediated intercellular adhesion, and the background of this immunohistochemistry and morphology is generally a biallelic genetic alteration of the CDH-1 gene coding E-cadherin. However, the morphology may often deviate from the classical, and immunohistochemistry may also deviate from the typical, and then the diagnosis of invasive lobular carcinoma becomes less straight forward. Eventually, the definitions of this histological type, although similar, are not identical and this may also give ground to occasional different interpretations. This review summarizes different approaches to invasive lobular carcinomas and the deviations from what is considered normal.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and limited treatment options. This study evaluates the prognostic value of stromal markers in TNBC, focusing on the tumor–stroma ratio (TSR) and overall stroma ratio (OSR) in whole slide images (WSI), as well as the expression of type-I collagen, type-III collagen, and fibrillin-1 on tissue microarrays (TMAs), using both visual assessment and digital image analysis (DIA). A total of 101 female TNBC patients, primarily treated with surgery between 2005 and 2016, were included. We found that high visual OSR correlates with worse overall survival (OS), advanced pN categories, lower stromal tumor-infiltrating lymphocyte count (sTIL), lower mitotic index, and patient age (p < 0.05). TSR showed significant connections to the pN category and mitotic index (p < 0.01). High expression levels of type-I collagen (>45%), type-III collagen (>30%), and fibrillin-1 (>20%) were linked to significantly worse OS (p = 0.004, p = 0.013, and p = 0.005, respectively) and progression-free survival (PFS) (p = 0.028, p = 0.025, and p = 0.002, respectively), validated at the mRNA level. Our results highlight the importance of stromal characteristics in promoting tumor progression and metastasis and that targeting extracellular matrix (ECM) components may offer novel therapeutic strategies. Furthermore, DIA can be more accurate and objective in evaluating TSR, OSR, and immunodetected stromal markers than traditional visual examination.