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Purpose: This study aimed to validate the classification of breast cancer (BC) patients in progression risk groups based on total tumor load (TTL) value to predict lymph node (LN) affectation after neo-adjuvant systemic therapy (NAST) obtained in the NEOVATTL study., Methods/patients: This was an observational, retrospective, international, multicenter study including patients with infiltrating BC who received NAST followed by sentinel lymph node biopsy (SLNB) analyzed with one-step nucleic acid amplification (OSNA) from nine Spanish and two Italian hospitals. Patients were classified into three groups according to the progression risk, measured as disease-free survival (DFS), based on TTL values (> 250, 250-25,000, and > 25,000 copies/μL). The previous (NEOVATTL study) Cox regression model for prognosis was validated using prognostic index (PI) and Log ratio test (LRT) analyses; the value of TTL for axillary non-SLN affectation was assessed using receiver operating characteristic (ROC) curves., Results: We included 263 patients with a mean age of 51.4 (± SD 10.5) years. Patients with TTL > 25,000 copies/μL had a shorter DFS (HR 3.561 [95% CI 1.693-7.489], p = 0.0008 vs. TTL ≤ 25,000). PI and LRT analyses showed no differences between the two cohorts (p = 0.2553 and p = 0.226, respectively). ROC analysis showed concordance between TTL and non-SLN involvement (area under the curve 0.828), with 95.7% sensitivity and 92.9% specificity at a TTL cut-off of > 15,000 copies/μL., Conclusions: In BC patients who had received NAST and underwent SLNB analysis using OSNA, a TTL value of > 25,000 copies/μL was associated with a higher progression risk and > 15,000 copies/μL was predictive of non-SLN involvement., (© 2023. The Author(s).)

Metastasis to the breast from extramammary tumors are rare, and the most common cancer that metastasizes to this site is malignant melanoma (MM). Unfortunately, metastases from malignant melanoma reveal a widespread of the disease and a high likeliness of poor diagnosis. In this study, a case of left breast metastasis of MM in a young pregnant woman, with a fast progression of the mammary and systemic course of pathology and unfortunately poor prognosis is presented. Despite the role of pregnancy in MM has yet to be unraveled, our study encourages the theory that immunosuppression and hormonal changes due to pregnancy may aggravate melanoma prognosis.

Introduction: Metastasis from melanoma in the gastro-intestinal tract is a frequent event but, in the absence of an adequate clinical context and oncological anamnesis, it could be misdiagnosed by the pathologists. Moreover, amelanotic and/or poorly differentiated metastasis from melanoma in the gastro-intestinal tract can be easily underestimated., Materials and Methods: We describe the histological features of gastro-intestinal metastasis from melanoma in a multi-centric cohort of 49 patients. In 24/49 patients, we were able to compare histological findings such as the growth pattern and the melanotic pigment also in the primary melanoma., Results: The epithelioid pattern is the most common growth pattern observed in gastro-intestinal metastasis (57 %), followed by the mixed pattern (41 %) and the spindled pattern (2 %). We documented a discordant growth pattern between metastasis and primary in 9/24 cases and the absence of melanotic pigment in 8/49 cases., Discussion: Our experience highlights that pathologists should take into account the possibility of gastro-intestinal metastasis from melanoma also in cases with spindled-cells/amelanotic lesions, without a previous anamnesis of melanoma asportation, and in cases of a discordant growth pattern with the primary. A correct clinical integration and an aware immunohistochemical approach are imperative to best manage the bioptic sample in order to investigate the biological profiling and therefore plan a personalizated therapy., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Colorectal adenosquamous carcinoma (ASC) is exceedingly rare, comprising less than 0.1% of all colorectal malignancies, and is characterized by the admixture of glandular and squamous components. Due to its rarity, immunohistochemical and biological profiles have not been well investigated. The clinico-pathologic features of 29 cases of primary colorectal adenosquamous carcinomas, including four synchronous metastases, as well as the immunohistochemical expression of keratin 20, CDX2, keratin 34βE12, keratin 5/6, p63, p40, β-Catenin, Cyclin D1 and mismatch repair protein (MMR) expression in both squamous and glandular components are described. All ASCs showed aggressive clinico-pathologic features; all cases showed at least one aggressive pathologic characteristic (poorly differentiated, vascular invasion, infiltrative growth pattern) and 69% of cases were either stage III or IV. The squamous component was keratin 34βE12 positive in all cases and keratin 5/6 positive in 27 cases, while only 7 cases showed p63 and/or p40 expression. β-Catenin and Cyclin D1 showed different expression, with nuclear staining of Cyclin D1 in the squamous component of all cases (both primary and metastatic lesions) and nuclear staining of β-Catenin predominantly in the glandular component. All but one case showed proficient MMR profile. Sixteen patients (64%) died of their disease with median survival of 10 months. ASC show aggressive clinical outcome and aggressive pathologic characteristics. A peculiar keratin 34βE12 positive profile in the squamous component is seen differing from squamous cell carcinoma and non-intestinal ASC. The staining patterns for β-Catenin and Cyclin D1 between components, supports a possible divergent clonal evolution of the neoplasm., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

While the molecular functions of miR-200 family have been deeply investigated, a role for these miRNAs as breast cancer biomarkers remains largely unexplored. In the attempt to clarify this, we profiled the miR-200 family members expression in a large cohort of breast cancer cases with a long follow-up (H-CSS cohort) and in TCGA-BRCA cohort. Overall, miR-200 family was found upregulated in breast tumors with respect to normal breast tissues while downregulated in more aggressive breast cancer molecular subtypes (i.e. Luminal B, HER2 and triple negative), consistently with their function as repressors of the epithelial-to-mesenchymal transition (EMT). In particular miR-141-3p was found differentially expressed in breast cancer molecular subtypes in both H-CSS and TCGA-BRCA cohorts, and the combined analysis of all miR-200 family members demonstrated a slight predictive accuracy on H-CSS cancer specific survival at 12 years (survival c-statistic: 0.646; 95%CI 0.538-0.754).

Background: MicroRNA-10b (miR-10b) has a prominent role in regulating tumor invasion and metastasis by targeting the HOXD10 transcriptional repressor and has been found up-regulated in several tumor types., Methods: We evaluated the expression of miR-10b in paired tumor and normal specimens obtained from a prospective cohort of breast cancer patients with at least 36 months follow-up enrolled according to the REMARK guidelines (n = 150). RNA quality was measured and only samples with RNA Integrity Number (RIN) ≥7.0 were analyzed., Results: The relative expression of miR-10b in tumor as compared to its normal counterpart (RER) was determined by RT-qPCR. miR-10b RERs were higher in the subgroup of patients with synchronous metastases (n = 11, Median 0.25; IQR 0.11-1.02) as compared with patients without metastases (n = 90, Median 0.09; IQR 0.04-0.29) (p = 0.028). In the subgroup of patients without synchronous metastases (n = 90), higher miR-10b RERs were associated with increased risk of disease progression and death in both univariable (HR 1.16, p = 0.021 and HR 1.20, p = 0.015 respectively for 0.10 unitary increase of miR-10b RERs levels) and multivariable (HR1.30, p < 0.001, and HR 1.31, p = 0.003 respectively for 0.10 unitary increase of miR-10b RERs levels) Cox regression models. The addition of miR-10b RERs to the Nottingham Prognostic Index (NPI) provided an improvement in discrimination power and risk reclassification abilities for the clinical outcomes at 36 months. Survival C-indices significantly increased from 0.849 to 0.889 (p = 0.009) for OS and from 0.735 to 0.767 (p = 0.050) for DFS., Conclusions: Our results provide evidences that the addition of miR-10b RERs to the prognostic factors used in clinical routine could improve the prediction abilities for both overall mortality and disease progression in breast cancer patients.

Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions. We determined methylation status of the KEAP1 promoter in 102 primary breast cancers, 14 pre-invasive lesions, 38 paired normal breast tissues and 6 normal breast from reductive mammoplasty by quantitative methylation specific PCR (QMSP). Aberrant promoter methylation was detected in 52 out of the 102 primary breast cancer cases (51%) and 10 out of 14 pre-invasive lesions (71%). No mutations of the KEAP1 gene were identified in the 20 breast cancer cases analyzed by fluorescence based direct sequencing. Methylation was more frequent in the subgroup of patients identified as ER positive-HER2 negative tumors (66.7%) as compared with triple-negative breast cancers (35%) (p = 0.05, Chi-square test). The impact of the interactions between Er, PgR, Her2 expression and KEAP1 methylation on mortality was investigated by RECPAM multivariable statistical analysis, identifying four prognostic classes at different mortality risks. Triple-negative breast cancer patients with KEAP1 methylation had higher mortality risk than patients without triple-negative breast cancer (HR = 14.73, 95%CI: 3.65-59.37). Both univariable and multivariable COX regressions analyses showed that KEAP1 methylation was associated with a better progression free survival in patients treated with epirubicin/cyclophosfamide and docetaxel as sequential chemotherapy (HR = 0.082; 95%CI: 0.007-0.934). These results indicate that aberrant promoter methylation of the KEAP1 gene is involved in breast cancerogenesis. In addition, identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients.

Background: Angiokeratoma is a wart-like vascular lesion of the skin. There are five types of angiokeratoma: the Mibelli-type, the Fordyce-type, the solitary and multiple (papular) types, the angiokeratoma circumscriptum, and the angiokeratoma corporis diffusum. The "Mibelli-type" occurs on the acral sites, mainly digits, of young people affected by repeated attacks of chilblain, which result in a deleterious effects on vessel walls. The "Fordyce-type" occurs on the scrotal skin of young and adults as a secondary effect to an increased blood pressure in scrotal veins. An equivalent form affecting adult females and occurring analogously on the skin of the vulva is also on record. The "solitary and multiple papular types" of young individuals affect the lower extremities and is considered a consequence of a congenital deficiency of elastic tissue in regional veins. We suggest the term "acquired angiokeratomas" for these three above mentioned clinical forms of angiokeratomas, leaving apart the other two types which are essentially congenital. In fact the "angiokeratoma circumscriptum" is a nevoid hamartomatous lesion arising early in life during infancy or childhood, sometimes in association with other congenital malformation of other sites, while the "angiokeratoma corporis diffusum" almost always occurs in association with enzyme disorders, usually alpha-galactosidase A enzyme deficiency (Anderson-Fabry disease), an X-linked recessive disorder affecting homozigous male patients in their adulthood., Case Report: A case of multiple angiokeratomas of the scrotum (Fordyce-type) arisen in a 62-year old male patient following surgical amputation of the penis and bilateral inguino-crural lymphadenectomy for carcinoma of the penis is reported on., Results and Conclusion: Although they are well on record cases of angiokeratomas of the scrotum arising after surgical injuries to the outer vein pudenda (mainly following inguinocrural hernioplasty), based on a computerized search of the literature on theme this case represents the first iatrogenic example of such an occurrence. The pathogenetic mechanism leading to the the rise of angiokeratomas mediated by the increase of the blood pressure in the superficial scrotal veins is discussed. This example represents an additional case report of inevitable and sometimes unsuspected iatrogenic pathology in medicine.

There is still debate over the relative merits of cytology and histology in diagnosing hepatocellular carcinoma in cirrhotic livers. Previous comparisons of the diagnostic accuracies of these two methods may have been biased by sampling errors due to multiple punctures. We compared the diagnostic accuracies of cytology and microhistology using tissue and cells from the same point in liver nodules subsequently proved to be hepatocellular carcinoma. A single ultrasound-guided liver-nodule biopsy was obtained with a 20- to 21-G cutting needle from 131 cirrhotic patients. The solid portion of samples was used for microhistology; the remainder was subjected to smear cytology. The results of each type of examination were expressed as true positive, nonspecific malignancy, false negative, or inadequate for diagnosis. No false-positive diagnoses were made in 13 benign lesions. In 118 HCC nodules (particularly those <30 mm in diameter), cytology provided a significantly higher percentage of correct diagnoses (85.6%) that was only slightly inferior to that based on results of both studies (89.8%). The single-biopsy technique generally provides adequate tissue for histology and cytology specimens with a high cellularity. It reduces both the cost and the risks of fine-needle biopsy diagnosis of hepatocellular carcinoma.

Cerebral amyloidosis is a form of organ-limited amyloidosis, which doesn't involve any organ other than brain and which comprises several subtypes, including "congophilic angiopathy" (CA), "senile plaques" (SP), "neurofibrillary degeneration" (ND), "stellate amyloid cores" of spongiform encephalopathies. It is found in 5 to around 20% of human population in people aged 60 to 90 years, the increasing being strictly related to ageing. Usually it is associated to SP and occasionally to ND, being distinguished into familial and non-familial (age-related) variants. It affects intracortical and leptomeningeal variously sized vessels of the brain and is a leading pathogenetic factor in determining a rare but possibly even recurrent form of a massive intraparenchymal cerebral hemorrhage, constituting a 0.2 per cent of brain vascular accidents of any origin and a 5-10 per cent if only primary non traumatic brain hemorrhages are considered. A case of non-familial CA in a previously non-demented nor hypertensive female patient aged 65 years is reported on, who was admitted due to an almost abrupt onset of neurologic symptoms mainly dominated by a sudden loss of consciousness together with a left sensory-motor deficiency syndrome. The patient who had been operated on of unilateral mastectomy eight years earlier due to an invasive ductal carcinoma of the breast was found affected by a devastating brain hemorrhage in the right temporo-occipital lobes with subsequent deflection of the brainstem axis toward the opposite side detected by means of CT/MRI and angiographic investigations.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: The aims of this study were to evaluate the typing accuracy of smear cytology and microhistology and of their association in the diagnosis of hepatocellular carcinoma arising in liver cirrhosis, and to analyze the usefulness of smear cytology in the diagnosis of well-differentiated neoplasms., Methods: One hundred sixty patients with hepatocellular carcinoma underwent an ultrasound-guided fine-needle biopsy, providing material for cytological and histological study. In 73 patients, a double biopsy with noncutting and cutting needles was performed (double-needle group), whereas in the remaining 87, a single biopsy with cutting needle was carried out (single-needle group)., Results: In the whole population examined, smear cytology, microhistology, and their association, provided the diagnosis of hepatocellular carcinoma in 128 (80%), 98 (61%), and 144 (90%) cases, respectively. The double-needle and the single-needle groups did not differ significantly as to typing accuracy. Smear cytology correctly diagnosed 54 of 64 neoplasms classified histologically as well-differentiated., Conclusions: Our results show that both smear cytology and microhistology should be applied immediately, when diagnosing hepatocellular carcinoma arising in liver cirrhosis, and that smear cytology is effective in the diagnosis of well-differentiated neoplasms.

Two patients with multiple myeloma and in vivo macroscopic nodular lesions of the liver are presented. The clinical aspects of this very unusual condition are briefly reviewed. In particular, the expression on neoplastic plasma cells of the cytoadhesion molecules CD56 and CD11a, which are involved in the cellular process of recirculation and homing, suggests a possible role for such markers in this atypical localization of the disease.

A papillary-cystic pancreatic tumour was excised in a 19-year-old girl, who was apparently free from recurrence 20 months later. Despite morphologic indications of malignancy, the prognosis after surgical removal of this uncommon tumour is good. Its origin probably is the epithelial cells of the small pancreatic ducts. The case is described and the literature is reviewed.