Search

Enhanced Recovery After Surgery (ERAS) protocols have changed perioperative care, aiming to optimize patient outcomes. This study assesses ERAS implementation effects on postoperative complications, length of hospital stay (LOS), and mortality in colorectal cancer (CRC) patients. A retrospective real-world analysis was conducted on CRC patients undergoing surgery within a Northern Italian Cancer Registry. Outcomes including complications, re-surgeries, 30-day readmission, mortality, and LOS were assessed in 2023, the year of ERAS protocol adoption, and compared with data from 2022. A total of 158 surgeries were performed, 77 cases in 2022 and 81 in 2023. In 2023, a lower incidence of postoperative complications was observed compared to that in 2022 (17.3% vs. 22.1%), despite treating a higher proportion of patients with unfavorable prognoses. However, rates of reoperations and readmissions within 30 days post-surgery increased in 2023. Mortality within 30 days remained consistent between the two groups. Patients diagnosed in 2023 experienced a statistically significant reduction in LOS compared to those in 2022 (mean: 5 vs. 8.1 days). ERAS protocols in CRC surgery yield reduced postoperative complications and shorter hospital stays, even in complex cases. Our study emphasizes ERAS’ role in enhancing surgical outcomes and recovery.

There is an ongoing need for biomarkers that could reliably predict the outcome of BC and that could guide the management of this disease. In this setting, we aimed to explore the prognostic value of the transcription factor P63 in patients with muscle-invasive bladder cancer (MIBC) having undergone radical cystectomy. The correlation between P63 expression and clinicopathological features (tumor stage, nodes involvement, patterns of muscularis propria invasion, papillary architecture, anaplasia, concomitant carcinoma in situ, lymphovascular invasion, perineural invasion, necrosis) and molecular subtyping (basal and luminal type tumors) was tested in 65 radical cystectomy specimens and matched with cancer-specific survival (CSS) and overall survival (OS). P63-negative tumors displayed significantly higher rates of pattern 2 of muscularis propria invasion (50% vs. 14%, p = 0.002) and variant histology (45% vs. 19%, p = 0.022) compared to P63-positive ones. According to the combined expression of CK5/6 and CK20 (Algorithm #1), P63-positive and P63-negative tumors were mostly basal-like and double-negative, respectively (p = 0.004). Using Algorithm #2, based on the combined expression of CK5/6 and GATA3, the vast majority of tumors were luminal overall and in each group (p = 0.003). There was no significant difference in CSS and OS between P63-positive and P63-negative tumors, but the former featured a trend towards longer OS. Though associated with pathological features harboring negative prognostic potential, P63 status as such failed to predict CSS and OS. That said, it may contribute to better molecular subtyping of MIBC.

Introduction: Colovesical fistula (CVF) is a condition with various aetiologies and presentations. Surgical treatment is necessary in most cases. Due to its complexity, open approach is preferred. However, laparoscopic approach is reported in the management of CVF due to diverticular disease. The aim of this study was to analyse the management and outcome of patients with CVF of different aetiologies treated with laparoscopic approach. Patients and Methods: This was a retrospective study. We retrospectively reviewed all patients undergoing elective laparoscopic management of CVF from March 2015 to December 2019. Statistical Analysis Used: None. Results: Nine patients underwent laparoscopic management of CVF. There were no intraoperative complications or conversions to open surgery. A sigmoidectomy was performed in eight cases. In one patient, a fistulectomy with sigmoid and bladder defect closure was performed. In two cases of locally advanced colorectal cancer with bladder invasion, a multi-stage procedure with temporary colostomy was chosen. In three cases, with no intraoperative leakage, we did not perform bladder suture. Four Clavien I–II complications were recorded. Two fragile patients died in the post-operative period. No patients required re-operation. At a median follow-up of 21 months (interquartile range: 6–47), none of the patients had recurrence of fistula. Conclusions: CVF can be managed with laparoscopic approach by skilled laparoscopic surgeons in different clinical scenarios. Bladder suture is not necessary if leakage is absent. Informed counselling to the patient must be guaranteed concerning the risk of major complications and mortality in case of CVF due to malignant disease.

Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are not included in the 5th WHO classification, while others are considered special morphologic patterns of invasive breast carcinoma of no special type. In this manuscript, we systematically review the literature on four different subtypes of invasive breast carcinoma, namely lymphoepithelioma-like breast carcinoma, breast carcinoma with osteoclast-like giant cells, signet-ring breast carcinoma, and metaplastic breast carcinoma with melanocytic differentiation. We describe their clinicopathological characteristics, focusing on the differential diagnosis, treatment, and prognosis.

Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 (JAK2), calreticulin (CALR), or thrombopoietin receptor/myeloproliferative leukemia (MPL). CALR mutations have been described essentially in JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting CALR and MPL mutations have been found in Ph-negative MPNs. BCR::ABL1 translocation and JAK2 mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of BCR::ABL1 translocation with a coexisting CALR mutation is even more uncommon. Herein, starting from a routinely diagnosed case of CALR-mutated primary myelofibrosis subsequently acquiring BCR::ABL1 translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with BCR::ABL1 and CALR co-occurrence.

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome–positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2-positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient’s treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented.

Colorectal cancer emerged as the third most prevalent malignancy worldwide, affecting nearly 2 million individuals in the year 2020. This study elucidates the pivotal role of a multidisciplinary team (MDT) in influencing the prognosis, as measured by relative survival rates, depending upon the stage and age. Cases recorded in an Italian Cancer Registry between 2017 and 2018 were included. Relative survival was reported at 1 and 3 years after diagnosis comparing MDT vs. no-MDT approaches. During the study period, 605 CRCs were recorded while 361 (59.7%) were taken care of by an MDT. Compared to no-MDT, MDT patients were younger with earlier stages and received more surgery. One year after diagnosis, survival was 78.7% (90% in MDT vs. 62% in no-MDT); stratifying by stage, in the MDT group there was no survival advantage for stage I (97.2% vs. 89.9%) and II (96.8% vs. 89.4%), but an advantage was observed for stage III (86.4% vs. 56.9%) and stage IV (63.7% vs. 27.4%). Similar values were observed at 3 years where a marked advantage was observed for stages III (69.9% vs. 35.1%) and IV (29.2% vs. 5.1%). The univariable analysis confirmed an excess risk in the no-MDT group (HR 2.6; 95% CI 2.0–3.3), also confirmed in the multivariable regression analysis (HR 2.0; 95% CI 1.5–2.5). Despite the increase in the number of MDT patients in 2018 (from 50% to 69%), this does not correspond to an improvement in outcome.

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments in the nomenclature for certain pathologies. Notably, each tumor entity now includes minimum essential and desirable criteria for reliable diagnosis. This classification highlights the importance of biological and molecular characterization alongside traditional cytological and architectural features. In this view, immunophenotyping through immunohistochemistry (IHC) plays a crucial role in bridging morphology and genetics. This article aims to present and discuss the role of key immunohistochemical markers that support the diagnosis of new entities recognized in the WHO classification, focusing on critical topics associated with single markers, in the context of specific tumors, such as the clear cell capillary renal cell tumor (CCPRCT), eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and so-called “other oncocytic tumors”, namely the eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). Their distinctive characteristics and immunophenotypic profiles, along with insights regarding diagnostic challenges and the differential diagnosis of these tumors, are provided. This state-of-the-art review offers valuable insights in biomarkers associated with novel renal tumors, as well as a tool to implement diagnostic strategies in routine practice.

Bladder cancer (BC) is one of the most prevalent cancers worldwide. Non-muscle invasive bladder cancer (NMIBC), comprising the majority of initial BC presentations, requires accurate risk stratification for optimal management. This review explores the evolving role of programmed cell death ligand 1 (PD-L1) as a prognostic biomarker in NMIBC, with a particular focus on its implications in the context of Bacillus Calmette-Guérin (BCG) immunotherapy. The literature suggests a potential association between elevated PD-L1 status and adverse outcomes, resistance to BCG treatment, and disease progression. However, conflicting findings and methodological issues highlight the heterogeneity of PD-L1 assessment in NMIBC, probably due to the complex biological mechanisms that regulate the interaction between PD-L1 and the tumor microenvironment. The identification of PD-L1 as a prognostic biomarker provides ground for tailored therapeutic interventions, including immune checkpoint inhibitors (ICIs). Nevertheless, challenges such as intratumoral heterogeneity and technical issues underscore the need for standardized protocols and larger, homogeneous trials. This review contributes to the ongoing debate on the personalized management of NMIBC patients, focusing on the advances and perspectives of incorporating PD-L1 as a biomarker in this setting.

Mantle cell lymphoma is a B-cell malignancy, which, in its classic form, usually involves lymph nodes and extranodal sites, and, among the extranodal sites, the gastrointestinal tract and the Waldeyer’s ring are most prevalent. MCL is rarely reported in the ocular adnexa, a site more frequently affected by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, which is a form of low-grade malignancy. The diagnosis of MCL presenting in the ocular adnexa requires special attention as its rarity in this location combined with the not uncommon CD5 negativity of the disease when occurring in the ocular adnexa, may lead the pathologist to overlook the diagnosis and misinterpret MCL as marginal zone B cell lymphoma, which has a totally different behavior. Herein, we present a case of primary bilateral conjunctival CD5-negative MCL in a patient having no other sites affected by lymphoma and we discuss possible diagnostic pitfalls.

Primary vitreoretinal lymphoma (PVRL), a rare aggressive malignancy primarily involving the retina and/or the vitreous, is a major diagnostic challenge for clinicians (who commonly misdiagnose it as chronic uveitis) as well as for pathologists (for biological and technical reasons). Delays in diagnosis and treatment are responsible for visual impairments and life-threatening consequences, usually related to central nervous system involvement. The identification of lymphoma cells in vitreous fluid, obtained by vitrectomy, is required for diagnosis. Of note, the scarcity of neoplastic cells in small volumes of vitreous sample, and the fragility of lymphoma cells with degenerative changes caused by previous steroid use for presumed uveitis makes diagnosis based on cytology plus immunophenotyping difficult. Interleukin levels, immunoglobulin heavy chain or T-cell receptor gene rearrangements, and MYD88 mutation are applied in combination with cytology to support diagnosis. We aim to describe the current laboratory technologies for PVRL diagnosis, focusing on the main issues that these methods have. In addition, new emerging diagnostic strategies, such as next-generation sequencing analysis, are discussed. The genetic profile of PVRL remains largely unexplored. Better knowledge of genetic alterations is critical for precision medicine interventions with target-based treatments of this lymphoma for which no standardised treatment protocol currently exists.

Abstract. Collision metastasis is a rare phenomenon of concomitant localization of 2 or more different tumors in the same lymph node. In most cases, primary malignancies are synchronous carcinomas arising in the same organ or area of the body. A 82-year-old man presented with hematuria and acute renal failure; he had undergone dermatological consultation ten months ago because of a large deep brown skin lesion in his dorso-lumbar region, which was not excised upon patient’s request. He underwent radical cystectomy with extended pelvic lymphadenectomy due to nonpapillary high-grade urothelial carcinoma, with focal squamous features, infiltrating the bladder wall and prostate gland. In one left iliac lymph node, small foci of metastatic urothelial carcinoma (positive for P63 and CK34betaE12) were close to melanoma cells (positive for HMB45). The patient refused further treatment and died of metastatic disease 12 months after cystectomy. There is no specific clinical feature for nodal collision metastasis. A polymorphic histologic appearance poses the suspect, but immunohistochemical stains are needed to define the primary tumors. Collision metastases are thought to carry a poor prognosis. Their clinical relevance is linked to the fact that the patient faces 2 different metastatic tumors that may require specific multidisciplinary approach once diagnosed as metastatic. We present, to the best of our knowledge, the first case of collision nodal metastasis from bladder cancer and melanoma, and describe its clinical and histopathological characteristics to raise awareness on this rare occurrence, which portends a poorer prognosis than each single tumor.

Abstract Background The cysts of the male pelvic floor represent a rare clinical entity. Their origin is linked to an altered development of paramesonephric and mesonephric ducts during embryogenesis. Case presentation We report our experience regarding two patients presenting cysts of the ejaculatory system treated with open and mini-invasive surgery. The patients referred to our clinic with nonspecific symptoms and the diagnosis was obtained by radiological investigations. The patient treated with an open approach developed a pelvic purulent collection and a fistula of the prostatic urethra, managed with surgical drainage and prolonged bladder catheterization. On the other hand, the patient treated with laparoscopic approach did not develop any complications. No sexual or ejaculatory disorders were reported. Conclusions Patients with congenital cysts of the pelvic floor must be adequately informed about the risks and benefits of surgery and a careful counseling is mandatory before surgery. Treatment is recommended for symptomatic patients and an endoscopic approach is associated with a high rate of recurrence. A laparoscopic approach, when possible, is desirable.

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable of suggesting the mammary origin of a metastatic carcinoma in the brain. The following histological features were collected from a series of 30 cases of brain metastases from breast cancer: (i) a solid growth pattern; (ii) the presence of comedonecrosis; and (iii) glandular differentiation. Our results showed that most cases histologically exhibited a solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility for leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 in the immunohistochemical panel.

Neoplasms with plasma cell differentiation may occasionally involve the skin. Cutaneous lesions may represent the first sign of an underlying systemic plasma cell malignancy, such as multiple myeloma, or the skin itself may be the primary site of occurrence of a hematological tumor with plasma cell differentiation. Starting from examples encountered in our daily practice, we discussed the diagnostic approach pathologists and clinicians should use when faced with cutaneous lesions with plasma cell differentiation. Cases of primary cutaneous marginal zone lymphoma, localized primary amyloidosis/amyloidoma, and cutaneous manifestations (secondary either to multiple myeloma or to plasmablastic lymphoma) are discussed, focusing on the importance of the adequate patient’s work-up and precise clinicopathological correlation to get to the correct diagnosis and appropriate treatment. The pertinent literature has been reviewed, and the clinical presentation, pathological findings, main differential diagnoses, treatment, and outcome of neoplasms with plasma cell differentiation involving the skin are discussed.

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma. Globally, DLBCL is an aggressive disease, requiring an accurate diagnosis and prompt treatment. The diagnosis is often made on biopsy samples of a nodal mass, however, approximately 40% of DLBCL cases arise at extranodal sites. The most common extranodal site is the gastrointestinal tract, however any extranodal area may be primarily involved. Primary urinary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas, whereas secondary involvement of the urinary bladder by a systemic lymphoma is a more common event. Despite being rare, DLBCL is considered to represent the predominant primary urinary bladder lymphoma. The majority of cases reported in the bladder belong to the DLBCL, NOS group, and there are only rare cases of EBV-positive DLBCL, NOS. In this review, we summarize the current knowledge on DLBCL primarily occurring in the urinary bladder, with the aim of increasing clinician and pathologist awareness on this aggressive lymphoma rarely arising in the urinary bladder. Additionally, we focus on those entities which should be taken into consideration in the differential diagnosis, highlighting potential diagnostic pitfalls.

Hematological neoplasms sharing a blastic morphology may involve the skin. The skin may be either the primary site of occurrence of hematological malignancies with blastic features or cutaneous lesions are the first manifestation of an underlying systemic malignancy. The assessment of skin biopsies of hematological neoplasms with blastic features poses diagnostic problems and requires expert hematopathologists considering a wide range of differential diagnoses. The precise diagnosis of diseases sharing blastic features but with different outcomes and requiring distinct therapies is essential for patient management. The present paper mainly focuses on cutaneous involvement of the blastoid variant of mantle cell lymphoma and lymphoblastic lymphoma of B-cell or T-cell origin. The relevant literature has been reviewed and the clinical aspects, pathological features, prognosis, and therapy of both blastoid mantle cell lymphoma and lymphoblastic lymphoma involving the skin are discussed. A focus on other hematological entities with blastic features, which may involve the skin, to be taken into consideration in differential diagnosis is also given.

Urothelial carcinoma with an inverted growth pattern (UC-IGP) is a peculiar entity within the spectrum of urothelial lesions. While efforts have been made over the last few decades to unravel its carcinogenesis and relationship with conventional urothelial carcinoma, the exact classification of inverted urothelial lesions is a matter of debate. The morphological features of UC-IGP pose several issues in differential diagnosis with other mostly benign lesions. Various techniques, including immunohistochemistry, UroVysion, and many molecular methods, have been employed to study the exact nature of this lesion. The aim of this review is to provide a comprehensive overview of the morphological and immunophenotypical aspects of UC-IGP. Moreover, we present and discuss the immunohistochemical and molecular markers involved in diagnosis and prognosis of UC-IGP lesions.

Summary: Background: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p

Background and Objectives: Anterior rectal resection (ARR) represents one of the most frequently performed methods in colorectal surgery, mainly carried out for rectal cancer (RC) treatment. Defunctioning ileostomy (DI) has long been chosen as a method to “protect” colorectal or coloanal anastomosis after ARR. However, DI does not rule out risks of more or less serious complications. A proximal intra-abdominal closed-loop ileostomy, the so-called virtual/ghost ileostomy (VI/GI), could limit the number of DIs and the associated morbidity. Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Meta-analysis was performed by use of RevMan [Computer program] Version 5.4. Results: The five included comparative studies (VI/GI or DI) covering an approximately 20-year study period (2008–2021). All included studies were observational ones and originated from European countries. Meta-analysis indicated VI/GI as significantly associated with lower short-term morbidity rates related to VI/GI or DI after primary surgery (RR: 0.21, 95% CI: 0.07–0.64, p = 0.006), fewer dehydration (RR: 0.17, 95% CI: 0.04–0.75, p = 0.02) and ileus episodes after primary surgery (RR: 0.20, 95% CI: 0.05–0.77, p = 0.02), fewer readmissions after primary surgery (RR: 0.17, 95% CI: 0.07–0.43, p = 0.0002) and readmissions after primary surgery plus stoma closure surgery (RR: 0.14, 95% CI: 0.06–0.30, p < 0.00001) than the DI group. On the contrary, no differences were identified in terms of AL after primary surgery, short-term morbidity after primary surgery, major complications (CD ≥ III) after primary surgery and length of hospital stay after primary surgery. Conclusions: Given the significant biases among meta-analyzed studies (small overall sample size and the small number of events analyzed, in particular), our results require careful interpretation. Further randomized, possibly multi-center trials may be of paramount importance in confirming our results.

Molecular subtyping of bladder cancer (BC) aims to capture the biological heterogeneity of this complex disease in order to provide better patient risk stratification. Immunohistochemical (IHC) markers are regarded as promising surrogates to classify BCs into luminal and basal subtypes in routine practice. We investigated the correlation between the molecular subclassification, assessed through IHC, and the conventional prognostic variables of a cohort of 93 muscle-invasive BCs (MIBCs), with a focus on the pattern of muscularis propria (MP) invasion, and evaluated their association with outcome. Basal, luminal, double-positive (DP), and double-negative (DN) phenotypes were identified according to the coordinate expression of 1 basal (CK5/6) and 2 luminal (CK20, GATA3) markers, and accounted for 33.3%, 32.3%, 3.2%, and 31.2% (Scheme #1) and 9.7%, 60.2%, 26.9%, and 3.2% (Scheme #2). There was a significant association between the pattern of MP invasion and the molecular subtypes according to Scheme #2, in that all 8 basal and DN cases, as well as 83% of DP cases, had a non-infiltrative invasion pattern. No consistent differences were observed in terms of OS and CSS between the molecular subtypes obtained through surrogate IHC markers. In keeping with previous studies, we report the correlation between the identification of BC subtypes and the presence of morphological prognostic factors, supporting the need for a comprehensive pathological evaluation, including clinicopathological and molecular parameters, in order to improve the diagnosis and management of MIBC.

Abstract Background Primary effusion lymphoma is a rare, aggressive large B-cell lymphoma strictly linked to infection by Human Herpes virus 8/Kaposi sarcoma-associated herpes virus. In its classic form, it is characterized by body cavities neoplastic effusions without detectable tumor masses. It often occurs in immunocompromised patients, such as HIV-positive individuals. Primary effusion lymphoma may affect HIV-negative elderly patients from Human Herpes virus 8 endemic regions. So far, rare cases have been reported in transplanted patients. The purpose of our systematic review is to improve our understanding of this type of aggressive lymphoma in the setting of transplantation, focusing on epidemiology, clinical presentation, pathological features, differential diagnosis, treatment and outcome. The role of assessing the viral serological status in donors and recipients is also discussed. Methods We performed a systematic review adhering to the PRISMA guidelines. The literature search was conducted on PubMed/MEDLINE, Web of Science, Scopus, EMBASE and Cochrane Library, using the search terms “primary effusion lymphoma” and “post-transplant”. Results Our search identified 13 cases of post-transplant primary effusion lymphoma, predominantly in solid organ transplant recipients (6 kidney, 3 heart, 2 liver and 1 intestine), with only one case after allogenic bone marrow transplantation. Long-term immunosuppression is important in post-transplant primary effusion lymphoma commonly developing several years after transplantation. Kaposi Sarcoma occurred in association with lymphoma in 4 cases of solid organ recipients. The lymphoma showed the classical presentation with body cavity effusions in absence of tumor masses in 10 cases; 2 cases presented as solid masses, lacking effusions and one case as effusions associated with multiple organ involvement. Primary effusion lymphoma occurring in the setting of transplantation was more often Epstein Barr-virus negative. The prognosis was poor. In addition to chemotherapy, reduction of immunosuppressive treatment, was generally attempted. Conclusions Primary effusion lymphoma is a rare, but often fatal post-transplant complication. Its rarity and the difficulty in achieving the diagnosis may lead to miss this complication. Clinicians should suspect primary effusion lymphoma in transplanted patients, presenting generally with unexplained body cavity effusions, although rare cases with solid masses are described.

Mycosis fungoides (MF) is defined as an epidermotropic primary cutaneous T-cell lymphoma composed of small-to-medium-sized T lymphocytes with cerebriform nuclei and with a T-helper phenotype. LeBoit first described an unusual variant of MF with dermal acid mucin deposition. Such a variant was still considered in the list of clinicopathological variants of MF by Cerroni and colleagues. We herein report a case of patch-stage MF with abundant papillary dermal mucin deposition in a clinical setting of an erythematous patch on the lower abdomen and thigh.

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies.

Abstract Background Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a rare low-grade clonal lymphoid proliferation, included as a provisional entity in the current World Health Organization classification. The disease is generally localized to the gastrointestinal tract, mainly small bowel and colon. Involvement of other organs is infrequently reported. The majority of patients show a protracted clinical course with persistent disease. A prolonged survival, even without treatment, is common. Case presentation A 28-year-old woman had a 2-year history of dyspepsia and lactose intolerance. Autoimmune diseases and celiac disease were excluded. No gross lesions were identified by endoscopy. Multiple gastric biopsies showed a small-sized lymphoid infiltrate, expanding the lamina propria, with a non-destructive appearance. The lymphoid cells were positive for CD3, CD4, CD5, CD7 and negative for CD20, CD8, CD56, CD103, PD1, CD30, ALK1, CD10, BCL6, perforin, TIA-1, Granzyme B and Epstein-Barr virus-encoded RNA. KI-67 index was low (5%). Molecular analysis revealed a clonal T-cell receptor γ rearrangement. Bone marrow was microscopically free of disease, but molecular testing identified the same T-cell receptor γ rearrangement present in the gastric biopsies. After the diagnosis of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, the patient received steroid therapy, only for 2 months. She is alive, with a stable disease restricted to the stomach, at 12 months from diagnosis. Conclusions Indolent T-cell lymphoproliferative disorder is usually a disease of adulthood (median age: 51 yrs). The small bowel and colon are the sites most commonly involved. Our case occurred in a young woman and affected the stomach, sparing small intestine and colon. Clonality testing identified involvement of bone marrow, a site infrequently affected in this disease. Our aim is focusing on the main diagnostic issues. If appropriate immunostainings and molecular analysis are not performed, the subtle infiltrate may be easily overlooked. The risk of misdiagnosis as more aggressive lymphomas, causing patient overtreatment, needs also to be considered.

Abstract Background Eosinophilic lung diseases represent a heterogeneous group of disorders with prominent infiltrate of eosinophils in lung interstitium and alveolar spaces. Peripheral blood eosinophilia is often present. Infections, drugs, allergens, toxic agents have to be evaluated as possible causes of eosinophilic lung infiltrates. The category of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 and PCM1-JAK2 represents an uncommon cause of eosinophilic lung infiltrate. Case presentation We report the case of a 70-year old man complaining of dry cough and dyspnea. Ground glass-opacities were seen on imaging studies and peripheral blood eosinophilia was present. A thorough step-wise patient’s evaluation led to identify the clonal nature of eosinophilia and the diagnosis of myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA was made. Conclusions Correlation with clinical history, laboratory tests and imaging studies is essential to achieve the correct diagnosis when facing with eosinophilic lung infiltrates. A prolonged eosinophilia can cause life-threatening organ damage. Identification of PDGFRA rearrangement, as in the present case, is particularly critical given the sensitivity and excellent response to imatinib, which has completely changed the natural history of this neoplasm.

Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein–Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response.

Uterine leiomyomas usually arise from the uterine body (95%), and rarely from the cervix (0.6%) or other urogenital sites. Lipoleiomyomas are benign, uncommon variants of leiomyomas (0.03–0.2%), histologically composed of smooth muscle cells and mature adipocytes; they usually occur in the uterine body and exceptionally in the cervix. We performed the first systematic literature review of cervical lipoleiomyomas (PRISMA guidelines), presenting five new cases. Including our series, thirty-one detailed cases were reported in the literature (mainly in Asia). The age range was 35–74 years, revealing a higher mean age than conventional cervical leiomyomas (46.5 vs. 39.4 years). Patients were usually multiparous (94%), typically complaining of vaginal bleeding (11/31, 36%), pelvic/abdominal pain (10/31, 32%), and/or urinary disturbances (6/31, 19%) 1 week to 10 months before presentation. Clinical examination revealed a pedunculated tumor (48%), or prolapse of ≥1 pelvic organs (16%). Twenty-four (77%) patients underwent total hysterectomy ± additional surgery; simple myomectomy/excision was performed in five (16%) cases. Only one (3%) of our cases recurred 2 years after partial excision; no evidence of disease was found 13 years after recurrence excision. Adipocytes occupied ≤50% of the tumor volume. Hyaline or myxoid changes and cartilaginous metaplasia were uncommon histological findings. Surgically challenging cases or pregnant patients may require expert gynecologists. Interventional radiology or conservative treatments were rarely proposed.

Pediatric thymomas are extremely rare and slow-growing malignant tumors. The recent publication of the first Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) Tumor–Node–Metastasis (TNM) stage classification and updated treatment guidelines for thymomas has prompted us to perform a review of the literature on pediatric thymomas. A search of English-language articles in the PubMed, Cochrane, Web of Science, and Embase databases was conducted. Additional articles were identified through reference lists of retrieved publications. Thirty-two articles involving 82 pediatric thymomas were included. Males comprised 60% of patients, and 13% manifested myasthenia gravis (MG). Histotype B1 (45%) and stage I (52% Masaoka–Koga and 71% UICC/AJCC TNM) were the most frequent. Of note is the possibility that the lack of cases with mixed histologies in the reviewed publications might be related to a sampling issue, as it is well known that the more sections are available for review, the more likely it is that the majority of these neoplasms will show mixed histologies. Both staging systems showed a gradual increase in the percentage of cases, with more advanced stages of disease moving from type A to B3 thymomas. Complete surgical resection (R0) was the main therapeutic approach in Masaoka–Koga stage I (89%) and UICC/AJCC TNM stage I (70%) thymomas. Advanced stages of disease and incomplete surgical resection were most often associated with recurrence and death. An association between stage and outcome, and completeness of resection and outcome, was found. Interestingly, though an association between histotype and staging was found, this does not take into account the possibility of mixed histologies which would reduce the clinical impact of histologic subtyping over staging.

Background and Objectives: Surgery remains the only possible curative treatment for advanced gastric cancer (AGC). Peritoneal metastases are estimated to occur in approximately 55–60% AGC patients. Greater omentum is the most common metastatic area in AGC. At present, omentectomy alone or bursectomy are usually carried out during gastric cancer surgery. We performed a meta-analysis in order to evaluate long-term and short-term outcomes among AGC patients, who have undergone radical gastrectomy with or without complete omentectomy (CO). Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed by use of RevMan (Computer program) Version 5.4. Results: The eight included studies covered an approximately 20 years long study period (2000–2018). Almost all included studies were retrospective ones and originated from Asian countries. Meta-analysis indicated gastrectomy without CO as significantly associated with longer 3-year (RR: 0.94, 95% CI: 0.90–0.98, p = 0.005) and 5-year overall survivals (OS) (RR: 0.93, 95% CI: 0.88–0.98, p = 0.007). Moreover, we found longer operative time (MD: 24.00, 95% CI: −0.45–48.45, p = 0.05) and higher estimated blood loss (MD: 194.76, 95% CI: 96.40–293.13, p = 0.0001) in CO group. Conclusions: Non-complete omentectomy (NCO) group had a statistically greater rate in 3-year and 5-year OSs than the CO group, while the CO group had significantly longer operative time and higher estimated blood loss than the NCO group. Further randomized, possibly multi-center trials may turn out of paramount importance in confirming our results.

Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups have developed molecular classification schemes for BC, mainly based on their mRNA expression profiles. A “consensus” classification has recently been proposed to combine the published systems, agreeing on a six-cluster scheme with distinct prognostic and predictive features. In order to implement molecular subtyping as a risk-stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The first part of this review deals with the steps resulting in the development of a molecular subtyping of BC, its prognostic and predictive implications, and the main features of immunohistochemical markers used as surrogates to stratify BC into pre-defined molecular clusters.

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a “consensus” classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.

Abstract Background Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a rare Epstein-Barr virus (EBV) positive lymphoproliferative disorder included in the current World Health Organization (WHO) classification. It arises within fibrinous material in the context of hematomas, pseudocysts, cardiac myxoma or in relation with prosthetic devices. In these clinical settings the diagnosis requires an high index of suspicion, because it does not form a mass itself, being composed of small foci of neoplastic cells. Despite overlapping features with diffuse large B-cell lymphoma associated with chronic inflammation, it deserves a separate classification, being not mass-forming and often following an indolent course. Case presentation A 64-year-old immunocompetent woman required medical care for cerebral hemorrhage. Computed Tomography (CT) angiography identified an aneurysm in the left middle cerebral artery. A FA-DLBCL was incidentally identified within thrombotic material in the context of the arterial aneurysm. After surgical removal, it followed a benign course with no further treatment. Conclusions The current case represents the first report of FA-DLBCL identified in a cerebral artery aneurysm, expanding the clinicopathologic spectrum of this rare entity. A complete literature review is additionally made.

Abstract Background Timing and adequacy of peritoneal source control are the most important pillars in the management of patients with acute peritonitis. Therefore, early prognostic evaluation of acute peritonitis is paramount to assess the severity and establish a prompt and appropriate treatment. The objectives of this study were to identify clinical and laboratory predictors for in-hospital mortality in patients with acute peritonitis and to develop a warning score system, based on easily recognizable and assessable variables, globally accepted. Methods This worldwide multicentre observational study included 153 surgical departments across 56 countries over a 4-month study period between February 1, 2018, and May 31, 2018. Results A total of 3137 patients were included, with 1815 (57.9%) men and 1322 (42.1%) women, with a median age of 47 years (interquartile range [IQR] 28–66). The overall in-hospital mortality rate was 8.9%, with a median length of stay of 6 days (IQR 4–10). Using multivariable logistic regression, independent variables associated with in-hospital mortality were identified: age > 80 years, malignancy, severe cardiovascular disease, severe chronic kidney disease, respiratory rate ≥ 22 breaths/min, systolic blood pressure < 100 mmHg, AVPU responsiveness scale (voice and unresponsive), blood oxygen saturation level (SpO2) < 90% in air, platelet count < 50,000 cells/mm3, and lactate > 4 mmol/l. These variables were used to create the PIPAS Severity Score, a bedside early warning score for patients with acute peritonitis. The overall mortality was 2.9% for patients who had scores of 0–1, 22.7% for those who had scores of 2–3, 46.8% for those who had scores of 4–5, and 86.7% for those who have scores of 7–8. Conclusions The simple PIPAS Severity Score can be used on a global level and can help clinicians to identify patients at high risk for treatment failure and mortality.

Abstract Background Duodenal stump fistula (DSF) remains one of the most serious complications following subtotal or total gastrectomy, as it endangers patient’s life. DSF is related to high mortality (16–20%) and morbidity (75%) rates. DSF-related morbidity always leads to longer hospitalization times due to medical and surgical complications such as wound infections, intra-abdominal abscesses, intra-abdominal bleeding, acute pancreatitis, acute cholecystitis, severe malnutrition, fluids and electrolytes disorders, diffuse peritonitis, and pneumonia. Our systematic review aimed at improving our understanding of such surgical complication, focusing on nonsurgical and surgical DSF management in patients undergoing gastric resection for gastric cancer. Methods We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. PubMed/MEDLINE, EMBASE, Scopus, Cochrane Library and Web of Science databases were used to search all related literature. Results The 20 included articles covered an approximately 40 years-study period (1979–2017), with a total 294 patient population. DSF diagnosis occurred between the fifth and tenth postoperative day. Main DSF-related complications were sepsis, abdominal abscess, wound infection, pneumonia, and intra-abdominal bleeding. DSF treatment was divided into four categories: conservative (101 cases), endoscopic (4 cases), percutaneous (82 cases), and surgical (157 cases). Length of hospitalization was 21–39 days, ranging from 1 to 1035 days. Healing time was 19–63 days, ranging from 1 to 1035 days. DSF-related mortality rate recorded 18.7%. Conclusions DSF is a rare but potentially lethal complication after gastrectomy for gastric cancer. Early DSF diagnosis is crucial in reducing DSF-related morbidity and mortality. Conservative and/or endoscopic/percutaneous treatments is/are the first choice. However, if the patient clinical condition worsens, surgery becomes mandatory and duodenostomy appears to be the most effective surgical procedure.

Background and Objectives: Gastrectomy with D2 lymphadenectomy is the standard surgical treatment with curative intent for patients with gastric cancer (GC). Over the last three decades, surgeons have been increasingly adopting laparoscopic surgery for GC, due to its better short-term outcomes. In particular, laparoscopic gastrectomy (LG) has been routinely used for early gastric cancer (EGC) treatment. However, LG suffers from technical limitations and drawbacks, such as a two-dimensional surgical field of view, limited movement of laparoscopic tools, unavoidable physiological tremors and discomfort for operating surgeon. Therefore, robotic surgery has been developed to address such limitations. Materials and Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines in order to investigate the benefits and harms of robotic gastrectomy (RG) compared to the LG. PubMed/MEDLINE, Scopus, Cochrane Library (Cochrane Database of Systematic Re-views, Cochrane Central Register of Controlled Trials-CENTRAL) and Web of Science (Science and Social Science Citation Index) databases were used to search all related literature. Results: The 7 included meta-analyses covered an approximately 20 years-study period (2000–2020). Almost all studies included in the meta-analyses were retrospective ones and originated from Asian countries (China and Korea, in particular). Examined overall population ranged from 3176 to 17,712 patients. If compared to LG, RG showed both operative advantages (operative time, estimated blood loss, number of retrieved lymph nodes) and perioperative ones (time to first flatus, time to restart oral intake, length of hospitalization, overall complications, Clavien-Dindo (CD) ≥ III complications, pancreatic complications), in the absence of clear differences of oncological outcomes. However, costs of robotic approach appear significant. Conclusions: It is impossible to make strong recommendations, due to the statistical weakness of the included studies. Further randomized, possibly multicenter trials are strongly recommended, if we want to have our results confirmed.

Abstract Background Intravascular lymphoma is a rare type of non-Hodgkin lymphoma mostly of B-cell lineage. A few cases of intravascular lymphoma have been found to be of NK/T-cell origin, mainly affecting the skin and central nervous system. Case presentation A 54-year-old Caucasian man sought care because of a 2 weeks history of jaundice and intermittent fever, not responsive to antibiotics and antipyretics. Laboratory tests showed low blood oxygen concentration and pancytopenia. Serum microbiological tests were negative. Computerized tomography (CT) scan revealed hepatosplenomegaly and diffuse ground-glass opacities in both lungs without interlobular septal thickening. Despite oxygen therapy, the clinical conditions rapidly deteriorated leading to death 3 days after admission. Autopsy revealed a multiorgan involvement by an Epstein-Barr virus positive NK/T-cell lymphoma, strikingly growing within the blood vessel lumina, in absence of skin lesions. Conclusions The current case highlights the pathological features of this rare entity, the protean clinical presentation of which is often misleading, resulting in delayed diagnosis and treatment.

n/a

Background: Para-aortic lymph node (PALN) metastases represent patterns of initial recurrence in only 2–6% CRC patients, after an estimated 23–28 month time interval. An increasing trend towards curative surgery has been witnessed in patients presenting with controlled PALN recurrence. Nevertheless, lack of consensus has impaired an unambiguous statement for PALN recurrence resection. Methods: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, which led us to gain deeper insight into the prognostic factors and long-term outcomes after resection for synchronous or metachronous pathologically confirmed CRC isolated para-aortic lymph node metastases (PALNM). Pubmed/MEDLINE, Embase, Scopus, Cochrane Library and Web of Science databases were used to search all related literature. Results: The nine articles included covered a study period of 30 years (1988–2018), with a total of 161 patients. At presentation, most primary CRCs were located in the colon (74%) and 95.6%, 87.1% and 76.9% patients had T3–T4, N1–N2 and well/moderately differentiated CRC, respectively. We identified a 59.4–68% 3-year OS rate and 53.4–87.5% 5-year OS rate, with a 25–84 months median OS, 26.3–61% 3-year DFS rate and 0–60.5% 5-year DFS rate, with a 14–24 month median DFS. Overall, 62.1% re-recurrence rate ranged from 43.8% to 100%. Conclusions: Although PALNMs resection in CRC patients may be considered a feasible and beneficial option, no conclusions or recommendations can be made taking into account the current evidence. Therefore, further randomized, possibly multicenter trials are strongly recommended and mandatory if we want to have our results confirmed and patient selection criteria clearly identified.

Infections often complicate the course of hematological diseases and may represent a diagnostic challenge. In particular, visceral leishmaniasis diagnosis may be missed in lymphoma patients, as lymphoma-related immunosuppression can lead to a misleadingly negative Leishmania serology and to atypical clinical manifestations, including the lack of fever, considered a common symptom in leishmaniasis. Herein, we report a case of visceral leishmaniasis in a patient with a long history of B-cell chronic lymphocytic leukemia presenting with increasing fatigue and diarrhea, in the absence of fever. Leishmania serology was negative. Bone marrow biopsy performed with the clinical suspicion of transformation to high-grade lymphoma disclosed intracytoplasmic inclusion bodies resembling Leishmania amastigotes within the cytoplasm of macrophages, and CD1a immunohistochemical expression helped to confirm the diagnosis of leishmaniasis. Liposomal amphotericin B was administered with complete symptom resolution. The correct identification of Leishmania is critical as visceral leishmaniasis represents a severe disease with an often fatal outcome, particularly in frail patients, unless promptly recognized and adequately treated. A review of the literature of visceral leishmaniasis cases occurring in B-cell chronic lymphocytic leukemia patients is performed.

Immunotherapy targeting the PD-1–PD-L1 axis yielded good results in treating different immunologically ‘‘hot’’ tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11–41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

EBV is the first known oncogenic virus involved in the development of several tumors. The majority of the global population are infected with the virus early in life and the virus persists throughout life, in a latent stage, and usually within B lymphocytes. Despite the worldwide diffusion of EBV infection, EBV-associated diseases develop in only in a small subset of individuals often when conditions of immunosuppression disrupt the balance between the infection and host immune system. EBV-driven lymphoid proliferations are either of B-cell or T/NK-cell origin, and range from disorders with an indolent behavior to aggressive lymphomas. In this review, which is divided in three parts, we provide an update of EBV-associated lymphoid disorders developing in the gastrointestinal tract, often representing a challenging diagnostic and therapeutic issue. Our aim is to provide a practical diagnostic approach to clinicians and pathologists who face this complex spectrum of disorders in their daily practice. In this part of the review, the chronic active EBV infection of T-cell and NK-cell type, its systemic form; extranodal NK/T-cell lymphoma, nasal type and post-transplant lymphoproliferative disorders are discussed.

Mycosis fungoides and nodal classic Hodgkin lymphoma (cHL) have been reported to occur concurrently or sequentially in the same patient. A long-lasting mycosis fungoides more often precedes the onset of nodal cHL, although few cases of nodal cHL followed by mycosis fungoides have been observed. Skin involvement is a rare manifestation of cHL that may be observed in the setting of advanced disease. The decrease in skin involvement in cHL is mainly due to the improved therapeutic strategies. The concurrent presence of mycosis fungoides and cutaneous localization of classic Hodgkin lymphoma represents a very uncommon event, with only two cases reported so far. Herein, we describe the case of a 71-year-old man, with a history of recurrent nodal cHL, who developed MF and, subsequently, the cutaneous localization of cHL. The clinicopathological features of the two diseases are described focusing on the main differential diagnoses to be taken into consideration, and a review of the literature is performed.