Germinotropic lymphoproliferative disorder: a systematic review.

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms "germinotropic" and "lymphoproliferative disorder." Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

Fibrin-associated large B-cell lymphoma: first case report within a cerebral artery aneurysm and literature review.

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.

A tricky and rare cause of pulmonary eosinophilia: myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA.

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.

Correction to: Management of duodenal stump fistula after gastrectomy for malignant disease: a systematic review of the literature.

Following publication of the original article [1], the authors have notified us that due to administrative reasons they would like to modify the first affiliation from.

Management of duodenal stump fistula after gastrectomy for malignant disease: a systematic review of the literature.

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.

Erdheim-Chester disease: description of two illustrative cases involving the lung.

AIM: Erdheim-Chester disease represents a clonal systemic proliferation of histiocytes. Bone is the most common site of involvement, although almost any organ, including the lungs, can be affected. METHODS AND RESULTS: The diagnosis of Erdheim-Chester disease can be difficult, owing to its rarity and protean presentation. Correlation between clinical, radiological and histological findings is mandatory for identification of the disease. Foamy histiocytes, lacking Langerhans cell markers, represent the typical histological findings, although their absence does not rule out Erdheim-Chester disease. Identification of BRAF mutation can be helpful in making the diagnosis, and allows for the development and application of targeted therapies in this setting. CONCLUSIONS: Herein, we describe two cases presenting with lung involvement and vertebral lesions, lacking the more typical long-bone involvement. One case histologically mimicked Rosai-Dorfman disease. However, both cases harboured the pathognomonic BRAFV600E mutation.

Intravascular NK/T-cell lymphoma, Epstein-Barr virus positive with multiorgan involvement: a clinical dilemma.

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.

Primary histiocytic sarcoma presenting as diffuse leptomeningeal disease: Case description and review of the literature.

Histiocytic sarcoma is a rare malignant neoplasm arising most commonly in lymph nodes, intestinal tract, skin and soft tissue. The incidence of primary CNS histiocytic sarcoma is even rarer with a total of just 27 cases reported in the literature so far. Herein we describe the first autopsy case of histiocytic sarcoma presenting as a diffuse leptomeningeal disease in absence of a CNS tumor-forming parenchymal lesion. The clinical, pathological and immunophenotypic features are described and an updated literature review on primary CNS histiocytic sarcoma is included.

RIN2 syndrome: Expanding the clinical phenotype.

Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc.

The classification of neuroendocrine neoplasms of the lung and digestive system according to WHO, 5th edition: similarities, differences, challenges, and unmet needs.

Neuroendocrine neoplasms (NENs) are a group of disease entities sharing common morphological, ultrastructural and immunophenotypical features, yet with distinct biological behavior and clinical outcome, ranging from benign to frankly malignant. Accordingly, a spectrum of therapeutic options for each single entity is available, including somatostatin analogues (SSA), mTOR-inhibitors, peptide receptor radionuclide therapy (PRRT), non-platinum and platinum chemotherapy. In the last few decades, several attempts have been made to better stratify these lesions refining the pathological classifications, so as to obtain an optimal correspondence between the scientific terminology and, the predictive and prognostic features of each disease subtype, and achieve a global Classification encompassing NENs arising at different anatomical sites. The aim of this review was to analyze, compare and discuss the main features and issues of the latest WHO Classifications of NENs of the lung and the digestive system, in order to point out the strengths and limitations of our current understanding of these complex diseases.

Persistent Response and Prolonged Survival Following Pembrolizumab Discontinuation Due to Long-Lasting Autoimmune Colitis in Advanced NSCLC: A Case Report.

Pembrolizumab is a programmed death receptor-1 (PD-1) inhibitor that has been approved for treatment of a wide variety of malignancies including non-small-cell lung cancer (NSCLC). Immune-mediated colitis is a known adverse effect of pembrolizumab which can lead to the treatment interruption, although not compromising the control of the oncological disease. Herein, we report the case of a 59-year-old woman on pembrolizumab for advanced NSCLC which developed a severe and persistent colitis treated with infliximab for several months following anti-PD-1 antibody discontinuation. This strategy resulted in an improvement but not complete recovery of the gastrointestinal toxicity despite revealed sustained response and control of the oncological disease with prolonged survival over 24 months.

Gastrointestinal Manifestations in Systemic Mastocytosis: The Need of a Multidisciplinary Approach.

Mastocytosis represents a heterogeneous group of neoplastic mast cell disorders. The basic classification into a skin-limited disease and a systemic form with multi-organ involvement remains valid. Systemic mastocytosis is a disease often hard to diagnose, characterized by different symptoms originating from either the release of mast cell mediators or organ damage due to mast cell infiltration. Gastrointestinal symptoms represent one of the major causes of morbidity, being present in 60-80% of patients. A high index of suspicion by clinicians and pathologists is required to reach the diagnosis. Gastrointestinal mastocytosis can be a challenging diagnosis, as symptoms simulate other more common gastrointestinal diseases. The endoscopic appearance is generally unremarkable or nonspecific and gastrointestinal mast cell infiltration can be focal and subtle, requiring an adequate sampling with multiple biopsies by the endoscopists. Special stains, such as CD117, tryptase, and CD25, should be performed in order not to miss the gastrointestinal mast cell infiltrate. A proper patient's workup requires a multidisciplinary approach including gastroenterologists, endoscopists, hematologists, oncologists, and pathologists. The aim of this review is to analyze the clinicopathological features of gastrointestinal involvement in systemic mastocytosis, focusing on the relevance of a multidisciplinary approach.

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 3).

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.

How Can We Treat Vulvar Carcinoma in Pregnancy? A Systematic Review of the Literature.

According to our systematic literature review (PRISMA guidelines), only 37 vulvar squamous cell carcinomas (VSCCs) were diagnosed during pregnancy (age range: 17-41 years). The tumor size range was 0.3-15 cm. The treatment was performed after (14/37, 38%), before (10/37, 27%), or before-and-after delivery (11/37, 30%). We found that 21/37 (57%) cases were stage I, 2 II (5%), 11 III (30%), and 3 IVB (8%). HPV-related features (condylomas/warts; HPV infection; high-grade squamous intraepithelial lesion) were reported in 11/37 (30%) cases. We also found that 9/37 (24%) patients had inflammatory conditions (lichen sclerosus/planus, psoriasis, chronic dermatitis). The time-to-recurrence/progression (12/37, 32%) ranged from 0 to 36 (mean 9) months. Eight women died of disease (22%) 2.5-48 months after diagnosis, 2 (5%) were alive with disease, and 23 (62%) were disease-free at the end of follow-up. Pregnant patients must be followed-up. Even if they are small, newly arising vulvar lesions should be biopsied, especially in women with risk factors (HPV, dermatosis, etc.). The treatment of VSCCs diagnosed in late third trimester might be delayed until postpartum. Elective cesarean section may prevent vulvar wound dehiscence. In the few reported cases, pregnancy/fetal outcomes seemed to not be affected by invasive treatments during pregnancy. However, clinicians must be careful; larger cohorts should define the best treatment. Definite guidelines are lacking, so a multidisciplinary approach and discussion with patients are mandatory.