This systematic review article aims to investigate the clinical and radiological imaging characteristics of adrenal abnormalities in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome. We searched the literature in PubMed, the Cochrane Library, and the Web of Science Core Collection. Ultimately, we analyzed 11 studies with 22 patients plus our 1 patient, totaling 23 patients. The mean age was 47.0 ± 12.6 years. There were 20 male and 3 female patients, respectively. The histopathological analysis of lymph nodes was conducted in 15 patients (65.2%), and the diagnosis was consistent with TAFRO syndrome in all 15 patients. Among the 23 patients, 11 patients (18 adrenal glands) showed adrenal ischemia/infarction, 9 patients (13 adrenal glands) showed adrenal hemorrhage, and 4 patients (7 adrenal glands) showed adrenomegaly without evidence of concurrent ischemia/infarction or hemorrhage. One patient demonstrated unilateral adrenal hemorrhage and contralateral adrenomegaly. In patients with adrenal ischemia/infarction, the adrenal glands displayed poor enhancement through contrast-enhanced computed tomography (CT). In patients with adrenal hemorrhage, the adrenal glands revealed high attenuation through non-enhanced CT and hematoma through magnetic resonance imaging. Adrenomegaly, with or without adrenal ischemia/infarction or hemorrhage, was observed in all patients (23/23, 100%). The subsequent calcification of the affected adrenal glands was frequently observed (9/14, 64.3%) when a follow-up CT was performed. Abdominal pain was frequent (15/23, 65.2%), all of which occurred after the disease\'s onset, suggesting the importance of considering TAFRO syndrome as a cause of acute abdomen. Given the absence of evidence of adrenal abnormalities in non-TAFRO-idiopathic multicentric Castleman disease (iMCD), they may serve as diagnostic clues for differentiating TAFRO syndrome from non-TAFRO-iMCD.

UNASSIGNED: TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis/renal failure, and organomegaly) syndrome is a systemic inflammatory disorder and unique clinicopathological variant of idiopathic multicentric Castleman disease that was proposed in Japan. Prompt diagnosis is critical because TAFRO syndrome is a progressive and life threating disease. Some cases are refractory to immunosuppressive treatments. Renal impairment is frequently observed in patients with TAFRO syndrome, and some severe cases require hemodialysis. Histological evaluation is important to understand the pathophysiology of TAFRO syndrome. However, systemic histopathological evaluation through autopsy in TAFRO syndrome has been rarely reported previously.
UNASSIGNED: A 46-year-old Japanese man with chief complaints of fever and abdominal distension was diagnosed with TAFRO syndrome through imaging studies, laboratory findings, and pathological findings on cervical lymph node and bone marrow biopsies. Interleukin (IL)-6 and vascular endothelial growth factor (VEGF) levels were remarkably elevated in both blood and ascites. Methylprednisolone (mPSL) pulse therapy was initiated on day 10, followed by combination therapy with PSL and cyclosporine A. However, the amount of ascites did not respond to the treatment. The patient became anuric, and continuous renal replacement therapy was initiated from day 50. However, the patient suddenly experienced cardiac arrest associated with myocardial infarction (MI) on the same day. Although the emergent percutaneous coronary intervention was successfully performed, the patient died on day 52, despite intensive care. Autopsy was performed to ascertain the cause of MI and to identify the histopathological characteristics of TAFRO syndrome.
UNASSIGNED: Bacterial peritonitis, systemic cytomegalovirus infection, and Trichosporon asahii infection in the lungs were observed on autopsy. In addition, sepsis-related myocardial calcification was suspected. Management of infectious diseases is critical to reduce mortality in patients with TAFRO syndrome. Although the exact cause of MI could not be identified on autopsy, we considered embolization by fungal hyphae as a possible cause. Endothelial injury possibly caused by excessive secretion of IL-6 and VEGF contributed to renal impairment. Fibrotic changes in anterior mediastinal fat tissue could be a characteristic pathological finding in patients with TAFRO syndrome.

Castleman disease (CD) is a rare lymphoproliferative disorder known to represent at least four distinct clinicopathologic subtypes. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on number of enlarged lymph nodes (unicentric versus multicentric), according to viral infection by human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV), and with relation to clonal plasma cells (POEMS). In recent years, significant molecular and genetic abnormalities associated with CD have been described. However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process. Here, we review all cases of CD with molecular abnormalities described in the literature to date, and correlate cytogenetic, molecular, and genetic abnormalities with disease subtypes and phenotypes. Our review notes complex karyotypes in subsets of cases, specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases. Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD. Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD. Our comprehensive review of genetic and molecular abnormalities in CD identifies subtype-specific and novel pathways which may allow for more targeted treatment options and unique biologic therapies.

Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is one of the few pathogens recognized as direct carcinogen, being involved in the pathogenesis of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. KSHV is a relatively recently discovered virus, with still limited possibilities for diagnosis and treatment. Therefore, ongoing studies are trying to answer the main issues related to the management of KSHV infection and its associated diseases. This review updates the current knowledge of the KSHV infection, discussing aspects related to epidemiology, virological features, clinical manifestations, diagnosis and treatment.

Castleman disease (CD), also known as angiofollicular hyperplasia, is a rare disorder characterized by nonmalignant mediastinal lymph node enlargement provoked by excess interleukin-6 (IL-6) secretion. It could be unicentric or multicentric (MCD). Here, we describe a 27-year-old man with a prior history of AIDS, Kaposi sarcoma (KS), and latent syphilis who presented to the ED for persistent fatigue, fever, chills, night sweats, and productive cough. Infectious workup was negative, and the patient continued to have a high fever despite empiric antibiotic therapy. Bone marrow biopsy was performed and was negative for malignancy. The patient eventually underwent a left clavicular lymph node biopsy, which showed a plasma cell variant CD with positive immunostaining for human herpesvirus 8 (HHV-8), and high HHV-8 viral load. We started the patient on rituximab and liposomal doxorubicin, but unfortunately, the patient had a severe anaphylactic reaction to the rituximab, so we could not proceed with this treatment. We, therefore, started tocilizumab treatment, which improved the patient\'s general condition, and he was eventually discharged from our hospital. Upon follow-up 11-months later, a repeat CT scan of the chest and abdomen showed a near-complete treatment response with decreased lymphadenopathy throughout and hepatosplenomegaly. IL-6 overproduction in patients with CD is linked to the production of inflammatory cytokines and has a role in tumor angiogenesis, which makes it potential for IL-6 targeted therapy. The diagnosis of CD, especially MCD, requires a high index of suspicion, and a lymph node biopsy is essential in the diagnosis. Tocilizumab, an IL-6 receptor antibody, could potentially be considered as a practical therapeutic approach in managing HHV-8 positive MCD patients who do not tolerate or respond to initial rituximab therapy.