Update on Pathologic Conditions, Imaging Findings, Prevention, and Management of Human Papillomavirus-related Neoplasms.

Human papillomavirus (HPV) is the most common sexually transmitted infection that proliferates in the squamous epithelium and is the most common source of viral-related neoplasms. Low-risk subtypes (HPV-6 and -11) cause respiratory papillomas (laryngeal, tracheal, and bronchial) and condyloma acuminata of the penis, anus, and perineal region (anogenital warts). High-risk subtypes (HPV-16, -18, -31, and -33) are responsible for oropharyngeal squamous cell carcinoma (SCC) that involves the tongue base, tonsils, posterior pharyngeal wall, and larynx and malignancies of the anogenital region (cancers of the cervix, vagina, vulva, penis, and anal canal). Recent studies have increasingly shown a favorable treatment response and substantial differences in the overall prognosis associated with HPV-associated oropharyngeal cancers. Given this fact, oropharyngeal, cervical, and penile SCCs are classified as HPV-associated and HPV-independent cancers in the current World Health Organization classification. Imaging is essential in the early detection, diagnosis, and staging of HPV-associated cancers. Imaging also helps assess treatment response and postoperative complications and is used for long-term surveillance. HPV-associated oropharyngeal SCCs have well-defined borders and solid and cystic nodal metastases at imaging. Updated screening and vaccination guidelines are currently available that have great potential to decrease the overall disease burden and help control this worldwide public health concern. Novel therapeutic strategies, such as immunotherapies, are being explored, and imaging biomarkers that can predict treatment response and prognosis are being investigated; radiologists play a pivotal role in these efforts. ©RSNA, 2024 Supplemental material is available for this article.

Tumefactive Nonneoplastic Proliferative Pseudotumors of the Kidneys and Urinary Tract: CT and MRI Findings with Histopathologic Correlation.

A diverse spectrum of pathologically distinct, nonneoplastic, proliferative conditions of the kidneys and urinary tract demonstrate a expansile growth pattern similar to that of neoplasms. The renal pseudotumors include myriad causes of infections as well as rare noninfectious causes such as sarcoidosis, amyloidosis, and immunoglobulin G4-related disease (IgG4-RD). Rare entities such as cystitis cystica, endometriosis, nephrogenic adenoma, and pseudosarcomatous myofibroblastic proliferation and distinct types of prostatitis comprise tumefactive nontumorous disorders that affect specific segments of the urinary tract. The pseudotumors of the kidneys and urinary tract demonstrate characteristic histopathologic and epidemiologic features, as well as protean clinical manifestations, natural history, and imaging findings. Many patients present with genitourinary tract-specific symptoms or systemic disease. Some cases may be incidentally discovered at imaging. Some entities such as perinephric myxoid pseudotumors, IgG4-RD, fibroepithelial polyp, and nephrogenic adenoma display specific anatomic localization and disease distribution. Imaging features of multisystem disorders such as tuberculosis, sarcoidosis, and IgG4-RD provide supportive evidence that may allow precise diagnosis. Fungal pyelonephritis, xanthogranulomatous pyelonephritis, IgG4-RD, actinomycosis, and endometriosis show markedly low signal intensity on T2-weighted MR images. Although some pseudotumors exhibit characteristic imaging findings that permit correct diagnosis, laboratory correlation and histopathologic confirmation are required for definitive characterization in most cases. A high index of suspicion is a prerequisite for diagnosis. Accurate diagnosis is critical for instituting optimal management while preventing use of inappropriate therapies or interventions. Surveillance CT and MRI are frequently used for monitoring the response of pseudotumors to therapy. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Immunosuppressive Therapy in Solid Organ Transplantation: Primer for Radiologists and Potential Complications.

The availability of effective immunosuppressive medication is primarily responsible for the dramatic improvement in long-term graft survival rates after solid organ transplantation. The commonly used drugs include monoclonal/polyclonal antibodies, corticosteroids, calcineurin inhibitors (cyclosporine and tacrolimus), antimetabolites, mammalian target of rapamycin, and many novel drugs. Prolonged immunosuppression is accompanied by several well-described potentially life-threatening complications. In addition to drug-related side effects, recipients of solid organs are unavoidably at a higher risk for infections and malignancies. Select infections and malignancies in solid organ transplant patients have distinctive imaging findings, and radiologists play a crucial role in the timely diagnosis and management of these conditions.

Wunderlich Syndrome: Comprehensive Review of Diagnosis and Management.

Wunderlich syndrome (WS), which was named after Carl Wunderlich, is a rare clinical syndrome characterized by an acute onset of spontaneous renal hemorrhage into the subcapsular, perirenal, and/or pararenal spaces, without a history of antecedent trauma. Patients may present with a multitude of symptoms ranging from nonspecific flank or abdominal pain to serious manifestations such as hypovolemic shock. The classic symptom complex of flank pain, a flank mass, and hypovolemic shock referred to as the Lenk triad is seen in a small subset of patients. Renal neoplasms such as angiomyolipomas and clear cell renal cell carcinomas that display an increased proclivity for hemorrhage and rupture contribute to approximately 60%-65% of all cases of WS. A plethora of renal vascular diseases (aneurysms or pseudoaneurysms, arteriovenous malformations or fistulae, renal vein thrombosis, and vasculitis syndromes) account for 20%-30% of cases of WS. Rare causes of WS include renal infections, cystic diseases, calculi, kidney failure, and coagulation disorders. Cross-sectional imaging modalities, particularly multiphasic CT or MRI, are integral to the detection, localization, and characterization of the underlying causes and facilitate optimal management. However, large-volume hemorrhage at patient presentation may obscure underlying causes, particularly neoplasms. If the initial CT or MRI examination shows no contributary causes, a dedicated CT or MRI follow-up study may be warranted to establish the cause of WS. Renal arterial embolization is a useful, minimally invasive, therapeutic option in patients who present with acute or life-threatening hemorrhage and can help avoid emergency radical surgery. Accurate diagnosis of the underlying cause of WS is critical for optimal patient treatment in emergency and nonemergency clinical settings. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Mesotheliomas and Benign Mesothelial Tumors: Update on Pathologic and Imaging Findings.

A diverse spectrum of benign entities and malignant neoplasms originate from the monotonous mesothelium that lines the serosal membranes of the pleural, pericardial, and peritoneal cavities. The mesothelium of myriad sites shows a common origin from the lateral plate mesoderm; primary mesothelial tumors thus demonstrate similar pathogenesis, imaging findings, and treatment options. Significant changes have been made in the 2021 World Health Organization (WHO) classification schemata of the pleural and pericardial tumors on the basis of recent advances in pathology and genetics. While malignant mesotheliomas are biologically aggressive malignancies that occur primarily in patients exposed to asbestos with attendant poor survival rates, well-differentiated papillary mesothelial tumors and adenomatoid tumors charter a benign clinical course with an excellent prognosis. Mesothelioma in situ is a newly characterized entity represented by recurrent unexplained pleural effusions without any identifiable mass at imaging or thoracoscopy. Immunohistochemical markers based on BAP1, MTAP, CDKN2A, and TRAF7 gene mutations help differentiate diffuse mesotheliomas from benign mesothelial proliferations and localized mesotheliomas. Cross-sectional imaging modalities, including US, CT, MRI, and fluorine 18-fluorodeoxyglucose (FDG) PET/CT, permit diagnosis and play a major role in staging and assessing surgical resectability. Imaging studies are invaluable in providing noninvasive and quantitative assessment of tumor response in patients with unresectable disease. Owing to significant overlap in patient characteristics and pathomorphology, accurate diagnosis based on advanced histopathology techniques and genetic abnormalities is imperative for optimal management and prognostication. While patients with nonepithelioid pleural mesotheliomas benefit from immunotherapy, novel targeted therapies for CDKN2A-, NF2-, and BAP1-altered mesotheliomas are under consideration. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Programmed ventricular stimulation in structural heart disease: Implications of patterns of ventricular arrhythmias induced to long-term outcomes.

INTRODUCTION: Currently available data gives some credence to utility of VT induction studies in patients with stable ischemic cardiomyopathy, there are some unresolved questions as to define sensitive threshold for low-risk and the prognostic relevance of ill sustained or non-specific tachycardia on induction study. We evaluated potential ability of VT inducibility to predict likelihood of SHD (Structural heart disease) patients for subsequent arrhythmic or adverse cardiac events. MATERIAL AND METHODS: All consecutive patients with syncope/documented arrhythmia who had VT induction done were included and patients with VT storm, ACS,uncontrolled HF were excluded. We studied in 4 groups-monomorphic VT, sustained polymorphicVT, ill sustainedVT/VF and no VT/VF induced. The primary-endpoints were - Sudden death, all-cause mortality and secondary-endpoints were - MACE (AICD shock, death,HF, recurrence of VT). We screened 411 patients and included 169 within inducible (n = 79) and non-inducible group (n = 90). RESULTS: There were a higher number of patients with coronary artery disease, LV dysfunction, patients on amiodarone in inducible group and no difference in usage of beta-blockers. Recurrence of VT, composite of MACE was significantly higher in inducible group (p < 0.05). Mortality was not different in 3 groups compared with no VT/VF group. We found that monomorphic VT group had significantly higher MACE as compared to others and also predicted recurrence of VT and AICD shock and showed a trend towards significance for prediction of mortality. Inducible patients on AICD had mortality similar to non-inducible group. CONCLUSION: Induction of monomorphicVT/polymorphicVT with ≤3extrastimuli is associated with a higher number of MACE events on follow up. Induction of monomorphicVT predicts recurrence of VT/ICD shock.

Morphomolecular Classification Update on Hepatocellular Adenoma, Hepatocellular Carcinoma, and Intrahepatic Cholangiocarcinoma.

Hepatocellular adenomas (HCAs), hepatocellular carcinomas (HCCs), and intrahepatic cholangiocarcinomas (iCCAs) are a highly heterogeneous group of liver tumors with diverse pathomolecular features and prognoses. High-throughput gene sequencing techniques have allowed discovery of distinct genetic and molecular underpinnings of these tumors and identified distinct subtypes that demonstrate varied clinicobiologic behaviors, imaging findings, and complications. The combination of histopathologic findings and molecular profiling form the basis for the morphomolecular classification of liver tumors. Distinct HCA subtypes with characteristic imaging findings and complications include HNF1A-inactivated, inflammatory, ß-catenin-activated, ß-catenin-activated inflammatory, and sonic hedgehog HCAs. HCCs can be grouped into proliferative and nonproliferative subtypes. Proliferative HCCs include macrotrabecular-massive, TP53-mutated, scirrhous, clear cell, fibrolamellar, and sarcomatoid HCCs and combined HCC-cholangiocarcinoma. Steatohepatitic and ß-catenin-mutated HCCs constitute the nonproliferative subtypes. iCCAs are classified as small-duct and large-duct types on the basis of the level of bile duct involvement, with significant differences in pathogenesis, molecular signatures, imaging findings, and biologic behaviors. Cross-sectional imaging modalities, including multiphase CT and multiparametric MRI, play an essential role in diagnosis, staging, treatment response assessment, and surveillance. Select imaging phenotypes can be correlated with genetic abnormalities, and identification of surrogate imaging markers may help avoid genetic testing. Improved understanding of morphomolecular features of liver tumors has opened new areas of research in the targeted therapeutics and management guidelines. The purpose of this article is to review imaging findings of select morphomolecular subtypes of HCAs, HCCs, and iCCAs and discuss therapeutic and prognostic implications. Online supplemental material is available for this article. ©RSNA, 2022.

Malignant Gastrointestinal Neuroectodermal Tumor: A New Kid on the Block?

ABSTRACT: Also referred to as "osteoclast-rich, clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT)," malignant gastrointestinal neuroectodermal tumor is a newly described, rare, aggressive sarcoma that commonly arises in the small bowel, stomach, and colon. Histogenesis is likely from an autonomous nervous system-related primitive cell of neural crest origin. The hallmark genetic finding of EWS-CREB1 or EWS-ATF1 fusion transcripts clinches the diagnosis. Annular constrictive lesions tend to be smaller, show homogenous contrast enhancement on computed tomography, and may present with bowel obstruction. Larger, expansile masses tend to be exophytic and show heterogeneous contrast enhancement. Surgical resection is the mainstay of treatment. Frequent recurrences, metastases, and death from disease in 75% of patients portend a poor prognosis. Targeted chemotherapy based on specific tumor pathways is being developed.

Anastomosing hemangioma: a current update on clinical, pathological and imaging features.

Anastomosing hemangioma (AH) is a rare, benign vascular neoplasm with distinctive histopathology and characteristic tumor distribution. AHs show marked proclivity to involve the kidneys, gonads and the retroperitoneal soft tissues; kidney is the most common target site often in the context of end stage renal disease. Recent studies have identified activating mutations of GNA genes that drive the molecular pathogenesis of AHs. AH appears as a solitary, well-circumscribed, hypervascular tumor that charters a benign course with an excellent prognosis. The purpose of this article is to provide a current update on clinical, pathological and imaging features of anastomotic hemangioma.

Mesenchymal neoplasms of the urinary bladder: a comprehensive review with focus on cross-sectional imaging findings.

Mesenchymal neoplasms of the urinary bladder are exceedingly rare and display remarkable diversity. These tumors demonstrate distinct pathological features as well as variable biological behavior and cross-sectional imaging findings. The rarity of tumors, nonspecific symptoms and seemingly normal cystoscopic findings (particularly with small and exophytic tumors) frequently lead to misdiagnosis or missed diagnosis. While some tumors display characteristic cross-sectional imaging findings that may suggest a diagnosis, imaging findings are mostly nonspecific. Histopathological examination is required for accurate diagnosis, management and prognostication. The purpose of this article is to review the cross-sectional imaging findings of a diverse spectrum of mesenchymal tumors of the urinary bladder.

Gastrointestinal Manifestations of Immunodeficiency: Imaging Spectrum.

There is a wide spectrum of hereditary and acquired immunodeficiency disorders that are characterized by specific abnormalities involving a plethora of humoral, cellular, and phagocytic immunologic pathways. These include distinctive primary immunodeficiency syndromes due to characteristic genetic defects and secondary immunodeficiency syndromes, such as AIDS from HIV infection and therapy-related immunosuppression in patients with cancers or a solid organ or stem cell transplant. The gut mucosa and gut-associated lymphoid tissue (the largest lymphoid organ in the body), along with diverse commensal microbiota, play complex and critical roles in development and modulation of the immune system. Thus, myriad gastrointestinal (GI) symptoms are common in immunocompromised patients and may be due to inflammatory conditions (graft versus host disease, neutropenic enterocolitis, or HIV-related proctocolitis), opportunistic infections (viral, bacterial, fungal, or protozoal), or malignancies (Kaposi sarcoma, lymphoma, posttransplant lymphoproliferative disorder, or anal cancer). GI tract involvement in immunodeficient patients contributes to significant morbidity and mortality. Along with endoscopy and histopathologic evaluation, imaging plays an integral role in detection, localization, characterization, and distinction of GI tract manifestations of various immunodeficiency syndromes and their complications. Select disorders demonstrate characteristic findings at fluoroscopy, CT, US, and MRI that permit timely and accurate diagnosis. While neutropenic enterocolitis affects the terminal ileum and right colon and occurs in patients receiving chemotherapy for hematologic malignancies, Kaposi sarcoma commonly manifests as bull's-eye lesions in the stomach and duodenum. Imaging is invaluable in treatment follow-up and long-term surveillance as well. Online supplemental material is available for this article. ©RSNA, 2022.

Mesenchymal Neoplasms of the Prostate and Seminal Vesicles: Spectrum of Disease with Radiologic-Pathologic Correlation.

There is a wide spectrum of benign and malignant mesenchymal neoplasms of the prostate, which account for less than 1% of all prostatic tumors. These include distinctive tumors that arise from the specialized prostatic stroma and site-agnostic neoplasms such as smooth muscle tumors, fibrous or myofibroblastic neoplasms, neurogenic tumors, vascular tumors, and a plethora of sarcomas. Select tumors show classic sites of origin within the prostate. While stromal tumors of uncertain malignant potential (STUMPs) commonly involve the peripheral zone at the prostate base, leiomyomas typically originate from the central prostate toward the apex. Some "prostatic" neoplasms such as gastrointestinal stromal tumors, solitary fibrous tumor (SFT), paragangliomas, and neurogenic tumors arise primarily from periprostatic soft tissues. Most mesenchymal tumors of the prostate and seminal vesicles manifest as large tumors that cause nonspecific symptoms; prostate-specific antigen level is not typically elevated. Diverse mesenchymal neoplasms demonstrate characteristic histopathologic and immunocytochemical features and variable cross-sectional imaging findings. While leiomyoma and SFT typically display low signal intensity on T2-weighted images, synovial sarcomas commonly show hemorrhage. Diagnosis is difficult because of the rarity and lack of awareness of the tumors and the significant overlap in histopathologic features. Select tumors show characteristic genetic abnormalities that allow the diagnosis to be established. For example, more than 90% of SFTs are characterized by a unique NAB2-STAT6 gene fusion, and more than 95% of synovial sarcomas are associated with a distinctive SYT-SSX chimeric transcript. Accurate diagnosis is imperative for optimal management owing to markedly different tumor biology as well as attendant therapeutic and prognostic implications. While STUMPs commonly recur, sarcomas typically charter an aggressive course with poor prognosis. Online supplemental material is available for this article. ©RSNA, 2022.

Long term outcomes after bare metal stent implantation.

Long term outcome data after BMS implant is not available from the Indian subcontinent. This is a prospective observational study which aims to study long term outcomes after BMS implant at a tertiary care centre. 100 consecutive patients underwent BMS implant and were followed up for 20 years. LAD was the most common vessel involved and different types of BMS were implanted. All-cause mortality was noted in 21% (n = 21) whereas cardiac mortality was seen in 16% (n = 16). Cumulative revascularisation free survival at 20 years was 71%. The study showed that long term outcomes after BMS implant were fare and acceptable.

Testicular Germ Cell Tumors: Classification, Pathologic Features, Imaging Findings, and Management.

Testicular germ cell tumors (TGCTs) demonstrate a wide variety of histopathologic, genetic, pathogenetic, and immunocytochemical characteristics and various clinical-biologic profiles and prognoses. Most TGCTs arise from an intratubular precursor cell referred to as germ cell neoplasia in situ (GCNIS), which is an embryonic germ cell with the potential to differentiate into a plethora of embryonic and extraembryonic lineages. Advances in pathologic examination and genetics paved the way for the 2016 World Health Organization (WHO) classification system, which recognizes two pathogenetically distinct groups of TGCTs. Although postpubertal tumors originate from GCNIS, almost all prepubertal tumors belong to the non-GCNIS category. Molecular testing for chromosome 12p amplification helps to distinguish the two tumor categories. Imaging techniques such as US, CT, MRI, and fluorine 18 (18F)-fluorodeoxyglucose PET/CT are pivotal to the diagnosis and staging, evaluation of complications and treatment response, and long-term surveillance of TGCTs. In addition, select MRI findings may help to differentiate a seminoma from a nonseminomatous mixed TGCT. Accurate diagnosis of TGCTs has therapeutic and prognostic implications. Although seminomas show exquisite response to chemotherapy and radiation therapy, postpubertal teratomas are highly resistant to both. The 2016 WHO classification system introduced changes in the diagnosis and management of TGCTs, including the development of new treatment and follow-up guidelines. Radiologists play an essential role in the optimal treatment of patients with TGCTs. Online supplemental material is available for this article. ©RSNA, 2021.

Mucin-producing Cystic Hepatobiliary Neoplasms: Updated Nomenclature and Clinical, Pathologic, and Imaging Features.

Cystic hepatobiliary neoplasms with mucin-producing epithelium-mucinous cystic neoplasm of the liver (MCN) and intraductal papillary neoplasm of the bile duct (IPNB)-are rare and distinct entities that have unique clinical, pathologic, and imaging features. They are differentiated pathologically by the presence of subepithelial ovarian-like hypercellular stroma (OLS), which is the defining histopathologic feature of MCN. MCN is commonly a benign, large, solitary, symptomatic, multiloculated cystic mass without biliary communication that occurs in middle-aged women. On the other hand, IPNBs are a heterogeneous spectrum of tumors, which are commonly associated with invasive carcinoma, occur in older patients, and can be differentiated from MCN by communication with the biliary tree, intraductal masses, associated biliary ductal dilatation, and absent OLS. Understanding of these rare neoplasms has grown and evolved over time and continues to today, but uncertainty and controversy persist, related to the rarity of these tumors, relatively recent designation as separate entities, inherent clinicopathologic heterogeneity, overlapping imaging features, and the fact that many prior studies likely included MCN and cystic IPNB together as a single entity. Confusion regarding these neoplasms is evident by historical inconsistencies and nonstandardized nomenclature through the years. Awareness of these entities is important for the interpreting radiologist to suggest a particular diagnosis or generate a meaningful differential diagnosis in the appropriate setting, and is of particular significance as MCN and cystic IPNB have overlapping imaging features with other more common hepatobiliary cystic masses but have different management and prognosis. Online supplemental material is available for this article. Work of the U.S. Government published under an exclusive license with the RSNA.

Machine Learning and Deep Learning in Oncologic Imaging: Potential Hurdles, Opportunities for Improvement, and Solutions-Abdominal Imagers' Perspective.

ABSTRACT: The applications of machine learning in clinical radiology practice and in particular oncologic imaging practice are steadily evolving. However, there are several potential hurdles for widespread implementation of machine learning in oncologic imaging, including the lack of availability of a large number of annotated data sets and lack of use of consistent methodology and terminology for reporting the findings observed on the staging and follow-up imaging studies that apply to a wide spectrum of solid tumors. This short review discusses some potential hurdles to the implementation of machine learning in oncologic imaging, opportunities for improvement, and potential solutions that can facilitate robust machine learning from the vast number of radiology reports and annotations generated by the dictating radiologists.

Pancreas in Hereditary Syndromes: Cross-sectional Imaging Spectrum.

A wide spectrum of hereditary syndromes predispose patients to distinct pancreatic abnormalities, including cystic lesions, recurrent pancreatitis, ductal adenocarcinoma, nonductal neoplasms, and parenchymal iron deposition. While pancreatic exocrine insufficiency and recurrent pancreatitis are common manifestations in cystic fibrosis and hereditary pancreatitis, pancreatic cysts are seen in von Hippel-Lindau disease, cystic fibrosis, autosomal dominant polycystic kidney disease, and McCune-Albright syndrome. Ductal adenocarcinoma can be seen in many syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma syndrome, Lynch syndrome, hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, and familial pancreatic cancer syndrome. Neuroendocrine tumors are commonly seen in multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau disease. Pancreatoblastoma is an essential component of Beckwith-Wiedemann syndrome. Primary hemochromatosis is characterized by pancreatic iron deposition. Pancreatic pathologic conditions associated with genetic syndromes exhibit characteristic imaging findings. Imaging plays a pivotal role in early detection of these conditions and can positively affect the clinical outcomes of those at risk for pancreatic malignancies. Awareness of the characteristic imaging features, imaging-based screening protocols, and surveillance guidelines is crucial for radiologists to guide appropriate patient management. ©RSNA, 2021.

Temporal evolution of metastatic disease: part I-an in-depth review of the evolution of metastatic disease across diverse spectrum of non-neural solid tumors on serial oncologic imaging studies and relevant practical applications.

With improved survival rates of patients with metastatic disease due to continuously evolving multimodality treatment options, radiologists are increasingly interpreting imaging studies from patients with protracted metastatic disease. It is thus crucial for radiologists to have an in-depth understanding of the temporal evolution of metastatic spread and the accompanying findings on imaging studies, to provide accurate interpretation that supports optimal management. A general overview of the evolution of cancer spread on serial imaging studies and common pathways of tumor spread across multiple tumor types and tumor locations is not readily available in radiology literature. The key common pathways of tumor spread across diverse spectrum of tumors relevant to radiologists are summarized in a logical schematic approach which focusses on aiding radiologists to understand the pathways of spread resulting in current sites of metastatic disease involvement and then to potentially predict future sites of metastatic involvement. This article also summarizes the practical applications of this knowledge to the routine oncologic imaging interpretation.

Temporal evolution of metastatic disease: part II-a novel proposal for subcategorization of metastatic disease from non-neural solid tumors with diverse histologies and locations.

Tumor spread is a continuous process and metastases can further disseminate. Currently, metastatic disease from most primary tumors is subcategorized as M0 if absent and M1 if present. However, metastatic disease in different locations may have different prognostic implications, even if it is from the same primary tumor. The current staging systems for metastatic disease have not evolved to match our understanding of the disease's evolution or the evolving treatment paradigms. Primary tumor-specific subcategorization of metastatic disease is currently available for a few tumors, but not all of them imply further remote spread of tumor, similar to tumor (T) and N (node) subcategorizations of the TNM staging, nor are they applicable to wide spectrum of other tumors. In this era of precision medicine, tumor-type agnostic therapies based on common biomarkers rather than primary tumor sites are emerging, but a subcategorization system applicable to metastatic disease from diverse primary tumor locations and with diverse histologies is not available. In this article, we discuss the need to further classify the metastatic disease and present a subcategorization applicable to metastatic disease from non-neural solid tumors from different primary tumor sites and with different histologies, which is based on the temporal spread of metastatic disease. Our proposed subcategorization scheme for metastatic disease into M0, M1, M2 and M3, is universally applicable to a diverse spectrum of non-neural solid tumors, and increasing M subcategorization represents further remote spread of tumor.