Endocrinopathies Associated With Immune Checkpoint Inhibitor Use.

OBJECTIVE: To provide a clinical approach towards immune checkpoint inhibitor (ICI)-associated endocrinopathies, their link with cancer outcomes, factors which differentiate them from other immune related adverse events, and health systems innovation to improve care for these patients. METHODS: A literature search for articles pertaining to ICIs and endocrinopathies was performed and supplemented by expert opinions of the authors. RESULTS: While immune related adverse events can affect almost any organ, they frequently target the endocrine glands, most commonly thyroid. Different classes of ICIs have varying frequencies of endocrinopathies related to hypophysitis, thyroiditis, diabetes mellitus, and rarely hypoadrenalism and hypoparathyroidism. ICI-associated endocrinopathies share some features with classic endocrine autoimmunity but appear to be a distinct entity. They can be challenging to diagnose and manage due to nonspecific clinical features, use of exogenous glucocorticoids, and at times rapid and severe hormone deficiency. The role of anti-inflammatory high-dose glucocorticoids is minimal, and the ICI does not usually require permanent discontinuation. ICI-associated endocrinopathies usually cause permanent hormone deficiency necessitating long-term management and patient engagement. ICI-thyroiditis has been associated with improved survival, while other endocrinopathies have not shown a significant association with outcomes in cancer patients receiving ICIs. Oncoendocrinology teams can improve the care of patients with ICI-associated endocrinopathies. CONCLUSION: This narrative review provides guidance to clinicians prescribing ICIs and those managing ICI-associated endocrinopathies, and complements the frameworks provided by major scientific societies in this field.

Detection and Management of Perioperative Hyperglycemia at a Tertiary Cancer Center.

INTRODUCTION: To improve the detection and management of perioperative hyperglycemia at our tertiary cancer center, we implemented a glycemic control quality improvement initiative. The primary goal was to decrease the percentage of diabetic patients with median postoperative glucose levels > 180 mg/dL during hospitalization by 15% within 2 years. METHODS: A multidisciplinary team standardized preoperative screening, preoperative, intraoperative, and postoperative hyperglycemia management. We included all patients undergoing nonemergent inpatient and outpatient operations. We used a t test, rank sum, chi-square, or Fisher's exact test to assess differences in outcomes between patients at baseline (BL) (10/2018-4/2019), during the first phase (P1) (10/2019-4/2020), second phase (P2) (5/2020-12/2020), and maintenance phase (M) (1/2021-10/2022). RESULTS: The analysis included 9891 BL surgical patients (1470 with diabetes), 8815 P1 patients (1233 with diabetes), 10,401 P2 patients (1531 with diabetes) and 30,410 M patients (4265 with diabetes). The percentage of diabetic patients with median glucose levels >180 mg/dL during hospitalization decreased 32% during the initiative (BL, 20.1%; P1, 16.9%; P2, 12.1%; M, 13.7% [P < .001]). We also saw reductions in the percentages of diabetic patients with median glucose levels >180 mg/dL intraoperatively (BL, 34.0%; P1, 26.6%; P2, 23.9%; M, 20.3% [P < .001]) and in the postanesthesia care unit (BL, 36.0%; P1, 30.4%; P2, 28.5%; M, 25.8% [P < .001]). The percentage of patients screened for diabetes by hemoglobin A1C increased during the initiative (BL, 17.5%; P1, 52.5%; P2, 66.8%; M 74.5% [P < .001]). CONCLUSIONS: Our successful initiative can be replicated in other hospitals to standardize and improve glycemic control among diabetic surgical patients.

Clinical outcomes of immune checkpoint inhibitor diabetes mellitus at a comprehensive cancer center.

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients. Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020. Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients. Conclusion: Development of ICI-DM is associated with long-term insulin dependence and pancreatic atrophy; the use of diabetes technology in this patient population can help improve glycemic control.

Cancer treatment with immune checkpoint inhibitors can cause irreversible side effects. In this study, we describe the clinical presentations of 76 patients who developed immune checkpoint inhibitor diabetes mellitus, a rare complication of checkpoint inhibitor therapy that requires lifelong treatment with insulin therapy. Most patients presented with a life-threatening hyperglycemic emergency and had experienced weight loss and hyperglycemia several weeks prior to diagnosis. After diagnosis, these patients are at risk for high and low blood sugars, but the use of glucose monitoring devices and insulin pumps can help improve blood sugar control. In our study, the development of this complication did not affect survival for melanoma patients. We need to improve awareness of this rare complication to ensure timely treatment for patients.

A CASE OF ACQUIRED GENERALIZED LIPODYSTROPHY ASSOCIATED WITH PEMBROLIZUMAB IN A PATIENT WITH METASTATIC MALIGNANT MELANOMA.

OBJECTIVE: To describe an unusual immune-related adverse event (irAE), acquired generalized lipodystrophy (AGL), from checkpoint inhibitor therapy in a patient treated with pembrolizumab. METHODS: This is a case report of a 67-year-old male with metastatic melanoma who was treated with pembrolizumab. Prior to pembrolizumab, the patient was treated with another immune-checkpoint inhibitor and developed autoimmune hemolytic anemia. After starting pembrolizumab, he developed a scrotal mass consistent with panniculitis and after several subsequent cycles, he developed AGL. RESULTS: Loss of subcutaneous fat, unexplained weight loss in combination with worsening insulin resistance and worsening hypertriglyceridemia after initiation of pembrolizumab were consistent with AGL. Autoimmune disorders and other etiologies were ruled out. Despite this irAE, the patient continued to receive pembrolizumab given stabilization of melanoma with treatment. CONCLUSION: We report the second case of a patient who developed AGL secondary to pembrolizumab, and the fourth case to report such complication secondary to antiprogrammed cell death receptor-1 inhibitors. As use of checkpoint inhibitors becomes more common to treat several types of cancer, it is vital for clinicians to recognize these rare irreversible complications that are not frequently reported in clinical trials.

Endocrine surgery in the Coronavirus disease 2019 pandemic: Surgical Triage Guidelines.

BACKGROUND: In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. METHODS: An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS. RESULTS: Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management. CONCLUSIONS: These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID-19.

Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.

BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae. METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT. RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis. CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.

Predictors of Hypothyroidism in Hodgkin Lymphoma Survivors After Intensity Modulated Versus 3-Dimensional Radiation Therapy.

PURPOSE: To identify predictors of hypothyroidism after chemoradiation therapy for Hodgkin lymphoma (HL) and to compare outcomes after intensity modulated radiation therapy (IMRT) with those after 3-dimensional (3D) conformal radiation therapy (CRT). METHODS AND MATERIALS: Ninety patients who underwent involved-site IMRT in 2009 through 2014 were evaluated for treatment-induced hypothyroidism, defined as elevated thyroid-stimulating hormone or decreased free thyroxine levels (or both). Receiver operating characteristic curve analysis identified individuals at low versus high risk based on dosimetric variables. Dosimetric cutoff points were verified with an external data set of 50 patients who underwent 3D-CRT. RESULTS: In the IMRT group, most patients (75 [83%]) had stage II HL, and the median prescribed dose was 30.6 Gy; in the 3D-CRT group, 32 patients (64%) had stage II HL, and the median prescribed dose was 32.0 Gy. No differences were found in the proportions of patients with bilateral (P = .982) or unilateral (P = .074) neck involvement between the 2 groups. Hypothyroidism rates were marginally higher in the IMRT group, with estimated 3-year rates of freedom from hypothyroidism of 56.1% in the 3D-CRT group and 40% in the IMRT group (P = .057). Univariate analysis showed that smaller thyroid volume and higher thyroid dose were associated with hypothyroidism in both groups (P < .05). In the IMRT group, the percentage of the thyroid gland volume receiving ≥25 Gy (V25) and the absolute volume of the thyroid gland spared from 25 Gy (VS25Gy) were the strongest predictors of hypothyroidism (P = .001 and P < .001, respectively). Cutoff points of 63.5% (V25) and 2.2 mL (VS25Gy) classified patients as high risk (80%-82%) or low risk (37%-44%) (P < .001). Use of a thyroid avoidance structure reduced the incidence of hypothyroidism (P < .05) in the IMRT group. CONCLUSIONS: The percentage of the thyroid receiving 25 Gy and the volume of the thyroid spared from 25 Gy predicted the risk of hypothyroidism after either IMRT or 3D-CRT for HL. IMRT may confer a higher risk than 3D-CRT unless a treatment avoidance structure is used during planning.

Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress.

PURPOSE OF REVIEW: The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5 years. RECENT FINDINGS: The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors. MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.

Co-Managing Patients with Type 1 Diabetes and Cancer.

The life expectancy of people with type 1 diabetes is improving and now approaches that of those without diabetes. As this population ages, a growing number will be diagnosed with and treated for cancer. Cancer treatments can drastically affect insulin requirement and glycemic control through multiple mechanisms including high doses of glucocorticoids and targeted therapies that directly interfere with cellular pathways involved in the action of insulin. Patients with cancer frequently also have alterations in gastrointestinal motility or appetite and require supplemental enteral or parenteral nutrition. Few studies have evaluated these patients directly, but data on patients with and without diabetes suggest that glycemic control may play a larger role in cancer outcomes than is often recognized. Collaboration between the treating oncologist and diabetologist allows people with diabetes to receive the most effective therapies for their cancers without undue risk of hypoglycemia or adverse outcomes due to hyperglycemia.

Denosumab: a new agent in the management of hypercalcemia of malignancy.

Hypercalcemia of malignancy is an oncologic emergency due to tumoral factors that stimulate osteoclast-mediated bone resorption. It requires a combination of recommended treatments (i.e., hydration, bisphosphonate and calcitonin), which may be deleterious in patients with compromised cardiac or renal function or may not control serum calcium levels long term. Recurrent or refractory hypercalcemia may preclude the use of chemotherapeutic agents needed to effectively treat the underlying cancer, which is the cause of hypercalcemia. Denosumab, a fully human monoclonal antibody against RANKL, inhibits the maturation, function and survival of osteoclasts. An open-label, single-arm study of denosumab in patients with hypercalcemia of malignancy despite recent bisphosphonate treatment revealed positive results. Thus, the US FDA recently approved denosumab for the indication of hypercalcemia of malignancy, increasing the options available for patients with this debilitating and life-threatening condition.

Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma.

OBJECTIVE: Pheochromocytomas (PHs) and sympathetic paragangliomas (PGs) are tumors that produce catecholamines, predisposing patients to cardiovascular disease and gastrointestinal effects such as constipation. OBJECTIVES: i) determine the prevalence of constipation, its risk factors, and its impact on survival; ii) identify whether a systematic combination of fiber, water, and laxatives was effective for treatment of constipation. DESIGN AND METHODS: We retrospectively studied 396 patients with PH/PG diagnosed in 2005-2014. The study population was patients with constipation as a presenting symptom; the control group was patients without constipation as a presenting symptom. The MD Anderson Symptom Inventory was used to assess constipation and quality of life. RESULTS: Twenty-three patients (6%) had constipation. Constipation was associated with headaches, palpitations, diaphoresis, weight loss, and excessive noradrenaline production (P<0.0001). Eighteen of these patients had non-metastatic primary tumors larger than 5 cm and/or extensive metastases. No statistically significant differences in age, sex, and genotype were noted between the study and control groups. In patients without metastases, resection of the primary tumor led to symptom disappearance. A systematic combination of fiber, water, and laxatives was associated with symptom improvement. Two patients who presented unmanaged constipation died because of sepsis from toxic megacolon. CONCLUSIONS: Constipation is a rare and potentially lethal complication in patients with PH/PGs. Severe constipation can be prevented by recognizing and treating mild symptoms.

Safe and effective dosing of basal-bolus insulin in patients receiving high-dose steroids for hyper-cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy.

BACKGROUND: Hyperglycemia occurs in cancer patients receiving high-dose steroids with cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyper-CVAD) protocol. The purpose of our study was to determine insulin requirements in patients with hyperglycemia on hyper-CVAD therapy using a systematic algorithm. SUBJECTS AND METHODS: We did a retrospective chart review of 23 leukemia inpatients with hyperglycemia (two glucose values >250 mg/dL) on hyper-CVAD chemotherapy managed by the Endocrine Diabetes Inpatient Team algorithm. We reviewed demographic and glycemic data, insulin dosages, and use of oral hypoglycemic agents. Using our algorithm, the dose of insulin for each patient was titrated daily and with each subsequent cycle of hyper-CVAD. RESULTS: Ninety-one percent of patients had known diabetes. The median body mass index was 32.5 (range, 21.6-40.9) kg/m², and median age was 61 (range, 40-80) years. The overall trend in glucose values across cycles showed a statistically significant decrease with each subsequent cycle of hyper-CVAD. Hyperglycemia accounted for 81% of glucose measurements in the first cycle and 60% of glucose values in the last cycle. Patients received 1-1.3 units/kg of insulin per cycle, and insulin requirements were similar across cycles. The distribution of basal versus bolus insulin for each cycle was 63-77% prandial and 23-37% basal. Nine of the 23 patients had at least one glucose value <70 mg/dL, which accounted for 1.3% of all recorded glucose values. None of the patients had severe hypoglycemia. CONCLUSIONS: Multiple-dose insulin therapy initiated at 1-1.2 units/kg/day, distributed as 25% basal and 75% prandial, reduced hyperglycemia in patients who were receiving high-dose dexamethasone as part of hyper-CVAD.

The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2.

CONTEXT: Pheochromocytoma (PHEO) occurs in 50% of patients with multiple endocrine neoplasia type 2 (MEN2). It is unknown if the presence of PHEO is associated with more aggressive medullary thyroid cancer (MTC). OBJECTIVE: To present our experience with MEN2 PHEO and evaluate whether PHEO impacts MTC overall survival in patients with RET codon 634 mutations. DESIGN: We performed a retrospective chart review of MEN2 patients at MD Anderson Cancer Center from 1960 through 2012. PATIENTS: The study group comprised 85 patients (group 1) with MEN2-associated PHEO. Of these, 59 patients (subgroup 1) with RET codon 634 mutations were compared to 48 patients (group 2) with RET codon 634 mutations, but without MEN2-associated PHEO. MAIN OUTCOME MEASURES: Of 85 patients with MEN2 and PHEO, 70 had MEN2A and 15 had MEN2B. Median age at PHEO diagnosis was 32 years. The initial manifestation of MEN2 was MTC in 60% of patients, synchronous MTC and PHEO in 34%, and PHEO in 6% of patients. Of patients, 72% had bilateral PHEO, and most tumors were synchronous (82%). Subgroup analysis of MEN2 patients with and without PHEO, who were carriers of RET codon 634, the most common mutation with PHEO, showed no significant differences in the stage of MTC at initial diagnosis. The median follow-up time for patients with PHEO was 249 months and without PHEO was 67 months (P < .01). Survival analyses among RET 634 carriers did not show shorter survival for patients with PHEO. The median survival time for patients with PHEO was 499 months and without PHEO was 444 months (P < .05). CONCLUSIONS: PHEO in MEN2 patients are usually bilateral and unlikely to be metastatic. Subgroup analysis of patients with RET 634 mutations with and without PHEO showed that PHEO was not associated with a more advanced stage of MTC at diagnosis or a shorter survival.

Reduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis.

PURPOSE: The association between oral bisphosphonate (BP) intake and colorectal cancer (CRC) risk has been investigated in several recent studies with conflicting results. We summarized the evidence from the published studies in a categorical, dose-response meta-analysis. METHODS: Relevant studies were identified by a search of MEDLINE and EMBASE databases through January 15, 2012. We included studies that reported effect size estimates with 95% CIs for the association between exposure to oral BPs and risk of CRC. RESULTS: Three case-control studies with a total of 16,998 CRC cases and 108,197 controls and one cohort study with 94,405 individuals exposed to BPs and 283,181 unexposed to BPs were included in meta-analysis. The random effect model meta-analysis suggested reduced risk of CRC with exposure to oral BPs with pooled odds ratio (OR) of 0.87 (95% CI, 0.78 to 0.97). Significant inverse relationship was noted for 10 or more prescriptions categories, with pooled ORs of 0.71 (95% CI, 0.58 to 0.87). Similarly, the analysis for 1 to 3 years of use and more than 3 years of use of BPs suggested a significant inverse relationship, with pooled ORs of 0.76 (95% CI, 0.68 to 0.85) and 0.78 (95% CI, 0.61 to 0.99), respectively. CONCLUSION: This meta-analysis suggests that the use of oral BPs at a dose of 10 or more prescriptions or 1 or more years of duration is associated with reduced risk of CRC. Further randomized controlled trials are needed to prove this association.

Lung cancer-induced paraneoplastic syndromes.

PURPOSE OF REVIEW: Paraneoplastic syndromes occur commonly in patients with lung cancer, especially cancers of neuroendocrine origin. The syndromes can be the first clinical manifestation of malignant disease or a harbinger of cancer recurrence. To update the knowledge that would facilitate the care of lung cancer patients with paraneoplastic syndromes, this review focuses on the epidemiology, pathogenesis, clinical features, and current management of the more common and clinically relevant syndromes. RECENT FINDINGS: Certain combinations of clinical signs and symptoms (endocrine, neurologic, immunologic, dermatologic, metabolic, constitutional, and hematologic) are associated with lung carcinoma as a manifestation of the secretion of cytokines and hormones by these cells or as an associated immunologic response. These syndromes can be categorized by common causative mechanisms: hormonal syndromes, autoimmune syndromes, and other syndromes of less clear cause. Recent advances in medical technology have allowed better understanding of these syndromes and the development of novel diagnostic and therapeutic tools. SUMMARY: Increased awareness of paraneoplastic syndromes associated with lung cancer should lead to the earlier recognition and diagnosis of malignancies, thereby improving the overall prognosis of patients and alleviating associated comorbidities. Despite the recent advances in recognizing and treating paraneoplastic syndromes, many questions remain to be answered.

Opioid-induced biochemical alterations of the neuroendocrine axis.

Exogenous opioids have been used for decades to palliate cancer-related pain and other cancer-related manifestations and, more recently, to treat patients with pain not related to oncologic disease. While the goal of opioid treatment is symptomatic relief and improved quality of life, these patients often suffer from adverse side effects, including endocrine system abnormalities, of which hypogonadism is the best known. Opioids may interact with other hypothalamic-pituitary pathways and endocrine end organs, and in most cases these interactions are subtle and the effects unclear. The long-term effects of these agents on the endocrine system are still largely unknown. This article discusses the various effects of opioid agents on the endocrine system and provides information that allows early recognition of side effects that may alter the quality of life of patients affected by pain, awareness of the potential complications in opioid addicts, and detection and treatment of side effects in participants of an opioid detoxification program.

Role of EUS-FNA-based cytology in the diagnosis of mucinous pancreatic cystic lesions: a systematic review and meta-analysis.

BACKGROUND: Preoperative diagnosis of malignancy in pancreatic cystic lesions (PCLs) remains challenging. Most non-mucinous cystic lesions (NMCLs) are benign, but mucinous cystic lesions (MCLs) are more likely to be premalignant or malignant. AIM: The aim of this study was to assess the sensitivity, specificity, and positive and negative likelihood ratios (LRs) of EUS-FNA-based cytology in differentiating MCLs from non-mucinous PCLs. METHODS: We conducted a comprehensive search of MEDLINE, SCOPUS, Cochrane, and "CINAHL Plus" databases to identify studies, in which the results of EUS-FNA-based cytology of PCLs were compared with those of surgical biopsy or surgical excision histopathology. A DerSimonian-Laird random effect model was used to estimate the pooled sensitivity, specificity, and LRs, and a summary receiver-operating characteristic (SROC) curve was constructed. RESULTS: We included 376 patients from 11 distinct studies who underwent EUS-FNA-based cytology and also had histopathological diagnosis. The pooled sensitivity and specificity in diagnosing MCLs were 0.63 (95% CI, 0.56-0.70) and 0.88 (95% CI, 0.83-0.93), respectively. The positive and negative LRs in diagnosing MCLs were 4.46 (95% CI, 1.21-16.43) and 0.46 (95% CI, 0.25-0.86), respectively. The area under the curve (AUC) was 0.89. CONCLUSIONS: EUS-FNA-based cytology has overall low sensitivity but good specificity in differentiating MCLs from NMCLs. Further research is required to improve the overall sensitivity of EUS-FNA-based cytology to diagnose MCLs while evaluating PCL.