Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance. METHODS: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked. RESULTS: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%. CONCLUSIONS: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society.

Paraneoplastic syndromes (PNS) associated with Merkel cell carcinoma (MCC): A case series of 8 patients highlighting different clinical manifestations.

BACKGROUND: Paraneoplastic syndromes (PNS) are commonly associated with neuroendocrine cancers, such as small cell lung cancer. OBJECTIVES: We examined the association of PNS in Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer. METHODS: We identified PNS associated with MCC based on chart review of a Seattle-based repository and examined the incidence of MCC-associated hyponatremia in an independent cohort within Kaiser Permanente Northern California. RESULTS: Eight PNS cases were identified from the Seattle repository. Three distinct PNS types were observed: cerebellar degeneration (1 case), Lambert-Eaton myasthenic syndrome (2 cases), and malignancy-associated hyponatremia (5 cases). Moreover, the incidence of severe hyponatremia (serum sodium <125 mmol/L) coincident with MCC was identified among 4.3% (9 of 211) patients with MCC in the Kaiser Permanente Northern California cohort. LIMITATIONS: We did not have access to complete medical records on all patients so it was not possible to determine the prevalence of PNS in MCC. CONCLUSIONS: MCC can be associated with PNS similar to those found in other neuroendocrine cancers. Clinicians should be aware of these presentations as PNS often precede the identification of the underlying malignancy and usually resolve with appropriate treatment of the cancer.

Clinical utility of a circulating tumor cell assay in Merkel cell carcinoma.

BACKGROUND: Quantitation of circulating tumor cells (CTCs) has utility in managing breast, colon, and prostate carcinomas. OBJECTIVE: We sought to determine whether a commercially available CTC assay provides prognostic information in Merkel cell carcinoma (MCC), insight into treatment responses, or both. METHODS: We analyzed CTCs in 52 specimens from 34 patients with MCC. RESULTS: The presence of CTCs correlated with extent of disease at blood draw (P = .004). Among 15 patients with regional nodal disease, CTC-negative patients had 80% disease-specific survival at 2 years after the test, versus 29% for CTC-positive patients (P = .015). Among the entire cohort, those without CTCs had 72% MCC-specific survival whereas CTC-positive patients had 25% survival (n = 34, median follow-up 19 months, P = .0003). Fifty seven percent of patients with MCC had a cytokeratin "dot" visible in 20% or more of CTCs, a feature that was absent among CTCs from other carcinomas (0 of 13 cases). LIMITATIONS: CTC assay was performed at variable times after diagnosis and heterogeneity in extent of disease affects interpretability of the data. CONCLUSION: CTC detection in MCC is feasible and appears to add prognostic information, particularly in patients with regional nodal disease. It may also assist clinical management in certain situations, including differentiating metastatic MCC cells from those of other carcinomas.

Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma.

BACKGROUND: The effects of primary tumor size on nodal involvement and of number of involved nodes on survival have not, to our knowledge, been examined in a national database of Merkel cell carcinoma (MCC). OBJECTIVE: We sought to analyze a retrospective cohort of patients with MCC from the largest US national database to assess the relationships between these clinical parameters and survival. METHODS: A total of 8044 MCC cases in the National Cancer Data Base were analyzed. RESULTS: There was a 14% risk of regional nodal involvement for 0.5-cm tumors that increased to 25% for 1.7-cm (median-sized) tumors and to more than 36% for tumors 6 cm or larger. The number of involved nodes was strongly predictive of survival (0 nodes, 76% 5-year relative survival; 1 node, 50%; 2 nodes, 47%; 3-5 nodes, 42%; and ≥6 nodes, 24%; P < .0001 for trend). Younger and/or male patients were more likely to undergo pathological nodal evaluation. LIMITATIONS: The National Cancer Data Base does not capture disease-specific survival. Hence, relative survival was calculated by comparing overall survival with age- and sex-matched US population data. CONCLUSION: Pathologic nodal evaluation should be considered even for patients with small primary MCC tumors. The number of involved nodes is strongly predictive of survival and may help improve prognostic accuracy and management.

Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with a disease-specific mortality of approximately 40 %. The association of MCC with a recently discovered polyomavirus, combined with the increased incidence and mortality of MCC among immunocompromised patients, highlight the importance of the immune system in controlling this cancer. Initial management of MCC is summarized within the NCCN guidelines and in recently published reviews. The high rate of recurrent and metastatic disease progression in MCC, however, presents a major challenge in a cancer that lacks mechanism-based, disease-specific therapies. Traditional treatment approaches have focused on cytotoxic chemotherapy that, despite frequent initial efficacy, rarely provides durable responses and has high morbidity among the elderly. In addition, the immunosuppressive nature of chemotherapy is of concern when treating a virus-associated cancer for which survival is unusually tightly linked to immune function. With a median survival of 9.6 months after development of an initial metastasis (n = 179, described herein), and no FDA-approved agents for this cancer, there is an urgent need for more effective treatments. We review diverse management options for patients with advanced MCC, with a focus on emerging and mechanism-based therapies, some of which specifically target persistently expressed viral antigens. These treatments include single-dose radiation and novel immunotherapies, some of which are in clinical trials. Due to their encouraging efficacy, low toxicity, and lack of immune suppression, these therapies may offer viable alternatives to traditional cytotoxic chemotherapy.

Asymmetric lateral distribution of melanoma and Merkel cell carcinoma in the United States.

BACKGROUND: A recent report suggested a trend toward more ultraviolet-linked skin cancers arising on the left rather than the right side of the body in the United States. OBJECTIVE: We sought to test whether the reported incidences of two ultraviolet-linked skin cancers, malignant melanoma (MM) and Merkel cell carcinoma (MCC), are statistically significantly greater on the left than the right in the United States. METHODS: MMs (n = 82,587) and MCCs (n = 2384) occurring on the left or right side of the face, arm, or leg that were reported in the Surveillance, Epidemiology, and End Results registry between 1986 and 2006 were included for analysis. RESULTS: MM and MCC were significantly more likely to present on the left than the right (P < .01 for both MM and MCC). In all, 53% of arm melanomas, 51% of facial melanomas, and 52% of leg melanomas presented on the left. A total of 55% of arm MCCs and 52% of facial MCCs presented on the left, whereas leg MCCs were equally distributed. LIMITATIONS: National registry data did not provide information regarding sun exposure or driving habits. No equivalent registry data were available for basal or squamous cell carcinoma. CONCLUSIONS: Both melanoma and MCC are significantly more likely to arise on the left than the right, and this effect was most prominent on the arm. Driver-side automobile ultraviolet exposure (approximately 5-fold stronger on the left than right arm) is a likely contributing factor. It may be prudent to remind individuals prone to skin cancer to take appropriate sun precautions when driving in an automobile.

Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.

BACKGROUND: The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems. OBJECTIVE: We sought to determine the prognostic significance of tumor size, clinical versus pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC. METHODS: A total of 5823 prospectively enrolled MCC cases from the National Cancer Data Base had follow-up data (median 64 months) and were used for prognostic analyses. RESULTS: At 5 years, overall survival was 40% and relative survival (compared with age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal, and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I, ≤2 cm, 66% relative survival at 5 years; stage II, >2 cm, 51%; P < .0001). Patients with clinically local-only disease and pathologically proven negative nodes had better outcome (76% at 5 years) than those who only underwent clinical nodal evaluation (59%, P < .0001). LIMITATIONS: The National Cancer Data Base does not capture disease-specific survival. Overall survival for patients with MCC was therefore used to calculate relative survival based on matched population data. CONCLUSION: Although the majority (68%) of patients with MCC in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas.

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV+ MCC had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity.

Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.

PURPOSE: IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. PATIENTS AND METHODS: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. RESULTS: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. CONCLUSIONS: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.

Human CD4+ T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain.

Although CD4+ T cells likely play key roles in antitumor immune responses, most immuno-oncology studies have been limited to CD8+ T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4+ T cells. Here, we report the identification of CD4+ T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WEDLT209-228) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive MCC patients. Cellular staining with a WEDLT209-228-HLA-DRB1*0401 tetramer indicated that specific CD4+ T cells were detectable in 78% (14 of 18) of evaluable MCC patients, were 250-fold enriched within MCC tumors relative to peripheral blood, and had diverse T-cell receptor sequences. We also identified a modification of this domain that still allowed recognition by these CD4+ T cells but disabled binding to the Rb tumor suppressor, a key step in the detoxification of a possible therapeutic vaccine. The use of these new tools for deeper study of MCPyV-specific CD4+ T cells may provide broader insight into cancer-specific CD4+ T-cell responses.

Clinical Updates in Women's Health Care Primary and Preventive Care Review Summary: Common Dermatologic Conditions.

The skin is the largest organ in the human body, and as such, cutaneous problems constitute a common component of visits to medical professionals. The skin functions as a physiologic barrier and a major organ of homeostasis. The practicing obstetrician-gynecologist can play an important role in identifying skin diseases and initiating management. Additionally, the skin often reflects internal disease states. An astute health care provider can identify systemic conditions early, with the goal of improving management. This monograph reviews common cutaneous conditions, both benign and malignant, hair and nail disorders, and skin conditions unique to the adult woman.

Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base.

BACKGROUND: Merkel cell carcinoma (MCC) has a high risk of recurrence after initial surgical therapy. Adjuvant radiation therapy (RT) and chemotherapy may be used to reduce the risk of locoregional and systemic recurrence, respectively, but there are conflicting data regarding their impact on survival. We performed a retrospective analysis of MCC cases from the National Cancer Data Base (NCDB) to assess whether adjuvant therapy was associated with differences in survival. METHODS: Six thousand nine hundred and eight MCC patients with staging, treatment, and survival data were included. Multivariable analyses were conducted for overall survival (OS) with various treatment modalities while adjusting for prognostic variables including age, sex, comorbidities (Charlson/Deyo score), margin status, primary tumor site and size, and lymph node status. All statistical tests were two-sided. RESULTS: For localized MCC (stage I: n = 3369, stage II: n = 1474 ), surgery plus adjuvant RT was associated with statistically significantly better OS than with surgery alone in multivariable analyses (stage I: hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.80, P < .001; stage II: HR = 0.77, 95% CI = 0.66 to 0.89, P < .001). In patients with regional nodal metastases (stage III: n = 2065 ), neither adjuvant RT nor chemotherapy was associated with statistically significantly improved or worsened OS. CONCLUSIONS: In this study of the largest MCC cohort reported to date, adjuvant RT was associated with improved OS in stages I-II MCC. Neither adjuvant RT nor chemotherapy was associated with improved OS in stage III MCC. These results, with the limitations of retrospective analyses, are consistent with earlier studies suggesting benefit with adjuvant RT but do not support the routine use of adjuvant chemotherapy in MCC.

Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.

Cytotoxic chemotherapy is commonly used to treat advanced Merkel cell carcinoma (MCC). However, its efficacy in distant metastatic MCC patients is unclear, in part because most prior reports aggregated these patients with those receiving adjuvant chemotherapy and combined chemoradiation for whom prognosis and outcomes may differ. In this retrospective study, we analyzed detailed records from 62 patients with distant metastatic MCC treated with cytotoxic chemotherapy. Efficacy outcomes including response rate (RR), durability of response (DOR), progression-free survival (PFS), and overall survival (OS) were evaluated. In this cohort, platinum plus etoposide was the most commonly used first-line regimen (69%). RR to first-line chemotherapy was 55% (34/62) with complete responses (CR) in 13% (8/62) and partial responses (PR) in 42% (26/62) while 6% (4/62) had stable disease and 39% (24/62) had progressive disease. Median PFS was 94 days and median OS was 9.5 months from start of chemotherapy. Among responding patients (n = 34), median PFS was 168 days and median DOR was 85 days. Among 30 of the 62 patients who received second-line chemotherapy, RR was 23% (7/30; 1 CR, 6 PR), median PFS was 61 days, and median DOR was 101 days. In summary, first-line chemotherapy is associated with a high RR in metastatic MCC, but responses are typically not durable, and the median PFS is only 3 months. These results suggest rapid emergence of chemoresistance in MCC tumors, and may serve as a useful comparator for immunotherapies currently being explored for metastatic MCC.

Postoperative radiation therapy is associated with a reduced risk of local recurrence among low risk Merkel cell carcinomas of the head and neck.

PURPOSE: Merkel cell carcinoma (MCC) is a rare and often aggressive skin cancer. Typically, surgery is the primary treatment. Postoperative radiation therapy (PORT) is often recommended to improve local control. It is unclear whether PORT is indicated in patients with favorable Stage IA head and neck (HN) MCC. METHODS AND MATERIALS: We conducted a retrospective analysis of 46 low-risk HN MCC cases treated between 2006 and 2015. Inclusion criteria were defined as a primary tumor size of ≤ 2 cm, negative pathological margins, negative sentinel lymph node biopsy, and no immunosuppression. Local recurrence (LR) was defined as tumor recurrence within 2 cm of the primary surgical bed and estimated with the Kaplan-Meier method. RESULTS: Omission of PORT was offered to all 46 patients, of which 23 patients received PORT and 23 did not. No patient received adjuvant chemotherapy. There were no significant differences in surgical margins, tumor size, depth, lympho-vascular invasion status, or demographics between the two patient groups. Median follow-up for all patients was 3.7 years. Six of the 23 patients who did not receive PORT developed an LR. Compared to the group that received PORT, there was a significantly higher risk of LR in the group treated without PORT (26% vs. 0%, P = .02). Median time to LR was 11 months. All local failures were effectively salvaged. There was no difference in MCC-specific and overall survival between the 2 groups. CONCLUSIONS: For patients with HN MCC, omission of PORT was associated with a significantly higher risk of local recurrence even among those patients with the lowest-risk tumors (i.e., Stage IA without immune suppression). Thus, it is important to weigh the benefits of PORT against the side effect profile on a case-specific basis for each patient.

Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated cancer with limited therapeutic options for metastatic disease. Cytotoxic chemotherapy is associated with high response rates, but responses are seldom durable and toxicity is considerable. Here, we report our experience with palliative single-fraction radiotherapy (SFRT) in patients with metastatic MCC. We conducted retrospective analyses of safety and efficacy outcomes in patients that received SFRT (8 Gy) to MCC metastases between 2010 and 2013. Twenty-six patients were treated with SFRT to 93 MCC tumors located in diverse sites that included skin, lymph nodes, and visceral organs. Objective responses were observed in 94% of the measurable irradiated tumors (86/92). Complete responses were observed in 45% of tumors (including bulky tumors up to 16 cm). "In field" lesion control was durable with no progression in 77% (69/89) of treated tumors during median follow-up of 277 days among 16 living patients. Clinically significant toxicity was seen in only two patients who had transient side effects. An exploratory analysis suggested a higher rate of in-field progression in patients with an immunosuppressive comorbidity or prior recent chemotherapy versus those without (30% and 9%, respectively; P = 0.03). Use of SFRT in palliating MCC patients was associated with an excellent in field control rate and durable responses at treated sites, and with minimal toxicity. SFRT may represent a convenient and appealing alternative to systemic chemotherapy for palliation, for which most patients with oligometastatic MCC are eligible. SFRT may also synergize with emerging systemic immune stimulants by lowering tumor burden and enhancing presentation of viral/tumor antigens.

Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma.

IMPORTANCE: Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine-derived skin cancer with high rates of recurrence and associated mortality. Few published studies have used comprehensive patient data and long-term follow-up to examine factors that predict MCC outcomes. OBJECTIVE: To characterize MCC in a large defined-population cohort and analyze predictors of disease recurrence and survival. SETTING, DESIGN, AND PARTICIPANTS: Retrospective cohort study of 218 patients with MCC from the cancer registry of Kaiser Permanente Northern California, a large integrated health care delivery system. Patients were diagnosed as having MCC and followed up from January 1, 1995, through December 31, 2009. We examined host (age, sex, race, and immunosuppression), tumor (anatomic site, size, and extent), diagnostic (results of imaging and pathologic nodal evaluation), and treatment (surgery, radiation therapy, and chemotherapy) variables for their association with MCC outcomes. EXPOSURE: Host, tumor, diagnostic, and treatment factors. MAIN OUTCOMES AND MEASURES: Recurrence (locoregional and distant) of MCC and patient survival (overall and MCC specific). RESULTS: We estimated adjusted hazard ratios (AHRs) and 95% CIs for outcomes using Cox proportional hazards regression models. After adjustment for host, tumor, diagnostic, and treatment variables, tumor extent (categorized as local, regional, and distant) remained significantly associated with all outcomes. Immunosuppression was associated with higher MCC-specific mortality (AHR, 4.9 [95% CI, 1.7-14.4]), and an unknown primary site was associated with a lower risk for distant metastasis (0.1 [0.0-0.7]) and improved survival (0.4 [0.2-0.9]). Pathological nodal evaluation was associated with a lower risk for metastasis (AHR, 0.2 [95% CI, 0.0-1.0]) and improved survival. Radiation treatment was associated with a decreased risk for locoregional recurrence (AHR, 0.3 [95% CI, 0.1-0.6]), whereas chemotherapy was not associated with any alteration in outcomes. CONCLUSIONS AND RELEVANCE: Tumor site and extent, results of pathologic nodal evaluation, and the presence of radiation treatment were associated with MCC recurrence. Immunosuppression, tumor extent, and results of pathologic nodal evaluation were associated with MCC-specific survival, whereas chemotherapy was not associated with any outcomes. Our findings may help to inform diagnostic and therapeutic management of MCCs.