Diagnostic yield of staging brain magnetic resonance imaging is low in Merkel cell carcinoma - A single-institution cohort study

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Journal: Journal of the American Academy of Dermatology (preprint). Accepted September 6, 2021. Please see the postprint on the JAAD Website.

Authors: Farees Saqlain, BA1, Sophia Z. Shalhout, PhD1,2, Kevin S. Emerick, MD1,3, Howard L. Kaufman, MD1,4, Yen-Lin E. Chen, MD1,5, James C. Cusack, MD1,4, Kayla Wright, BA2, and David Michael Miller, MD, PhD1,2,6^*^

Affiliations: 1Harvard Medical School, Boston, MA 02115, USA. 2Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. 3Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA. 4Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. 5Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. 6Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA

Corresponding Author: David M. Miller, MD, PhD, FAAD

Keywords: baseline imaging; clinical guidelines; distant metastasis; magnetic resonance imaging; MCC; Merkel cell carcinoma; MRI; nonmelanoma skin cancer; occult disease; scans; skin cancer; staging

Funding sources: This work was supported by Project Data Sphere, the American Skin Association, and ECOG-ACRIN.

Conflicts of interest: H.L. Kaufman is an employee of Ankyra Therapeutics. The other authors have no conflicts of interest to declare.

Abbreviations: CML: chronic myelogenous leukemia, CT: computerized tomography, IRB: institutional review board, MCC: Merkel Cell Carcinoma, MGB: Mass General Brigham, MRI: magnetic resonance imaging, PET: positron emission tomography, SEER: Surveillance, Epidemiology, and End Results Program

To the Editor:

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine cancer which often presents with regional and distant spread, but only rarely with brain involvement. Here we provide data on the diagnostic yield of brain magnetic resonance imaging (MRI) at presentation in 77 cases where such imaging was available, from a cohort of 346 patients diagnosed with MCC between 2016 and 2020 available from the Mass General Brigham (MGB) medical record. While further corroboration is needed, our data indicates that staging brain MRI scans rarely yield positive findings, suggesting that routine brain imaging, particularly for the majority of patients who present without neurologic symptoms, may not be indicated.

This study was approved by the MGB IRB. Of the 77 patients with brain MRI available <90 days from date of MCC diagnosis, 83.1% (n=64/77) were neurologically asymptomatic while 16.9% (n=13) presented with symptoms including altered mental status, headache, syncope, and speech or vision changes (Table 1). Most scans were ordered with contrast (89.6%; n=69) and <60 days from diagnosis (84.4%, n=65). One of 13 patients (7.7%) presenting with neurologic symptoms had brain metastases detected on MRI; this patient had nodal disease of unknown primary and a pre-existing hematologic malignancy (CML). None of the 64 neurologically asymptomatic patients had brain metastasis on MRI. Overall, only one of 77 patients (1.3%) who had brain MRI at presentation was found to have brain involvement.

There remains a lack of consensus regarding routine staging of the brain in MCC. A 2020 review of SEER data found a presenting brain metastasis rate of 6/3449; only 3 patients presented with single-site metastasis to the brain (<0.1%)1. The NCCN does not generally recommend staging imaging for local disease, but recommends whole body imaging, either brain MRI and CT or whole-body PET/CT, for advanced disease. Notably, staging brain MRI use varied in the NCCN panel, from use in cases with nodal disease to more limited use in the setting of suspected brain involvement or disseminated disease2. An Italian group has suggested routine brain MRI in all cases of T2-T4 tumors, and in T1 tumors with suspected brain involvement3. Notably, a recent study focusing on the diagnostic yield of non-brain staging imaging in MCC revealed that 13.2% of patients with clinically node-negative disease, and 10.8% of patients with clinically node-positive disease, were upstaged4.

Here we add to the MCC literature by reporting that the vast majority of brain MRIs obtained <90 days from diagnosis (76/77, or 98.7%) were negative for brain involvement. This is in contrast to a reported 12.5% diagnostic yield of staging brain MRI in neurologically asymptomatic patients with melanoma (21.8% in clinical stage III or IV disease)5. Given limitations in cohort size, our observations require corroboration. However, our data suggests that the utility of staging brain MRI for MCC patients who are neurologically intact, even in the setting of regional disease, is unclear. Focusing on neurologic symptoms, more so than clinical stage, in guiding decisions to obtain staging brain MRI may be higher-yield, particularly in low resource settings.

Table 1. Details on Demographics, Disease Characteristics and Brain MRI Outcomes in Neurologically Asymptomatic and Symptomatic Patients with Merkel Cell Carcinoma
Neurologically Asymptomatic (n=64)
Neurologically Symptomatic (n=13)
Characteristic Number Percent No %
Age(years)
<50 1 1.6 0 0.0
50-70 26 40.6 8 61.5
>70 37 57.8 5 38.5
Sex
Male 44 68.8 6 46.2
Female 20 31.3 7 53.8
Immunosuppression
HIV 0 0.0 0 0.0
Solid Organ Transplant 0 0.0 0 0.0
Hematologic malignancy/disorder 4 6.3 4 30.8
Medical Immunosuppression 3 4.7 1 7.7
Total 7 10.9 5 38.5
Tumor Category
T0 17 26.6 2 15.4
T1 18 28.1 5 38.5
T2 21 32.8 5 38.5
T3 4 6.3 1 7.7
T4 2 3.1 0 0.0
Undetermined 2 3.1 0 0.0
Clinical Stage*
I 13 20.3 4 30.8
IIA 11 17.2 1 7.7
IIB 2 3.1 0 0.0
III 26 40.6 5 38.5
IV 11 17.2 3 23.1
Undetermined 1 1.6 0 0.0
Time to Brain MRI Scan
<30 days 41 64.1 6 46.2
30-60 days 16 25.0 2 15.4
60-90 days 7 10.9 5 38.5
Setting of Brain MRI
With and Without Contrast 58 90.6 11 84.6
Without Contrast 4 6.3 2 15.4
Unknown 2 3.1 0 0.0
Ongoing Therapies
Systemic Antineoplastic Therapy 4 6.3 3 23.1
Ongoing Brain Radiation 0 0.0 0 0.0
Outcomes
MRI Positive for Brain Metastasis 0 0.0 1 7.7
Developed New Brain Involvement on f/u 2 3.1 0* 0.0
a Cases featured at least one of the following neurological symptoms at presentation: altered mental status/confusion, dizziness, facial pain, facial paresthesia, headache, syncope, speech changes, or vision changes.
b Cases with history of at least one of the following hematologic malignancies/disorders prior to Merkel Cell Carcinoma diagnosis: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Chronic Myelogenous Leukemia, Mantle Cell Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome, or Non-Hodgkin Lymphoma, Not Otherwise Specified.
c Patients who did not have history of hematologic malignancy/disorder and were medically immunosuppressed for inflammatory bowel disease or rheumatologic conditions at time of Merkel Cell Carcinoma diagnosis.
d Overall clinical stage based on physical exam and baseline staging imaging, including brain MRI.
e Excluding the single case with brain metastases detected at presentation, 0/12 remaining cases of patients neurologically symptomatic at presentation developed brain involvement with MCC during follow-up. Median follow-up time in days for asymptomatic patients: 441 (range: 36-1656); for symptomatic patients: 506.5 (range: 64-1799).


References
1. Xia Y-J, Cao D-S, Zhao J, Zhu B-Z, Xie J. Frequency and prognosis of metastasis to liver, lung, bone and brain from Merkel cell carcinoma. Future Oncol. 2020;16(16):1101-1113.
2. Bichakjian CK, Olencki T, Aasi SZ, et al. Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(6):742-774.
3. Rastrelli M, Del Fiore P, Buja A, Vecchiato A. A therapeutic and diagnostic multidisciplinary pathway for Merkel cell carcinoma patients. Frontiers in. Published online 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7174780/
4. Singh N, Alexander NA, Lachance K, et al. Clinical benefit of baseline imaging in Merkel cell carcinoma: Analysis of 584 patients. J Am Acad Dermatol. 2021;84(2):330-339.
5. Schlamann M, Loquai C, Goericke S, Forsting M, Wanke I. [Cerebral MRI in neurological asymptomatic patients with malignant melanoma]. Rofo. 2008;180(2):143-147.

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Farees Saqlain
Medical Student

My research interests include clinical and translational research in advanced skin cancers.

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