American Head & Neck Society

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Published on May 11, 2023 by AHNS Webmaster

Update on Merkel Cell Carcinoma

From the Authors Alia Tayara, BS1, Anne C. Kane, MD FACS2

1University of Mississippi Medical Center School of Medicine, Jackson, MS
2Department of Otolaryngology – Head and Neck Surgery, University of Mississippi Medical Center, Jackson, MS

Merkel Cell Carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin malignancy. There is rising incidence of MCC worldwide with head and neck being the most common primary site. At diagnosis, a significant proportion of patients are known to have metastasis to secondary locations at diagnosis with nodal metastases in 15-32% of patients and 5-12% with metastasis at distant sites1-5.MCC maintains a three-fold higher disease mortality than melanoma, with a predilection for patients who are elderly, immunosuppressed, and have history of significant sun exposure. 80% of MCC tumors are caused by Merkel Cell Polyoma Virus (MCPyV), a commensal virus of the human skin with the other major causative factor being UV light exposure6. The tendency for progression and early metastasis emphasizes the need for early detection, early diagnosis, and prompt initiation of treatment for this disease pathology6-7.

Due to the rarity of this pathology, there is a lack of prospective randomized clinical trials (RCTs) comparing treatment approaches and most of the data is retrospective in nature and therefore low-level evidence. NCCN guideline recommendations for clinically localized MCC is complete excision of primary lesion with 1-2cm margins and sentinel lymph node biopsy (SLNB). Mohs surgery may be utilized for lesion excision in appropriate circumstances. Patients with clinical evidence of nodal metastases may undergo ultrasound and fine needle aspiration to detect lymph node metastases preoperatively and should be recommended to undergo nodal dissection and/or radiation therapy8.

While imaging is encouraged in most cases of MCC, there is no consensus on what appropriate imaging should be with options including regional ultrasound, CT scan(s) and whole-body PET/CT8. The importance of baseline imaging has been shown in several studies, including Singh et al. who found that occult metastatic disease resulted in upstaging in 12-20% of patients with MCC presenting without suspicious H&P findings9. Several studies have indicated that whole body PET is more sensitive for detecting occult metastatic disease at baseline10. Zijlker et al. evaluated ultrasound and PET/CT as baseline imaging and found that 23% of patients in their study group with clinically localized MCC were upstaged to stage III disease with PET/CT and 3% were upstaged to stage IV disease. Therapeutic management was altered by 22% due to PET/CT imaging11. While this modality can provide a high rate of upstaging, sentinel lymph node biopsy (SLNB) remains the most reliable tool to identify subclinical nodal disease in patients with negative preoperative imaging4,12.

MCC has been shown to be a radiosensitive tumor and radiation therapy (RT) should be considered post-operatively in cases with high-risk features, close or positive margins or as an alternative to surgery in patients who are poor candidates8.  Radiation has been utilized as a primary modality of treatment in Australia and New Zealand with growing retrospective evidence showing relatively high local and regional control rates13. Use of adjuvant RT has been shown to improve rates of local control and overall survival in several retrospective studies regardless of tumor stage. Because of this, some advocate for consideration of adjuvant radiation after surgical excision in all cases of this high-risk pathology14-15. In contrast, a RCT of 83 patients with Stage I MCC found that was no improvement in overall survival (OS) or progression free survival (PFS) in patients undergoing adjuvant RT versus those undergoing clinical observation after surgical excision without high-risk features. However, there was a decreased rate of regional recurrence in the adjuvant RT group16.

MCC patients with distant metastatic disease represent a challenging cohort of patients that has traditionally had fairly dismal survival when treated with cytotoxic chemotherapy, with a median progression-free survival of approximately 3 months and progressive disease developing in 90% of patients within 10 months17. Immune checkpoint inhibitors (ICIs), in particular PD1/PDL1 inhibitors, have demonstrated potential to provide improved progression-free and overall survival compared to chemotherapy in MCC with distant metastatic disease. Virus-associated cancers, wherein viral antigens serve as tumor-specific antigens, have been proposed as a mechanistic marker than can predict response to anti-PD-1 therapy18. Several studies have shown that approximately 50% of Merkel cell carcinomas express PD-1 on tumor-infiltrating lymphocytes and express PD-L1 on tumor cells or infiltrating macrophages in an “adaptive resistance” pattern19-22.

JAVELIN Merkel 200 Phase II trial results demonstrated an overall response rate (ORR) of 62.1% using Avelumab as first-line therapy in patients with metastatic MCC, with a duration of response for over six months in 83% of responders. When used as a second-line therapy in patients with metastatic disease after failure of ³1 line of prior chemotherapy, the ORR was 33%, which is higher than ORRs reported in recent observational studies of second line chemotherapy23. Responses were shown to be durable in this population as well with estimated proportion of responses lasting greater than one year at 74%. This landmark trial led to the approval of Avelumab for MCC treatment in 201724. A Phase II trial of first-line therapy with pembrolizumab in 26 patients with advanced Merkel-cell carcinoma was found to have an ORR of 56%. Tumor regression appeared to be durable within an observation period of up to 9.7 months after initial documentation of response with progression free survival of 67% at 6 months. Responses were observed in both patients with virus-positive and virus-negative tumors and responses were not found to be correlated with PD-L1 expression18.  Treatment of advanced MCC with immunotherapy shows promising potential for long-term benefit not previously achieved with chemotherapy.

Immunotherapy as also been evaluated in the neoadjuvant setting. In the CheckMate 358 study, 39 patients received nivolumab for approximately 4 weeks prior to planned surgical resection, of which, 36 underwent surgery. There were high rates of pathologic complete response (pCR 47.2%) and radiographic response (54.5%) with responders having prolonged recurrence-free survival and no patients with pCR experiencing a tumor relapse within 19.3 months of mean follow up postoperatively25. This study has demonstrated that immunotherapy should be further explored as a potential adjunct to surgery in patients with MCC.

Understanding optimal duration of immunotherapy treatment in patients with metastatic MCC is essential. A study of 40 patients with metastatic MCC found that 35% of patients experienced progressive disease within a median of 12.3 months after immunotherapy discontinuation, including 26% of patients with a complete response, 57% of patients with a partial response and in 100% of those with stable disease. PFS after treatment cessation was 21 months. Of those who were able to be restarted on immunotherapy after progressive disease, response rate was 75%26. While the rate of progressive disease was lower in patients with complete response, this data is directly in contrast to the data for metastatic melanoma, where patients who cease treatment in a CR setting have durable remissions and a low incidence of relapse indicating that the same does not hold true for metastatic MCC. Despite this, it is promising that a high response rate remained in patients who progressed once they reinitiated ICI treatment.

Unfortunately, once ICIs have failed in the setting of advanced MCC, patients are left with very limited treatment options. Preliminary translational investigation has shown antineoplastic effects of dimethyl fumarate (DMF) in melanoma which Gambichler et al. sought to evaluate in MCC. Three different MCC virus negative cell lines were exposed to varying doses of DMF and all three showed significant reduction in cell viability and proliferation. This preliminary data warrants further exploration27.

Circulating tumor DNA has emerged as a predictive and prognostic tool for evaluating treatment response and early detection of relapse in several different forms of cancer28-30. There is emerging evidence for the utilization of this technology in MCC. In a pilot study, Park et al. demonstrated that ctDNA is both a sensitive biomarker of minimal residual disease and early relapse after definitive treatment. They also found that serial ctDNA testing may also be able to be used to risk-stratify patients who are more or less likely to respond to ICIs31. Akaike et al. performed a prospective study on 328 blood samples from 125 patients and further demonstrated support for this testing as a marker of early recurrence32. Future studies are needed to ascertain the role of ctDNA in MCC management, however it holds promise as a potential prognostic indicator and as a marker of early recurrence.

As MCC occurs most frequently in the head and neck region, it is crucial that we are aware of its rising incidence and new treatment potentials on the horizon. While ICIs have emerged as a promising treatment tool for advanced stage MCC, further research and clinical trials are needed to refine optimal treatment regimens in this aggressive disease pathology.

 

References

  1. Harms KL, Healy MA, Nghiem P, et al. Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System. Ann Surg Oncol. 2016;23(11):3564-3571. doi:10.1245/s10434-016-5266-4
  2. Bleicher J, Asare EA, Flores S, Bowles TL, Bowen GM, Hyngstrom JR. Oncologic outcomes of patients with Merkel Cell Carcinoma (MCC): A multi-institutional cohort study. Am J Surg. 2021;221(4):844-849. doi:10.1016/j.amjsurg.2020.08.013
  3. van Veenendaal LM, van Akkooi ACJ, Verhoef C, et al. Merkel cell carcinoma: Clinical outcome and prognostic factors in 351 patients. J Surg Oncol. 2018;117(8):1768-1775. doi:10.1002/jso.25090
  4. Zijlker LP, Bakker M, van der Hiel B, et al. Baseline ultrasound and FDG-PET/CT imaging in Merkel cell carcinoma. Journal of Surgical Oncology. 2023;127(5):841-847. doi:10.1002/jso.27193
  5. Fitzgerald TL, Dennis S, Kachare SD, Vohra NA, Wong JH, Zervos EE. Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States. Am Surg. 2015; 81:802–06. [PubMed: 26215243]
  6. Silling S, Kreuter A, Gambichler T, Meyer T, Stockfleth E, Wieland U. Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma. Cancers (Basel). 2022;14(24):6176. doi:10.3390/cancers14246176
  7. Wang AJ, McCann B, Soon WCL, et al. Merkel cell carcinoma: a forty-year experience at the Peter MacCallum Cancer Centre. BMC Cancer. 2023;23(1):30. doi:10.1186/s12885-022-10349-1
  8. Bichakjian CK, Olencki T, Aasi SZ, et al. Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2018;16(6):742-774. doi:10.6004/jnccn.2018.0055
  9. Singh N, Alexander NA, Lachance K, et al. Clinical benefit of baselineimaging in merkel cell carcinoma: analysis of 584 patients.J Am AcadDermatol. 2021;84(2):330‐339.
  10. Treglia G., Kakhki V.R.D., Giovanella L., Sadeghi R. Diagnostic Performance of Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography in Patients with Merkel Cell Carcinoma: A Systematic Review and Meta-Analysis. Am. J. Clin. Dermatol. 2013;14:437–447. doi: 10.1007/s40257-013-0040-x.
  11. Zijlker, LP et al. Baseline ultrasound and FDG-PET/CT imaging in Merkel cell carcinoma. J Surg Oncol 2023;127:841-847.
  12. George A, et al. Nucl Med Commun 2014;35:282-290; Hawryluk EB, et al. J Am Acad Dermatol 2013;68:592-599; Siva S, et al. J Nucl Med 2013;54:1223-1229
  13. Kok DL et al. The changing paradigm of managing Merkel cell carcinoma in Australia: An expert commentary. Asoa-Pac J Clinic Once 2020;16:312-319.
  14. Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J ClinOncol. 2007;25(9):1043-1047.
  15. Harrington C, Kwan W. Radiotherapy and conservative surgery in the locoregional management of Merkel cell carcinoma: the British Columbia Cancer Agency Experience. Ann Surg Oncol. 2016;23(2):573-578.
  16. Jouary T et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multi centric prospective randomized study. Ann Once. 2012 Apr;23(4):1074-80.
  17. Iyer J, Blom A, Doumani R, et al.. Response rate and durability of chemotherapy for metastatic Merkel cell carcinoma among 62 patients. J Clin Oncol 2014;32:52.
  18. Ngiem PT et al. PD-1 Blockade with Pembrolizumab in Advance Merkel-Cell Carcinoma N Engl J Med. 2016 June 30;374(26):2542-2552.
  19. Afanasiev OK, Yelistratova L, Miller N, et al. Merkel polyomavirus-specific T cells fluctuate with Merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res. 2013;19:5351–5360.
  20. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37. [PMC free article] [PubMed] [Google Scholar]
  21. Lipson EJ, Vincent JG, Loyo M, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res. 2013;1:54–63. [PMC free article] [PubMed] [Google Scholar]
  22. Dowlatshahi M, Huang V, Gehad AE, et al. Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T-cell exhaustion in reducing T-cell responses. J Invest Dermatol. 2013;133:1879–1889.
  23. Kaufman et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ³1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. Journal for ImmunoTherapy of Cancer (2018) 6:7. DOI 10.1186/s40425-017-0310-x
  24. D’Angelo SP, Russell J, Lebbé C, et al. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial. JAMA Oncol. 2018;4(9):e180077. doi:10.1001/jamaoncol.2018.0077
  25. Topalian SL, Bhatia S et al. Neoadjuvant Nivolumab for patient with Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial. J Clin Oncol 38:2476-2487.
  26. Weppler AM et al. Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation. European Journal of Cancer. 2023;183:109-118. doi:10.1016/j.ejca.2023.01.016
  27. Gambichler T, et al. The Antineoplastic Effect of Dimethyl Fumarate on Virus-Negative Merkel Cell Carcinoma Cell Lines: Preliminary Results. Cancers (Basel). 2023;15(2):547. doi:10.3390/cancers15020547.
  28. Powles T et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432-437. https://doi.org/10.1038/s41586-021-03642-9
  29. Bratman SV, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. 2020;1(9):873-881.
  30. Chera BS, et al. Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J Clin Oncol. 2020;38(10):1050-1058. 
  31. Park, S.J. et al. Circulating Tumor DNA as a Predictive Biomarker in Merkel Cell Carcinoma. J. Am. Acad. Dermatol. 2022, 87, 1209–1211.
  32. Akaike, T. et al. The Relationship between Circulating Tumor DNA with Merkel Cell Carcinoma Tumor Burden and Detection of Recurrence. J. Clin. Oncol. 2022, 40 (Suppl. 16), 9566.

 

 

 

Published on May 10, 2023 by AHNS Webmaster

AHNS Virtual Education Series: “Exploring Controversies in Management of Cutaneous Malignant Melanoma of the Head and Neck”


AHNS Virtual Education Series

Presented by the AHNS Cutaneous Cancer Section
“Exploring Controversies in Management of Cutaneous
Malignant Melanoma of the Head and Neck”
May 17, 2023 at 7:00 PM Eastern Time

Many advances have been made in the management of cutaneous malignant melanoma of the head and neck over the last decade with results from the MSLT I and II trials guiding our surgical management and increased utilization of immunotherapy for advanced stage melanoma. However, there is variability in how physicians apply this to the head and neck cohort, such as differences in the management of positive sentinel lymph node with completion lymphadenectomy versus observation, when to consider neoadjuvant or adjuvant immunotherapy, or the safe utilization of Mohs micrographic surgery for management of melanoma. This webinar will provide a lively discussion of relevant real-life cases that cover the breadth of these controversies to discuss best practices and evidence-based management of these patients.

Moderator:
Karen Y. Choi, MD, FACS

Panelists:
Mary Stevenson, MD – Mohs Dermatology – NYU (New York University)
Kelly Malloy, MD – Head and Neck Surgery – University of Michigan
Kerwin Shannon, FRACS – Head and Neck Surgery – Melanoma Institute Australia
Leslie Fecher, MD – Medical Oncology, University of Michigan
Devarati Mitra, MD, PhD- Radiation Oncology – MD Anderson Cancer Center
Jane Messina, MD – Dermatopathology – Moffitt Cancer Center

One-hour session is free to all registrants!

Published on May 3, 2023 by AHNS Webmaster

Today at 7:00 PM EST – AHNS Fellows’ Virtual Tumor Board – Advances in the Management of Melanoma


ZOOM Login:
https://us06web.zoom.us/j/81850036177?pwd=L1JoSVZvR20yNzdmTG1LT1VSQ0ZSdz09

Meeting ID: 818 5003 6177
Passcode: 131694

Published on April 27, 2023 by AHNS Webmaster

AHNS 2023 Register Now + Keynote Lecturer: Rebecca Richards-Kortum PhD

“Welcoming Back the World: Striving for Innovation, Quality, Compassion and Collegiality”
July 8-12, 2023, at The Palais des Congrès Convention Center in Montreal, CN

REGISTER NOW!

The AHNS has booked discounted group rates at three hotels. Please click on the following link to view the hotel options and rates: AHNS Hotel Reservations

A PROGRAM HIGHLIGHT

Keynote Lecturer: Rebecca Richards-Kortum PhD
The AHNS Program Service is honored to have Rebecca Richards-Kortum PhD as the Keynote Lecturer.

Guided by the belief that all of the world’s people deserve access to health innovation, Rebecca Richards-Kortum’s research and teaching focus is on the development of low-cost, high-performance technologies for remote and low-resource settings. She is known for providing vulnerable populations with access to life-saving health technologies that address diseases and conditions that cause high morbidity and mortality, such as cervical and oral cancer, premature birth, sickle cell disease and malaria.

Current technologies are being tested and applied through multidisciplinary collaborations with clinicians and researchers at Rice, the University of Texas MD Anderson Cancer Center, Baylor College of Medicine, University of Texas Health Science Center-Houston, and Northwestern University. International collaborations include researchers, clinicians and medical professionals at the London School of Hygiene & Tropical Medicine and its MARCH (Maternal, Adolescent, Reproductive and Child Health) Centre; Barretos Cancer Hospital in Brazil; the Queen Elizabeth Central Hospital in Blantyre, Malawi; the University of Malawi College of Medicine and the University of Malawi Polytechnic. Over the past few years, Richards-Kortum and collaborators have translated technologies from North America to both low- and medium-resource developing countries in Malawi, China, Botswana, El Salvador, and Brazil.

For two decades, Richards-Kortum’s laboratory has focused on translating research that integrates advances in nanotechnology and molecular imaging with microfabrication technologies to develop optical imaging systems that are inexpensive, portable, and provide rapid point-of-care diagnosis. When used with contrast agents, these rugged and portable optical imaging systems detect molecular signatures of pre-cancer, assess tumor margins, and monitor a patient’s response to therapy.

We look forward to her presentation on Monday, July 10th at 10:00am.

Please visit the AHNS website to view the scientific program to include the Saturday course series and other Keynote and Named Lecturers.

AHNS Additional Registrant Onsite Services

In addition to the newly added Camp AHNS Daycare Services, AHNS will also have a Prayer Room and Mother’s Room for registrants to use during their time at the conference.

The AHNS has booked discounted group rates at three hotels. Please click on the following link to view the hotel options and rates: AHNS Hotel Reservations

Register Now!

Published on April 22, 2023 by AHNS Webmaster

What’s New on AHNS.info Website- April 2023

Many of your AHNS Sections and Services have been hard at work providing excellent and educational webinar contents to you, our members, fellows and colleagues across the globe. Take a look at the new material available now on the website:

New Content on the AHNS Website!

Click on the highlighted links below to see What’s New from AHNS!

NEW – American Head and Neck Society (AHNS) is honored to launch the AHNS Peer Support Network Program.

NEW – Check out the NEW AHNS Find-A-Physician Page
The Find A Physician feature is now available for viewing AHNS member profiles and specialities. To search and review existing profiles, click the Find-A-Physician tab on the AHNS home page.

  • To create your profile, or to modify your existing profile:
  • Log in to the AHNS website.
  • In the Member Panel, click #5 to create a new profile, and click #6 if you already have a profile and wish to update it.
  • Members are encouraged to add their social media handles in order to be tagged on AHNS Instagram and Twitter pages. Both AHNS members and non members can view profiles.
  • If you are having trouble accessing your account click here

NEW Virtual Tumor Board from the CDMS:
“TORS or RT?: Oropharynx Dilemmas”, presented by the AHNS Mucosal Malignancy Section

Check out the AHNS Job Board!
The job postings are available to AHNS Members – be sure to log in to see the listings and to post new positions you want to share with the AHNS membership. Both members and non members can post listings so be sure to forward on this great opportunity to your colleagues.

AHNS Cutaneous Section is seeking authors for the Heads Up! Blog! If you have an area of expertise and would like to share your perspective, reach out to us at [email protected]

Graduates of AHNS ATC Fellowship from 2015 to 2020 check your email for the subject line AHNS Survey: Fellowship and Early Career Practice Challenges.
AHNS Young Members Service is conducting a mixed-methods study to explore attitudes and challenges early career head and neck surgeons face when transitioning to independent practice following fellowship training.
We hope the information gained from this study will help define areas for improvement in the AHNS fellowship curriculum by identifying ways to formalize guidance in early-career practice building.
This survey will take approximately 5-7 minutes to complete. If you did not receive the email please email: [email protected]

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News and Announcements

  • Journal Club May 2025 hosted by the Cutaneous Cancer Section for Skin Cancer Awareness Month May 23, 2025
  • AHNS YMCP Episode 11 – Melina Windon, MD, Janice Farlow, MD, Eric Gantwerker, MD May 8, 2025
  • Artificial Intelligence in Management of H&N Cancer: New Horizons Presented April 28, 2025
  • A conversation with Dr. Uppaluri: Neoadjuvant Therapy for Advanced H&N Mucosal April 25, 2025
  • The End of April Head and Neck Cancer Awareness Month Approaches! April 23, 2025

AHNS Meetings and Events

AHNS 2025 Annual Meeting
Held during the Combined Otolaryngology Spring Meetings (COSM)

May 14-18, 2025
Hyatt Regency New Orleans
New Orleans, Louisiana

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