Merkel cell carcinoma: The prognostic implications of an occult primary in stage IIIB (nodal) disease

doi:10.1016/j.jaad.2011.09.009

Journal of the American Academy of Dermatology

Volume 67, Issue 3, September 2012, Pages 395-399

https://doi.org/10.1016/j.jaad.2011.09.009 Get rights and content

Background

Merkel cell carcinoma is a highly aggressive cutaneous malignancy with a high rate of lymph node and distant metastatic disease. Approximately one third of patients present with stage IIIB (nodal) disease.

Objective

This cohort study was performed to analyze the outcome of patients with stage IIIB disease with or without an occult primary.

Methods

The details of 91 patients with stage IIIB (nodal) Merkel cell carcinoma treated curatively between 1985 and 2010 at 3 tertiary referral hospitals in Australia were reviewed. Kaplan-Meier plots were used with the primary end point being overall survival. Secondary end points were disease-free survival and relapse-free survival. A multivariate Cox regression analysis was performed for known prognostic factors.

Results

Of 91 patients with stage IIIB (nodal) disease, 36 (40%) had an occult primary. A total of 78 patients (86%) had surgery and 79 patients (87%) had definitive or adjuvant radiotherapy. With a median follow-up of 4.3 years, those with an occult primary did significantly better in terms of overall survival, disease-free survival, and relapse-free survival. On multivariate analysis, occult primary and patient age were the only factors predicting survival with hazard ratios of 0.30 (95% confidence interval 0.13-0.67) and 1.64 (95% confidence interval 1.13-2.38), respectively.

Limitations

This is a retrospective study over several decades with patients treated using various modalities.

Conclusion

This study indicates that for patients with stage IIIB (nodal) Merkel cell carcinoma, the presence of an occult primary confers a significantly better prognosis that may have implications in the future staging and treatment of patients with stage III disease.

Section snippets

Patient selection criteria

Eligibility for this study included a diagnosis of MCC between 1985 and 2010 treated with curative intent at 3 tertiary referral hospitals in Queensland and Westmead Hospital, Sydney, Australia. Patients were identified using either the Queensland Oncology Repository or the Westmead Hospital MCC database. All diagnoses were primary (not recurrent) disease and were verified through examination of clinical records. Patients were staged using clinical examination, computed tomography, positron

Patient characteristics

The median age at diagnosis for this cohort of 91 patients with stage IIIB nodal disease was 74 years (range, 41-91 years), and 63 patients (69%) were male. An occult primary was present in 36 patients (40%) with nodal involvement in the head and neck region of 23 of these patients (64%). For known primaries, a head and neck primary was present in 22 patients (40%), upper limb in 11 (12%), trunk in 9 (10%), and lower limb in 13 (14%). Patient demographic data are detailed in Table I.

Treatment

All 91

Discussion

This study represents one of the largest series of stage IIIB (nodal) MCC treated with curative intent in the literature. The prognostic significance of having an occult primary has been established in this study by conferring a 70% reduced risk of dying from MCC compared with patients with a known primary and nodal MCC. This was previously described in the Trans-Tasman Radiation Oncology Group 96:07 study using chemoradiotherapy for high-risk MCC where having an occult primary significantly

Conclusions

This large retrospective analysis of patients with stage IIIB (nodal) MCC suggests that patients with an occult primary have a 70% reduction in death and a 69% reduction in the risk of relapse. Current staging systems do not adequately accommodate the staging of patients with an occult primary and some refinement is required.

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Citation Excerpt :
In 12% to 15% of cases, MCC will present in 1 or more lymph nodes without an evident cutaneous primary site.6,8,9 The prognosis of MCC of unknown primary site compared to MCC with known primary site has been well studied, with evidence suggesting that an unknown primary site is associated with a better prognosis.5,6,10,11 Although few studies have investigated the prognostic utility of tumor primary site beyond unknown primaries, 1 recently published study identified MCC in the head/neck region to have a worse overall survival than tumors in the extremities.12
Merkel cell carcinoma (MCC) primary site has not been fully investigated as a potential prognostic factor.
To determine the incidence by tumor primary site of death due to MCC.
We undertook a retrospective analysis of the Survival, Epidemiology, and End Results database. MCC patients treated between 1973 and 2016 were grouped by tumor primary site and a competing risks analysis was performed to test the impact of primary site on disease-specific death. Cumulative incidence of Merkel cell carcinoma-specific mortality (CMMI) at 5 years was estimated for each primary site.
Of 9407 MCC patients identified, 6305 (67.0%) had localized disease, 2397 (25.5%) had regional metastasis, and 705 (7.5%) had distant metastasis. Tumor primary site was predictive of CMMI and varied by stage at diagnosis. Tumors involving the scalp/neck carried the highest CMMI among localized MCC (26.0%). Tumors involving the lip had the highest CMMI among MCC with regional metastasis (56.7%) and distant metastasis (82.1%).
Tumor size data were missing for a large proportion of patients, precluding stratification by stage according to current American Joint Committee on Cancer guidelines.
Probability of MCC disease-specific death varies by primary site. The primary site of the tumor may be useful as a prognostic indicator for MCC.
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Merkel cell carcinoma (MCC) is a high grade primary cutaneous neuroendocrine carcinoma and is among the most aggressive cutaneous malignancies. The rising incidence of MCC, together with its often rapidly aggressive course, underscore a critical need to recognize the histopathologic and the immunohistochemical features that inform its accurate diagnosis. In the current review, we summarize the current state of knowledge regarding the accurate diagnosis of MCC and the exclusion of other entities in the differential diagnosis. We provide a comprehensive review of genomic studies that identified the molecular-genetic drivers of MCC as well as a summary of studies identifying prognostic biomarkers that can facilitate risk stratification. Importantly, Merkel cell polyomavirus (MCPyV) appears to be causative in most cases of MCC and represents both a diagnostic and prognostic marker. Finally, as staging of MCC has undergone critical refinements with the introduction of the 8th Edition of the American Joint Committee on Cancer staging system, we provide an update on MCC staging. In particular, the prognostic significance of the sentinel lymph node (SLN) in MCC necessitates a systematic approach to its evaluation and diagnosis to ensure accurate and consistent risk stratification for patients, and we therefore provide a comprehensive overview of SLN evaluation in MCC. Finally, the intimate relationship between MCC and the integrity of the host immune system has led to paradigm-shifting therapeutic advances with the successful application of immune checkpoint blockade to treat patients with advanced disease, and we therefore summarize those studies and the correlative studies in which predictive biomarkers have been identified.
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Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with a high propensity for local recurrence and regional and distant metastases. The main treatment is surgery with narrow excision margins and draining nodes, plus or minus adjuvant radiotherapy (RT) on the surgical bed and/or lymph nodes. We performed a systematic review and meta-analysis of the benefits of adjuvant RT in MCC treatment. PubMed, EMBASE, and the Cochrane Library were systematically searched to identify relevant studies published before September 2018. Prospective trials and retrospective series comparing adjuvant RT vs. no RT in resected primary MCCs were included. Primary endpoint was to evaluate the outcomes of MCC patients who received adjuvant RT in term of overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) for OS and DFS were aggregated according to a fixed or random effect model. Secondary endpoints were local, locoregional, and distant DFS.
A total of 17,179 MCCs across 29 studies were analysed. There was a significant difference in OS between the RT and no RT arms (HR = 0.81, 95%CI 0.75–0.86, P < 0.001). There was also a significant difference in DFS in favour of adjuvant RT (HR = 0.45, 95%CI 0.32–0.62, P < 0.001). Adjuvant RT improved locoregional DFS and local DFS but not distant DFS (HR = 0.3, 95%CI 0.22–0.42; HR = 0.21, 95%CI 0.14–0.33, and HR = 0.79, 95%CI 0.49–1.14, respectively). Meta-regression analysis showed that high Newcastle–Ottawa scale scores, stage I–II MCCs, shorter follow-up durations, size >2 cm, and being of a younger age were associated with increased OS. This systematic review and meta-analysis suggests a survival and DFS benefit for postoperative radiation of MCCs. Intermediate stage MCCs derive the maximum benefit with local and regional relapses reduced by 80% and 70%, respectively. Conversely, distant metastases were not significantly prevented.
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View all citing articles on Scopus

: Funding sources: None.

: Conflicts of interest: None declared.

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Original articleMerkel cell carcinoma: The prognostic implications of an occult primary in stage IIIB (nodal) disease

Background

Objective

Methods

Results

Limitations

Conclusion

Section snippets

Patient selection criteria

Patient characteristics

Treatment

Discussion

Conclusions

Lancet Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma

Cancer

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

J Am Acad Dermatol

Merkel cell carcinoma: critical review with guidelines for multidisciplinary management

Cancer

Surgical management of Merkel cell carcinoma

Ann Surg

Effect of radiotherapy dose and volume of relapse in Merkel cell cancer of the skin

Int J Radiat Oncol Biol Phys

Role of postoperative radiotherapy in the management of Merkel cell

Am J Clin Oncol

Predictors of survival and recurrence in the surgical treatment of Merkel cell carcinoma of the extremities

J Surg Oncol

Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck

Head Neck

Merkel cell carcinoma: improved outcome with adjuvant radiotherapy

ANZ J Surg

Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin

J Clin Oncol

Merkel cell carcinoma: prognosis and treatment from a single institution

J Clin Oncol

Original article
Merkel cell carcinoma: The prognostic implications of an occult primary in stage IIIB (nodal) disease