Original contributionSupport for p63 expression as an adverse prognostic marker in Merkel cell carcinoma: report on a Canadian cohort☆
Introduction
Since its discovery in 1972 [1], neuroendocrine carcinoma of the skin, or Merkel cell carcinoma (MCC), has been a focus of interest in the medical literature. An uncommon, aggressive tumor, typically affecting elderly patients [2] (Fig. 1A), it has sparked controversy and scientific investigation from several perspectives. For instance, its cell of origin, be it eccrine, keratinocytic, neuroendocrine, or stem cell, remains enigmatic [3]. Its morphologic diversity, ranging from pure neuroendocrine (Fig. 1B) to a combined phenotype (the latter including neuroendocrine and other epithelial or sarcomatous elements; Fig. 2), has also fueled interest [4]. The recent discovery that MCCs incorporate Merkel cell polyoma virus (MCPyV) in their genetic material [5] prompted renewed enquiry into the potential etiopathogenic and prognostic implications of this finding. Of greatest practical significance, however, is the poor prognosis associated with MCC. Recent estimates of 5-year survival have been quoted at 40%, a human impact that may be compounded by the increasing annual incidence of the tumor [2].
The aggressive biological behavior of MCC has stimulated unstinting efforts to identify features of prognostic significance. These have focused on (i) clinical factors such as age, sex, anatomical site, and stage of disease [2], [6]; (ii) morphologic parameters including tumor size [2], [6], [7], [8], [9], [10], [11], cell size [7], [10], [11], proliferative rate [10], [11], [12], lymphovascular invasion (LVI) [7], [8], [9], [10], [11], and tumor-infiltrating lymphocytes [8], [10], [11], [13]; and, more recently, (iii) immunohistochemical expression of MCPyV [10], [14], [15], [16], [17], [18], [19] and/or of proteins related to the cell cycle such as c-KIT [15], [20], Bcl-2 [21], [22], p53 [10], [11], [15], [19], retinoblastoma protein [17], [19], survivin [21], [23], and p63 [10], [11], [12], [18], [19], [23], [24]. With the exception of tumor stage, a validated prognostic indicator, other factors remain unconfirmed as practically applicable tools.
In this context, our attention was drawn to promising recent studies linking immunohistochemical expression of p63 protein with an adverse outcome in MCC [10], [12], [18], [23], [24]. Its published role as an independent prognostic factor in localized, nonmetastatic disease [10] offers special potential in informing treatment decisions. Some studies evaluating this variable have yielded conflicting results [11], [19]. Hence, our aim was to investigate it further in a relatively large cohort of eastern Canadian cases of MCC, subgroups of which have formed the basis of previous reports [4], [25].
Section snippets
Methods
Ethical approval to pursue the study was obtained from all relevant authorities. All cases of MCC diagnosed between 1990 and 2012 within the province of Nova Scotia and at the Saint John Regional Hospital (New Brunswick) were identified through the Nova Scotia Cancer Registry (operated by Cancer Care Nova Scotia) and the New Brunswick Cancer Registry (operated by the New Brunswick Cancer Network). Blocks, slides, and pathology reports were obtained from the original hospitals.
Demographic and
Clinical features
The Cancer Registries identified 90 patients, 83 of which were included in the study. Five patients were excluded because slides and blocks were unavailable, or deeper levels no longer contained tumor cells, and 2 patients were excluded because a definitive diagnosis of MCC could not be verified. A summary of the clinical features is presented in Table 1. Follow-up times ranged from 3 to 720 weeks (mean, 174.7 ± 176.5 weeks). At last follow-up, 32 patients (38.6%) were alive and 51 patients
Discussion
The immunohistochemical expression of p63 in routine histopathology has various applications. p63 is crucial for differentiation and proliferation of stratified epithelia (eg, squamous, urothelial, and bronchial), where it is normally expressed in cells of the basal layer [26]. It is also expressed in the basal layer of prostate glands, in myoepithelial cells of the breast and salivary glands, in cytotrophoblasts, and in thymic epithelial cells [26]. p63 immunohistochemistry can therefore be
Acknowledgments
The authors gratefully acknowledge receipt of the Capital District Health Authority (CDHA) Resident Research Grant and the support provided by the CDHA Department of Pathology. The authors also thank Cancer Care Nova Scotia and the New Brunswick Cancer Network for their important contributions to the study. They acknowledge the cooperative spirit of laboratory personnel in the following outside hospitals who provided pathology materials: Saint John Regional Hospital, Dartmouth Regional
References (36)
- et al.
Pathologic 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
(2010) Primary neuroendocrine (Merkel cell) carcinoma of the skin: morphologic diversity and implications thereof
Hum Pathol
(2001)- et al.
Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival
J Am Acad Dermatol
(1997) - et al.
Expression of p63 is the sole independent marker of aggressiveness in localized (stage I-II) Merkel cell carcinomas
Mod Pathol
(2011) - et al.
Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma
J Invest Dermatol
(2011) - et al.
Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma
Hum Pathol
(2012) - et al.
Merkel cell carcinoma: correlation of KIT expression with survival and evaluation of KIT gene mutational status
Hum Pathol
(2010) - et al.
Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma
Modern Pathol
(2008) - et al.
The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites
Hum Pathol
(2012) - et al.
Merkel cell polyomavirus infection in both components of a combined Merkel cell carcinoma and basal cell carcinoma with ductal differentiation; each component had a similar but different novel Merkel cell polyomavirus large T antigen truncating mutation
Hum Pathol
(2013)
Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population
Hum Pathol
Trabecular carcinoma of the skin
Arch Derm
Which are the cells of origin in Merkel cell carcinoma?
J Skin Cancer
Clonal integration of a polyomavirus in human Merkel cell carcinoma
Science
Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study
J Cutan Pathol
Merkel cell carcinoma: histologic features and prognosis
Cancer
Five hundred patients with Merkel cell carcinoma evaluated at a single institution
Ann Surg
Increasing tumor thickness is associated with recurrence and poorer survival in patients with Merkel cell carcinoma
Ann Surg Oncol
Cited by (42)
Merkel cell carcinoma: an update
2023, Human PathologyRelationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal
2021, Human PathologyCitation Excerpt :A dual etiopathogenesis for the tumor exists, the majority of cases being linked to the Merkel cell polyomavirus (MCPyV) and the remainder to ultraviolet radiation–induced genetic damage [2]. The aggressive behavior of MCC has prompted efforts to identify clinical, histopathological, immunophenotypic, and genetic factors of prognostic relevance [3–10]. Clinical stage and viral status are of primary importance in this setting.
T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma
2020, Journal of Investigative DermatologyCitation Excerpt :However, the 5-year mortality rate in patients with stage Ia disease is approximately 20%, underscoring a critical unmet need to identify novel, stage-independent prognostic biomarkers (Fitzgerald et al., 2015; Tarantola et al., 2013). Although various clinical and pathologic variables have been investigated as prognostic biomarkers in MCC (Albores-Saavedra et al., 2010; Andea et al., 2008; Asioli et al., 2011; Feldmeyer et al., 2016; Fleming et al., 2014; Güler-Nizam et al., 2009; Skelton et al., 1997; Tarantola et al., 2013), integrity of the host immune system has emerged as the most significant. Immunosuppressed patients exhibit an increased propensity to develop MCC (Engels et al., 2002; Penn and First, 1999; Tadmor et al., 2012).
p63 expression in Merkel cell carcinoma: comparative immunohistochemistry invokes TAp63 as the dominant isoform involved
2020, Human PathologyCitation Excerpt :A semiquantitative assessment of nuclear positivity by these antibodies was conducted using an H-score. Briefly, the intensity of staining was graded as 0 (negative), 1 (weak), 2 (moderate), or 3 (strong), as illustrated previously [13]. The H-score was calculated in the standard manner (ie, the sum of the grades multiplied by the relevant percentage of tumor volume with that grade of intensity, yielding a score in the range of 0 to 300).
- ☆
Disclosure: Financial support was received from the Capital District Health Authority Resident Research Fund and from the Capital District Health Authority Department of Pathology. The authors report no conflicts of interest.