Zhang-Hui Yue, Yan Wang?, Fang Fang Jian-Fang Sun

1Department of Pathology,Hospital for Skin Diseases(Institute of Dermatology),Chinese Academy of Medical Sciences and Peking Union Medical College,Nanjing,Jiangsu 210042,China; 2Department of Dermatologic Surgery, Hospital for Skin Diseases (Institute of Dermatology), Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China.

Abstract

Keywords: Merkel cell carcinoma, squamous cell carcinoma, actinic keratosis, concurrence, case report

Introduction

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy that has a high rate of metastasis and mortality and occurs mainly in Caucasians. Although MCC is a neuroendocrine tumor,its specific etiology is unclear and its origin remains controversial. Like actinic keratosis (AK),MCC is often associated with ultraviolet radiation.AK can be regarded as a precancerous lesion of squamous cell carcinoma(SCC),andseveralcasesofmixedMCCandSCC have been reported previously. However, whether MCC can arise from AK remains unclear. We herein describe a Chinese woman with facial MCC and SCC based on AK,which may provide a clue for this question.

不同結(jié)晶時(shí)間下淀粉球晶熱力學(xué)性質(zhì)如表 2所示。由表2可以看出，淀粉球晶的起糊溫度（To）、峰值溫度（Tp）、終止溫度（Tc）和焓值（△H）顯著高于原淀粉，與Cai等[16]的研究結(jié)果一致；淀粉球晶的起糊溫度隨結(jié)晶時(shí)間的增加而升高，結(jié)晶24 h后淀粉球晶的起糊溫度、峰值溫度、終止溫度和焓值分別達(dá)到75.09 ℃、90.96 ℃、107.03 ℃和17.44 ℃。表明形成的淀粉球晶相對(duì)于蠟質(zhì)玉米淀粉結(jié)構(gòu)較為緊密，在較高溫度下才能破壞晶體結(jié)構(gòu)；吸熱焓值和淀粉結(jié)晶度有一定的對(duì)應(yīng)關(guān)系[25]，焓值越高，結(jié)晶度也相應(yīng)增加，這和XRD測(cè)得結(jié)果相吻合，也和Liu等[26]報(bào)道的結(jié)果一致。

Case report

An 86-year-old woman presented with a 3-year history of multiple dark brown patches on her face and hand. One year before presentation, a coin-sized patch appeared on her left cheek and slowly developed, and the patch easily bled after scratching. No treatment was administered.Lesions on the left cheek and forehead grew quickly in the following months. A dermatological examination was performed(Fig.1A–D),and no other obvious abnormalities were found in a physical examination.

Figure 1. Clinical manifestations of the patient with the concurrence of generalized actinic keratosis,Merkel cell carcinoma,and squamous cell carcinoma. (A) Two similar cauliflower-shaped tumors were present on the patient’s left cheek and temple (3.0×4.5 and 3.0×2.0cm2,respectively).(B)Brown papules were scattered on her face and neck.(C and D)Several conical elevated lesions with scales were present on her right hand.

A biopsy specimen taken from the patch two years ago revealed a diagnosis of AK(Fig.2A).Considering a clinical diagnosis of SCC, both tumors on her face were resected with a 1-cm margin.The histological characteristics of the left facial tumor suggested SCC (Fig. 2B), and immunohistochemical staining showed cytokeratin (CK) 20 positivity (Fig. 2C). The malignant cells were strongly positive for CAM5.2 (Fig. 2D) and partially positive for CD56 but negative for CK7,SOX-10,CK5/6,and S-100;these results confirmed the diagnosis of primary MCC.Additionally, based on the clinicopathological features of the frontal tumor, the diagnosis of SCC was confirmed(Fig.2E).The specimens from the patient’s right hand were pathologically diagnosed as AK (Fig. 2F). We recommended a combination of radiotherapy and chemotherapy after regional lymph node dissection, but the patient refused this treatment. She took Chinese herbal medicine for the next few years, and no abnormalities were noted after 3years of follow-up.The patient gave her agreement for this publication.

Discussion

Typical MCC usually presents in older patients with light skin tones and ranges in size from<1 to>2cm,appearing as a rapidly growing, painless, firm, nontender, shiny,flesh-colored, or bluish-red intracutaneous nodule that is most often located in sun-exposed areas.1The incidence has reportedly increased in the United States and European countries2but only a few cases of MCC have been reported in the Chinese population.

The diagnosis of MCC mainly depends on histological findings. MCC typically presents as a dermal mass that frequently extends into the subcutis.The tumor is composed of strands or nests of monotonously uniform round blue cells containing minimal cytoplasm and large basophilic nuclei with powdery dispersed chromatin and inconspicuous nucleoli.3The three main histologic patterns of MCC,namely the intermediate type,small cell type,and trabecular type, may help differentiate it from other entities.3Immunoreactivity for CK20 and CK5/6 distinguishes MCC from other undifferentiated tumors.CK20 is a fairly specific and sensitive marker for MCC and exhibits a characteristic paranuclear dot-like staining pattern.3In the present case,small cell lung cancer was excluded by positive CAM5.2 and CK20 staining. Lymphoma and malignant melanoma can be distinguished by S-100 protein expression.

Wide excision is the standard approach to the initial management of primary MCCs.A margin of at least 1 to 2cm of normal-appearing skin is recommended.4If the margins are close to or involved with the tumor,postoperative radiotherapy is indicated to increase the probability of achieving local disease control.In 2017,the USA Food and Drug Administration approved the first PD-1 receptor inhibitor,avelumab,for MCC treatment.4This approval has provided a new therapeutic choice for advanced MCCs, but avelumab is not yet available in China.The prognosis of MCC depends on diverse factors,including its histologic features, its Merkel cell polyomavirus (MCPyV) status, and the patient’s immune status.MCPyV-positive MCCs account for 80%of all MCCs and often have a better prognosis.5Although the 5-year overall survival rate is usually<55.8%,5localized primary tumors can be indolent and well-controlled with wide local excision alone in some patients.

Figure 2. Histopathologic findings of the patient with the concurrence of generalized actinic keratosis,Merkel cell carcinoma,and squamous cell carcinoma.(A)A biopsy specimen was taken from the left cheek 1year before presentation revealed a diagnosis of actinic keratosis.(B)Small cell carcinoma was shown by H&E staining(×100).(C)CK20 was weakly positive with a paranuclear dot pattern(×400).(D)CAM5.2 was positive(×400).(E)Marked cytologic atypia and keratosis were present in the tumor tissue,and solar keratosis-like changes could be seen in part of the epidermis, revealing SCC (H&E stain, ×400). (F) Actinic keratosis was present on the left hand (H&E stain, ×400).

MCCs occasionally coexist with other cutaneous tumors, such as basal cell carcinoma, SCC, AK, and seborrheic keratosis.MCC/SCC is the most common type of MCC-combined tumor with strong p53 and p63 labeling and MCPyV negativity.6Regrettably,an MCPyV detection test is not available in our institution.Ultraviolet irradiation and immunosuppression may be involved in the carcinogenesis of MCPyV-negative cases. In our case,the original AK lesion became MCC, and SCC occurred independently.Whether MCC transformed from AK in the present case is unclear because there was no continuity in the two cell types or the nonexistence of transitional cells.Based on the above theories and findings,we speculate that the three tumors in our patient originated from two distinct precursor cells and were influenced by a common carcinogen; alternatively, they may have arisen from the same pluripotent epidermal stem cell as a common reaction to chronic exposure to ultraviolet light and MCPyV.

In summary,the present case is very unusual because this is a Chinese patient reported to have co-occurrence of AK,SCC, and MCC. One of the original hypotheses of MCC might be supported by our patient’s history of a general distribution of AK and the development of MCC at a site originally exhibiting AK. However, further research is needed to confirm our conjectures.