Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus‐negative and combined Merkel cell carcinoma: A retrospective study

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin that is associated with Merkel cell polyomavirus (MCPyV). The clinical appearance and demographic characteristics of this tumor have been described using the mnemonic AEIOU: asymptomatic, expanding rapidly, immune suppression, older than 50 years, and ultraviolet‐exposed fair skin. In addition, MCC can be categorized based on morphology as pure MCC or combined MCC that exhibits neuroendocrine and other phenotypic elements. There is limited information regarding the clinical characteristics and prognosis of combined MCC. This retrospective study aimed to identify factors, such as ulceration or hyperkeratosis, that could predict MCPyV status and morphological variants. Twenty patients with MCC were divided into groups based on MCPyV status and morphology: MCPyV‐positive or MCPyV‐negative MCC and pure or combined MCC. The patients’ MCPyV status was immunohistochemically determined using the CM2B4 antibody to the MCPyV large T‐antigen. The patients’ clinicopathological characteristics were evaluated to identify predictors of MCPyV‐negative MCC and combined MCC. The presence of ulceration/hyperkeratosis predicted the presence of MCPyV‐negative MCC (80% of cases) and combined MCC (50% of cases). None of the 10 patients with MCPyV‐positive MCC had ulceration/hyperkeratosis. The clinical presence of ulceration/hyperkeratosis may help guide the diagnosis of MCPyV‐negative MCC and combined MCC.     

Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases

Summary Background A novel polyomavirus, the Merkel cell polyomavirus (MCPyV), has recently been identified in Merkel cell carcinoma (MCC). Objectives To investigate the specificity of this association through the detection, quantification and analysis of MCPyV DNA in lesional and nonlesional skin biopsies from patients with MCC or with other cutaneous diseases, as well as in normal skin from clinically healthy individuals. Methods DNA was extracted from lesional and nonlesional skin samples of patients with MCC or with other cutaneous diseases and from normal‐appearing skin of clinically healthy subjects. MCPyV DNA was detected by polymerase chain reaction (PCR) and quantified by real‐time PCR. Additionally, the T antigen coding region was sequenced in eight samples from seven patients. Results MCPyV DNA was detected in 14 of 18 (78%) patients with MCC, five of 18 (28%) patients with other skin diseases (P = 0·007) and one of six (17%) clinically healthy subjects. In patients with MCC, viral DNA was detected in nine of 11 (82%) tumours and in 10 of 14 (71%) nontumoral skin samples (P = 0·66). MCPyV DNA levels were higher in MCC tumours than in nontumoral skin from patients with MCC, and than in lesional or nonlesional skin from patients with other cutaneous disorders. Signature mutations in the T antigen gene were not identified in the two MCC tumour specimens analysed. Conclusions High prevalence and higher levels of MCPyV DNA in MCC supports a role for MCPyV in tumorigenesis. However, the high prevalence of MCPyV in the nontumoral skin and in subjects without MCC suggests that MCPyV is a ubiquitous virus.     

Merkel cell carcinoma in situ: New insights into the cells of origin

We report a case of a 71-year-old male who presented with a small skin-coloured plaque on his cheek. Histopathology demonstrated an intraepidermal carcinoma with follicular involvement. No evidence of dermal invasion was seen. Immunohistochemical studies showed areas of positive staining for CK20, EMA and synaptophysin. Histopathology findings were found to be most consistent with a diagnosis of intraepidermal carcinoma with features of Merkel cell carcinoma in situ, in combination with a squamous cell carcinoma in situ, with follicular involvement. Recent advances and findings suggest Merkel cell polyomavirus MCPyV-positive Merkel cell carcinoma and MCPyV-negative Merkel cell carcinoma have different cells of origin from different germ layers.     

Merkel细胞癌1例

患者男,56岁。腹部皮下结节4个月余,无自觉症状。体检：上腹部、中腹部及左季肋部可触及10余个散在皮下结节,直径0．5-1．8cm。组织病理示：瘤细胞呈巢团状、片状排列,浸润性生长,胞浆少。核膜清晰,核仁显著,部分可见核分裂相。免疫组化结果示：CK20（＋＋）,CKL（＋＋）,CgA（＋＋）,Syn（＋＋＋）,CD99（＋＋）,ki67〉70％。病理诊断：（腹壁）Merkel细胞癌。     

Merkel cell carcinoma with heterologous rhabdomyoblastic differentiation: the role of immunohistochemistry for Merkel cell polyomavirus large T-antigen in confirmation

Merkel cell carcinoma (MCC) represents an uncommon and lethal form of cutaneous malignancy. Historically, the pathogenesis of MCC has been presumed to be linked to ultraviolet light overexposure, but recently, it has been documented that some examples harbor polyomavirus genome, the presence of which is presumed to be of pathogenetic importance. Extremely rare cases of MCC may show heterologous differentiation. We report an example of MCC with heterologous rhabdomyosarcomatous differentiation, the third such case to date, with emphasis on its distinction from fusion-negative alveolar rhabdomyosarcoma. The role of immunohistochemistry for Merkel cell polyomavirus large T-antigen in this differential diagnosis is emphasized.     

Merkel Cell Polyomavirus Is Frequently Detected in Korean Patients with Merkel Cell Carcinoma

Background

Merkel cell carcinoma (MCC) is an increasingly common neuroendocrine cancer of the skin. Merkel cell polyomavirus (MCPyV) is one of the causative agents of MCC. The prevalence of MCPyV in primary MCC and sun-exposed non-MCC tumors has been known to have different results depending on where it was investigated.

Objective

This study assesses the prevalence of MCPyV from primary MCC and sun-exposed non-MCC tumors in Korea.

Methods

A molecular pathology study was performed on 7 tissue specimens of MCC, 1 tissue specimen of metastatic small cell carcinoma of the lung, and 32 tissue specimens of non-MCC tumors occurring from sun-exposed areas [8 basal cell carcinomas (BCCs), 8 squamous cell carcinomas (SCCs), 8 actinic keratoses (AKs), and 8 seborrheic keratoses (SKs)]. All specimens were analyzed to determine the presence of MCPyV-DNA using both polymerase chain reaction (PCR) and real-time quantitative PCR. Immunohistochemistry with monoclonal antibody of MCPyV large T antigen (CM2B4) was also conducted.

Results

Using both PCR, MCPyV sequences were detected in six of seven MCC tissue specimens (85.7%). Five (71%) of seven MCC tumors were immunoreactive for CM2B4. All five immunoreactive cases were positive for MCPyV. However, there was no association of MCPyV with BCC, SCC, AK, and SK.

Conclusion

Our results implicate that MCPyV may contribute to the pathogenesis of primary MCC, not of non-MCC skin tumors in Korea, and the persons with MCPyV infection are unusual in Korea compared to other areas.     

Histogenesis of pure and combined Merkel cell carcinomas: An immunohistochemical study of 14 cases

The histogenesis of Merkel cell carcinoma (MCC) has remained unresolved. Moreover, one of the questions is whether pure MCC and combined MCC represent the same histogenesis and entity. The existence of combined MCC suggests that MCC likely arise from pluripotent stem cells. Merkel cells (MC) localize within the bulge area, which is populated by hair follicle stem cells. We used hair follicle stem cell markers to investigate whether MCC share certain characteristics of these stem cells. Fourteen MCC specimens were examined histologically and immunohistochemically. There were six pure MCC and eight combined MCC. In six combined MCC, both MCC components and squamous components at least focally shared the expression of one or more of cytokeratin (CK)15, CK19 and CD200, which are hair follicle stem cell markers. On the other hand, four cases of pure MCC showed partially distinct CK19 expression, but did not show CK15 and/or CD200 expression. There was a distinct difference between pure MCC and combined MCC on the expression of hair follicle stem cell markers. The normal skin expressed CK15, CK19 and CD200 in the bulge area, whereas CK15 and CD200 were absent in the MC‐rich glabrous skin and touch domes. The results led us to hypothesize that combined MCC originate from the hair follicle stem cells. We postulate that combined MCC undergo multidirectional differentiation into squamous, glandular, mesenchymal and Merkel cells. Further investigation is warranted to confirm the histogenesis of pure MCC and combined MCC.     

Merkel细胞癌3例临床与病理分析

目的探讨Merkel细胞癌的临床与病理特点、病因学、诊断及鉴别诊断。方法观察3例Merkel细胞癌的组织病理特点和免疫组化染色结果,并复习相关文献。结果 3例均为老年患者,女2例,男1例。镜下见肿瘤主要位于真皮,呈巢索状和弥漫片状分布,癌细胞圆形、卵圆形或梭形,大小及形态较一致,胞质较少,核染色质细颗粒状,病理性核分裂像多见。免疫组化见CK20和神经内分泌标记阳性,HMB45,TTF-1,LCA和CD99等阴性。结论 Merkel细胞癌是一种发生于皮肤的少见的高度恶性神经内分泌肿瘤,易局部复发或转移。近年来发现的Merkel细胞多瘤病毒可能是其重要的致病因子。其临床病理及特征性的免疫组化表达有助于诊断及鉴别诊断。目前的治疗方法主要有手术切除和辅助放疗及化疗。     

An unusual case of diffuse Merkel cell carcinoma successfully treated with low dose radiotherapy

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. MCC should be included in the diagnosis of a rapidly growing infiltrating mass and histology as well as laboratory investigations such as Merkel cell polyoma virus (MCPyV) detection are valuable in its diagnosis. We present an unusual case of giant MCC‐positive MCPyV in a Greek woman located on the lower leg. Our patient is very unusual in terms of her extensive MCC and her rapid and complete response to radiotherapy.     

Merkel细胞癌多瘤病毒阳性的皮肤原发性Merkel细胞癌二例

【摘要】 目的 报道Merkel细胞癌多瘤病毒阳性的Merkel细胞癌2例。 方法 对诊治的2例Merkel细胞癌进行光镜观察及免疫组化标记,聚合酶链反应（PCR）检测Merkel细胞癌多瘤病毒并测序。 结果 2例均为男性,例1右下肢胫前肿物1年余,皮肤科检查见右胫前密集粉红色结节,融合成10 cm × 8 cm肿块,质硬,部分表面糜烂伴渗出及结痂,肿块周围亦可见多个大小不一的红色结节,活动性差。例2左膝肿物6月余,皮肤科检查见左膝内侧5 cm × 4 cm紫蓝色结节型肿物,质硬,边界不清,活动性差。2例患者皮损组织病理表现相似,肿瘤细胞大小一致,细胞核大、深染,染色质细腻,核分裂象易见;胞质少,红染。免疫组化：广谱细胞角蛋白（pan-CK）、细胞角蛋白20（CK20）、突触素（Syn）、嗜铬素（CgA）和神经元特异性烯醇化酶（NSE）均阳性,Ki-67（≥60%）阳性;细胞角蛋白7（CK7）、S100蛋白、HMB45、CD34、甲状腺转录因子1（TTF-1）和白细胞共同抗原（LCA）表达均阴性。2例Merkel细胞癌均经PCR检测到Merkel细胞癌多瘤病毒,而5例皮肤T细胞淋巴瘤、2例正常人皮肤和2例T细胞淋巴瘤细胞系MAC1和MAC2A均未检测到Merkel细胞癌多瘤病毒。 结论 Merkel细胞癌具有特征性的临床和组织病理表现,免疫组化标记、PCR检测Merkel细胞癌多瘤病毒对明确诊断具有重要作用。 【关键词】 癌,Merkel细胞; 多瘤病毒属     

Merkel cell carcinoma arising within a poroma: report of two cases

Merkel cell carcinoma (MCC) has been reported in association with other types of cutaneous neoplasms within the same lesion, including squamous cell carcinoma, Bowen's disease, actinic keratosis, follicular cysts, trichoblastoma and lentigo maligna, among others. However, the association of MCC and sweat gland tumors has never been described in the literature. We report two unique cases of MCC that developed within cutaneous poromas. A 56‐year‐old male (Patient 1) and an 81‐year‐old female (Patient 2) presented with nodules on the upper arm and lower back, respectively. Histopathologic study of both cases revealed a tumor in the dermis composed of poroid and cuticular cells intermingled with a proliferation of small round cells that showed characteristic histopathological and immunohistochemical features of MCC. In both cases, the two neoplasms were tightly admixed and distinct, suggesting that the MCC could have developed within a previously existing poroma. No morphological features of transition between the two tumors were seen. Neoplastic cells of MCC expressed immunoreactivity for chromogranin, synaptophysin, neuron‐specific enolase, CAM 5.2 and cytokeratin 20, the last two markers showing the characteristic paranuclear dot‐like pattern. In contrast, the poroma cells only expressed cytokeratin MNF116. Metastatic deposits were not identified in the regional lymph nodes or distantly.     

Merkel cell carcinoma metastatic to the transverse colon: Disease free after six years – cure or just prolonged remission?

Merkel cell carcinoma is an uncommon but highly immunogenic skin malignancy that has the potential to metastasize to any site in the body. Despite treatment many patients experience relapse, often to distant sites beyond the site of initial treatment. The development of distant soft tissue or visceral metastases is considered incurable, despite treatment with prognosis usually being measured in months. We report the case of an elderly man who developed colonic metastases from a head and neck primary and with treatment has survived disease free for over 6 years. Such reports are infrequently documented and highlight the unpredictable nature of this disease.     

皮肤Merkel细胞癌伴鳞状细胞癌1例

患者女,76岁。左面颊部肿物1年,明显增大1个月。皮损特点为紫红色球形肿物。皮损组织病理示:表皮见团块状鳞状上皮中-重度异型增生,突破基底膜;真皮全层见形态一致的肿瘤细胞浸润,巢状或片状分布,圆形或卵圆形,胞质少、嗜碱性,核大、散点状分布染色质,核仁明显,可见多数核分裂相。免疫组化:CK20(部分+),P63及CKH(鳞状分化的细胞+),Syn(+),CgA(+),CD56(+),LCA(-),CK7(-),S100(-)。诊断:皮肤Merkel细胞癌伴鳞状细胞癌。     

Intraepidermal proliferation of Merkel cells within a seborrheic keratosis: Merkel cell carcinoma in situ or Merkel cell hyperplasia?

Intradepidermal proliferation of Merkel cells without any dermal component has been interpreted as either a hyperplastic process secondary to chronic ultraviolet radiation or a neoplastic process, namely Merkel cell carcinoma (MCC) in situ. The recent criteria that have been proffered to diagnose MCC in situ, unfortunately, are identical to those that have been applied to Merkel cell hyperplasia in the past, posing a diagnostic quandary when faced with an intraepidermal proliferation of Merkel cells. Most previously reported cases of MCC in situ have occurred within associated epithelial lesion that includes solar (actinic) keratosis and squamous‐cell carcinoma in situ. Similarly, Merkel cell hyperplasia has been reported to occur in association with a variety of epithelial lesions as well as on chronically sun‐damaged skin. Herein, a case of an intraepidermal proliferation of Merkel cells within a seborrheic keratosis is presented accompanied by a discussion on whether the proliferation represents another case of Merkel cell carcinoma in situ or an incidental hyperplastic process on chronically sun‐damaged skin.     

Merkel cell carcinoma: epidemiology,clinical features,diagnosis and treatment of a rare disease

Merkel cell carcinoma is a rare skin cancer with neuroendocrine differentiation. The risk factors include sun exposure, advanced age, immunosuppression (such as transplant recipients, patients with lymphoproliferative neoplasms, or patients with HIV), and Merkel cell polyomavirus infection. Clinically, Merkel cell carcinoma appears as a cutaneous or subcutaneous plaque or nodule, but this tumor diagnosis is rarely made clinically. Therefore, histopathology and immunohistochemistry are usually necessary. Primary tumors without evidence of metastases are treated with complete surgical excision and appropriate surgical margins. The presence of occult metastasis in a lymph node is frequent and a sentinel lymph node biopsy should be performed. Postoperative adjuvant radiotherapy increases local tumor control. Recently, agents that block the PD-1/PD-L1 pathway have shown objective and durable tumor regression in patients with advanced solid malignancies. The first anti-PD-L1 antibody used in patients with Merkel cell carcinoma was avelumab, but pembrolizumab and nivolumab have also shown efficacy. This article describes the current state of knowledge of the epidemiology, diagnosis, and staging of Merkel cell carcinoma, as well as new strategies for its systemic treatment.     

Detection of calcium binding sites in Merkel cell granules of fetal rat skin

We utilized a cytochemical calcium-staining technique to detect a potential calcium binding site within Merkel cell granules. Calcium has been shown to be essential for exocytotic release in various neuroendocrine cells and recent investigations strongly support the hypothesis that Merkel cells should be considered to be neuroendocrine cells which release their specific granules as a part of their physiological functions. After the addition of 50 mM CaCl2 to glutaraldehyde as the primary fixative, buffer, and OsO4 as a postfixative, electron-dense particles with a characteristic staining pattern were found within many MCGs. Successful removal of these particles after incubation of sections in a solution containing EDTA indicated that these particles were formed by calcium deposits. The occurrence of calcium binding structures within MCGs may imply that they play a role in the process of granule release and/or granule maturation.     

The Merkel cell — a member of the APUD cell system?

Summary Merkel cells of sinus hair follicles of nude mice were investigated by fluorescence and electron microscopy following pretreatment with amine precursors (L-Dopa, L-5-Hydroxytryptophan) and monoaminoxidaseinhibitors (Marsilid, Harmaline). Neither in control animals nor in pretreated animals any evidence for an involvement of Merkel cells in monoamine metabolism could be found. Therefore, the hypothesis that Merkel cells might share the most constant cytochemical characteristics of the cells of the APUD series, i.e., to take up amine precursors, should definitely be left.Following Harmaline treatment, however, Merkel cells were found fluorescent; cytophotometric analysis of the fluorescence emission spectra of formaldehyde-treated and untreated tissue ascertained that this fluorescence was due merely to a specific Harmaline fluorescence. The significance of Harmaline uptake in Merkel cells, most probably in the Merkel cell granules, is discussed.