Primary Cutaneous Merkel Cell Carcinoma Research Articles

No difference in overall survival for primary cutaneous Merkel cell carcinoma after Mohs micrographic surgery and wide local excision: A multicenter cohort analysis

No difference in overall survival for primary cutaneous Merkel cell carcinoma after Mohs micrographic surgery and wide local excision: A multicenter cohort analysis

No difference in survival for primary cutaneous Merkel cell carcinoma after Mohs micrographic surgery and wide local excision

The preferred treatment for clinically node-negative Merkel cell carcinoma (MCC) is surgical excision in conjunction with sentinel lymph node biopsy. There is limited large-scale research on survival outcomes by surgical approach for management of the primary tumor. To compare overall and MCC-specific survival outcomes in clinically and pathologically node-negative MCC patients treated with wide-local excision (WLE) and Mohs micrographic surgery (MMS) in a nationally representative sample. Overall and MCC-specific survival outcomes for primary MCC tumors contained in the SEER-18 database from 1989 to 2015 were stratified by surgical modality and analyzed via competing risk analysis. A total of 2,359 US adults with MCC were included in the analysis. For overall and MCC-specific survival, there was no significant difference in survival outcomes between WLE and MMS on multivariable analysis ((HR 1.04 [95% CI 0.88 - 1.22]; SHR 0.76 [95% CI 0.53 - 1.09]). Sentinel lymph node biopsy (SLNB) was associated with improved overall survival and MCC-specific survival. Retrospective design of SEER and the lack of covariates such as comorbidities and immunostaining. There is no survival disadvantage for MMS compared to WLE as the surgical modality for primary cutaneous MCC. SLNB should be coordinated prior to MMS.

Evaluation of clinical characteristics and pre-biopsy impressions of primary Merkel cell carcinoma of the skin.

Merkel cell carcinoma is an aggressive carcinoma of the skin notable for protean presentation on physical exam. A retrospective cohort of 232 patients with primary cutaneous Merkel cell carcinoma was reviewed for availability of data on pre-biopsy clinical differential diagnosis based on clinical exam. Data was available for 192 patients (83%). The three most common impressions were cyst (33.3%), basal cell carcinoma (31.8%), and squamous cell carcinoma (19.8%). Merkel cell carcinoma was correctly suspected in only 13 cases (6.8%). A greater proportion of lesions that were less than or equal to 2 cm in diameter (10.2%) or carried BCC as a co-diagnosis (11.5%) were correctly suspected as Merkel cell carcinoma prior to biopsy, versus lesions greater than 2 cm in diameter (1.6%) or carrying SCC as a co-diagnosis (2.6%), suggesting that clinicians may be anchoring on the well-publicized concept of Merkel cell carcinoma as a small, pearly papule in real-world practice.

Two Clinical Cases of Metastatic Merkel Cell Carcinoma Illustrating Avelumab Tolerability in Elderly Patients

AbstractWe present two cases of primary cutaneous Merkel cell carcinoma in a 80-year and a 95-year old patient. Both patients had a wide local excision, but early recurrences occurred. Case 1 required palliative radiotherapy. He did not receive chemotherapy but case 2 did. They then proceeded to have immunotherapy with sustained responses lasting greater than 2 and 3 years. This report highlights an important new class of drug for the treatment of advanced Merkel cell carcinoma. Furthermore, our case report demonstrates that avelumab immunotherapy can be safely delivered to elderly patients, including 80- and 95-year-old patients. This report parallels the high and durable response rates to avelumab (including complete responses) that were shown in the JAVELIN phase II trials.

An Uncommon Case of Colonic Neuroendocrine Carcinoma with Scalp Metastasis

Abstract Introduction/Objective Neuroendocrine neoplasms of the colon account for <1% of all colorectal malignancies. While visceral metastasis of neuroendocrine neoplasms is commonly observed, cutaneous distant metastasis has infrequently been reported and correlates with an advance stage and progression of disease. To our knowledge, there have been only 10 cases of neuroendocrine neoplasms with metastasis to the scalp reported in the literature. Herein, we report an unusual case of colonic neuroendocrine carcinoma with scalp metastasis, that can be microscopically indistinguishable from the highly aggressive cutaneous neuroendocrine carcinoma, Merkel Cell Carcinoma. Methods/Case Report A 47-year-old female with a history of ileocecal neuroendocrine carcinoma and status post right hemicolectomy had developed liver metastasis and subsequently had an orthotopic liver transplant. PET scan later revealed multiple areas of increased activity involving the ribs, scalp and cervical lymph node that were concerning for malignancy. The scalp lesion consisted of a 7mm non-tender, mobile, violaceous, erythematous dermal nodule that was clinically concerning for cutaneous metastasis. A skin punch biopsy microscopically revealed a subcutaneous infiltrate of nests composed of neoplastic monotonous blue cells with the classic nuclear “salt and pepper” chromatin and scant eosinophilic cytoplasm. The lesional cells showed positive immunoreactivity for synaptophysin and chromogranin. With the given patient’s clinical history and presentation, the observed histological findings and immunophenotypic expression of the tumor cells supported a diagnosis of metastatic neuroendocrine carcinoma. Results (if a Case Study enter NA) N/A Conclusion Metastatic neuroendocrine carcinoma to the scalp is a rare entity and is infrequently encountered in dermatopathology. Given the location and the gross appearance of the scalp lesion, a wide differential diagnosis would include both benign and malignant tumors. In particular, Merkel Cell Carcinoma can grossly and histologically mimic metastatic colonic neuroendocrine carcinoma. Both entities would show synaptophysin and chromogranin uptake. However, metastatic tumors originating from the colon will demontrate CDX2 and SATB2 nuclear staining. We share this rare case of metastatic colonic neuroendocrine carcinoma as it is an important differential diagnosis for primary cutaneous Merkel Cell Carcinoma.

Morphologic Diversity of Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of unknown origin. We performed a retrospective histologic review of primary cutaneous MCCs diagnosed from 1997 to 2018 in several clinical institutions and literature review to determine the frequency of various unusual morphologic appearances of MCC. Of the 136 primary MCCs identified, intraepidermal carcinoma or epidermotropism was noted in 11/136 (8%) cases. An association with pilar cyst in 1/136 (0.7%) case, with actinic keratosis in 2/136 (1.5%) cases, with either invasive or in situ squamous cell carcinoma (SCC) in 14/136 (10%) cases, with poroma in 1/136 (0.7%), and with basal cell carcinoma in 1/136 (0.7%) case was noted. Trabecular pattern and rosettes were noted in 7/136 (5%) and 3/136 (2%) cases, respectively. There was one case of metastatic MCC in a lymph node with chronic lymphocytic leukemia and one rare case of metastatic MCC and SCC in a lymph node. Although uncommon, differentiation toward other cell lineage can be observed in both primary and metastatic MCCs. The tumor can assume a variety of histologic appearances including association with SCC, basal cell carcinoma, melanocytic neoplasm, and follicular cyst; as well as exhibit glandular, sarcomatous, and mesenchymal differentiation. This diversity of morphologic appearance of MCC reflects the complexity of its underlying pathogenesis.

Metabolic reprogramming and angiogenesis in primary cutaneous Merkel cell carcinoma: expression of hypoxia-inducible factor-1α and its central downstream factors.

Metabolic reprogramming and altered gene expression mediated by hypoxia-inducible factors play crucial roles during tumour growth and progression. Nevertheless, studies analysing the expression of hypoxia-inducible factor-1α and its downstream targets in Merkel cell carcinoma (MCC) are lacking but are warranted to shed more light on MCC pathogenesis and to potentially provide new therapeutic options. To analyse the immunohistochemical expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor-A (referred to as VEGF throughout the manuscript), VEGF receptor-2 (VEGFR-2), VEGF receptor-3 (VEGFR-3), glucose transporter-1 (Glut-1), monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CAIX) in primary cutaneous MCC. The 16 paraffin-embedded primary cutaneous MCCs (Merkel cell polyomavirus (McPyV) positive/negative: 11/5) were analysed by immunohistochemistry, namely HIF-1α, VEGF, VEGFR-2 (KDR), VEGFR-3 (FLT4), Glut-1, MCT4 and CAIX. An established quantification score (QS) was applied to quantitate the protein expression by considering the percentage of positive tumour cells (0: 0%; 1: up to 1%; 2: 2-10%; 3: 11-50%; 4: >50%) in relation to the staining intensity (0: negative; 1: low; 2: medium; 3: strong). HIF-1α was expressed in all MCCs and predominantly found at the invading edges of tumour margins. The HIF-1α downstream factors Glut-1, MCT4 and CAIX were expressed in 13 of 16 MCC (81%), 14 of 16 MCC (88%) and 16 of 16 MCC (100%), respectively. Interestingly, VEGF and VEGFR-2 were not expressed in tumour cells, whereas VEGFR-3 was expressed in all MCCs. HIF-1α was expressed significantly stronger in McPyV+ tumours (QS: 10.36±2.41) than in McPyV- tumours (QS: 5.40±1.34; P=0.002). Similarly, VEGFR-3 was also expressed significantly stronger in McPyV+ tumours (QS: 10.00±2.52) than in McPyV- tumours (QS: 5.40±3.43, P=0.019). Our data provide first evidence for a role of HIF-1α in induced metabolic reprogramming contributing to MCC pathogenesis. The metabolic signatures of McPyV+ and McPyV- tumours seem to show relevant differences.

A Report of 13 Cases of Merkel Cell Carcinoma: Single-Center Experience and Review of the Literature.

BackgroundThere is limited data knowledge of Merkel cell carcinoma (MCC) in Turkey aside from a few case reports.ObjectiveThe aim of this study was to describe the clinical characteristics, demographic features, therapeutic parameters, and outcome of primary cutaneous MCC cases from Turkey.MethodsDigital medical records of the 13 MCC patients who were followed-up at a tertiary referral center were retrospectively analyzed. Clinic, demographic, tumor characteristics, and survival of the patients were retrieved.ResultsMost of our patients were elderly. Female predominance was noticed. The most common primary site of the tumors was the lower extremities. The overall survival was 42 months, 68% at first year, 68% at third years, and 29% at fifth years.ConclusionThis is the first largest report from Turkish population with female predominance, and lower extremity tendency.

Hepatic Metastasis Presenting as Merkel Cell Carcinoma of Unknown Primary

Merkel cell carcinoma (MCC), a high grade cutaneous neuroendocrine tumor (NET), is often confused with basal cell carcinoma (BCC), basaloid squamous cell carcinoma (SCC), and other primary site small cell carcinomas. Usually limited to skin and regional lymph nodes, solid organ metastasis is uncommon and results in high mortality. We present a case of a man with abdominal pain and liver lesions who was diagnosed with Merkel cell carcinoma of unknown primary (MCCUP). A 74-year-old man presented with a one-week history of shortness of breath, pleuritic chest pain, and abdominal pain. Significant medical history included prostate adenocarcinoma and Moh's surgery for SCC and BCC. On examination, he demonstrated epigastric tenderness. Laboratory studies were remarkable for elevated liver enzymes and total bilirubin. Initial workup ruled out acute coronary syndrome and pulmonary embolism; however, chest CT showed multiple pulmonary nodules and a large peri-fissural nodule. Abdominal CT showed a mottled liver and lytic lesions in the vertebral column concerning for metastasis. A liver biopsy showed high-grade NET. Immunohistochemical (IHC) staining favoring MCC and excluding primary pulmonary and gastrointestinal SCC. Hospital course was complicated by worsening jaundice and ascites for which he underwent palliative chemotherapy without improvement. Repeat imaging showed worsening hepatic metastases as well as new lytic lesions. There was a decrease in size of the peri-fissural nodule, but no change in the other lung nodules. Palliative radiation therapy was elected and the patient passed away 4 months after presentation. MCC is a rare, aggressive NET, most common in Caucasians over age 65 with UV exposure. Most patients present with cutaneous disease and regional lymph node involvement. Systemic spread is rare; however, common metastatic sites include lymph nodes, lung, liver, and bone. MCCUP typically presents with nodal disease without known primary cutaneous MCC. Histologic diagnosis of MCCUP is difficult due to similarities with more common high-grade NETs, such as pulmonary or gastrointestinal small cell carcinoma. Key electron microscopic features include dense core granules and paranuclear intermediate filaments. CK-20 positivity, and TTF-1 and CDX-2 negativity on IHC staining, to exclude pulmonary and gastrointestinal SCC, are confirmatory. Outcomes for patients with MCC is poor; treatment typically involves palliative chemotherapy.2349_A Figure 1. Computed Tomography of the Abdomen w/contrast - The liver is enlarged with a heterogeneous and mottled appearance - Axial section2349_B Figure 2. Needle biopsy of liver showing a trabecular small cell carcinoma (MCC) at 200 magnification (H&E 20X)2349_C Figure 3. Merkel cell carcinoma marking with CK20 in a para-nuclear pattern at 600 magnification (60X)

Intratumoral and peritumoral lymphovascular invasion detected by D2-40 immunohistochemistry correlates with metastasis in primary cutaneous Merkel cell carcinoma

Primary cutaneous Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy in which lymphovascular invasion (LVI) correlates with more aggressive phenotype. The prognostic significance of LVI detected by D2-40 immunohistochemistry (IHC) in MCC remains controversial. We aimed to determine how LVI detected by D2-40 IHC compares with LVI detected by hematoxylin and eosin (H&E) staining in predicting MCC metastasis. Clinical and histopathologic features of MCCs diagnosed and treated in 2002 to 2015 were assembled and included 58 MCC tumors from 58 patients. H&E-stained tissue sections and D2-40 IHC studies were reviewed. When LVI was present, the location (peritumoral or intratumoral) and the size of the largest invaded vessel were recorded. LVI findings by H&E staining and D2-40 IHC were compared with each other and with histologic features and clinical outcomes. H&E staining showed LVI in 37 of 58 cases; D2-40 IHC confirmed LVI in 30 of these cases but failed to confirm LVI in 7. D2-40 IHC also detected 14 cases of LVI not identified on H&E staining. Histologically, D2-40-detected LVI was associated with infiltrative growth pattern and nonbrisk lymphoid infiltrate (P = .005 and P = .055, respectively). There was a statistically significant difference between the frequency of detection of peritumoral LVI by H&E in comparison to D2-40 IHC (P = .0009). MCCs in which D2-40 IHC-detected both intratumoral and peritumoral LVI were typically larger than MCCs without (mean, 24.5 mm versus 17.3 mm; P = .03) and more frequently metastasized (87% versus 51%; P = .03). D2-40 IHC detection of both intratumoral and peritumoral LVI is associated with metastasis.

Color Doppler Sonography of Merkel Cell Carcinoma.

We illustrate the color Doppler sonographic findings in primary cutaneous Merkel cell carcinoma. Eight cases (4 female and 4 male; mean age, 75.4 years) were collected. The most common affected regions were the face (63%) and the hip/buttock (25%). The mean transverse diameter and thickness were 21 and 14 mm, respectively. Fifty percent were oval, and 50% were dome shaped. All lesions were hypoechoic, with variable degrees of heterogeneity. All but 2 lesions were poorly defined. An acoustic reinforcement artifact was present in 3 and epidermal thickening in 2. All tumors had prominent and chaotic hypervascularity with arterial vessels (mean peak velocity, 11 cm/s; mean resistive index, 0.57).

Single-centre experience of primary cutaneous Merkel cell carcinoma of the head and neck between 1996 and 2014

We retrospectively reviewed the management at our centre of 25 patients with Merkel cell carcinoma (MCC) of the head and neck. We obtained details of the operation, including wide local excision, sentinel lymph node biopsy (SNB), neck dissection, postoperative radiotherapy, and clinical outcomes, from patients’ records. All patients were white, 11 were men and 14 women, mean age at presentation 81 years (range 67-90). At the time of diagnosis, 18 patients had stage I disease, and 7 stage II disease. Twenty had wide local excision and radiotherapy, and 5 had wide local excision alone. Wide local excision and radiotherapy are successful treatments. In patients with no sign of metastases, SNB at the time of excision is a well-researched option and should be considered the gold standard of care.

Anaemia due to gastric haemorrhage by a metastatic Merkel cell carcinoma.

Anaemia due to gastric haemorrhage by a metastatic Merkel cell carcinoma.

Merkel cell Polyomavirus and p63 status in Merkel cell carcinoma by immunohistocnemistry: Merkel cell Polyomavirus positivity is inversely correlated with sun damage, but neither is correlated with outcome

The aim of this study was to determine the frequency of Merkel cell polyomavirus (MPyV) and p63 positivity by immunohistochemistry in a large cohort of primary Merkel cell carcinoma (MCC) from a region with high rates of actinic damage. We also aimed to determine whether there is any relationship between these markers and histological correlates of chronic sun exposure and to identify whether these markers have prognostic significance in our population. Ninety-five cases of primary cutaneous MCC were identified and stained with immunohistochemical markers for MPyV and p63. The presence of solar elastosis and squamous dysplasia in the overlying/adjacent skin were recorded as markers of actinic damage. Follow up data were obtained from the Western Australian Cancer Registry. MPyV was detected by immunohistochemistry in 23% of cases. There was a statistically significantly lower rate of positivity in tumours associated with markers of chronic sun damage as assessed by the presence of solar elastosis and squamous dysplasia. There was no association with overall or disease specific survival. p63 positivity was detected in 17% of cases. There was no association with markers of actinic damage or with overall or disease specific survival.Our data demonstrate a significant difference in rates of immunohistochemical positivity for MPyV between MCC in sun-damaged and non-sun-damaged sites. This may go some way to explaining previously identified geographical differences. When compared with a number of studies from Europe and North America, p63 positivity is less common in our population and does not show the strong prognostic significance that has been found in these other regions.

Merkel cell carcinoma polyomavirus-positive primary cutaneous Merkel cell carcinoma: two case reports

Objective To estimate the value of detection of Merkel cell carcinoma polyomavirus (MCPyV)in the diagnosis of Merkel cell carcinoma (MCC).Methods Two cases of MCC were studied using light microscopy and immunohistochemistry.PCR was performed to detect DNA sequences encoding MCPyV large T antigen(LT)and viral protein 1 (VP1) in paraffin-embedded tissue specimens from the two patients with MCC,five patients with T cell lymphoma,two normal human controls,as well as in two T cell lymphoma cell lines MAC 1 and MAC2.DNA sequencing was also carried out.Results Both of the patients with MCC were male.The patient 1 presented with a mass in the right anterior shin for more than one year,and the patient 2 had a mass in the left knee for more than six months.Skin examination revealed densely distributed pink nodules in the right anterior shin,with confluence into an indurated plaque which measured 10 cm × 8 cm with superficial erosion,exudates and crusts and was surrounded by multiple irregularly sized erythematous nodules with limited mobility in the patient 1,as well as a royal blue,hard,poorly marginated nodular mass measuring 5 cm × 4 cm in the left medial knee with limited mobility in the patient 2.Pathological manifestations were similar in the two patients.Tumor cells were uniform with large hyperchromatic nuclei,eosinophilic and sparse cytoplasm,and fine chromatin.Mitotic figures were easily seen.Immunohistochemistry revealed that the tumor cells stained positive for pan-cytokeratin,synuclein (Syn),neuron-specific enolase (NSE),chromogranin (CgA),CK20,and Ki-67 (＞ or =60％),but negative for S100 protein,HMB45,CD34,thyroid transcription factor 1 (TTT-1),CK7 and leukocyte common antigen (LCA).MCPyV DNA was detected in both MCC specimens,but absent in the other skin specimens or T cell lymphoma cell lines.Conclusions MCC has distinctive clinical and pathological appearance.Immunohistochemistry and detection of MCPyV DNA sequences using PCR may be beneficial to the definitive diagnosis of MCC. Key words: Carcinoma, Merkel cell; Polyomavirus

Merkel cell carcinoma versus metastatic small cell primary bronchogenic carcinoma

Introduction: Merkel cell carcinoma (MCC) of the skin is a rare, aggressive, malignant neuroendocrine neoplasm. The tumor classically demonstrates positive immunohistochemistry (IHC) staining for chromogranin A(ChrA), cytokeratin 20 (CK20), neuron specific enolase (NSE) and/or achaete-acute complex-like 1 (MASH1). The newly identified Merkel cell polyomavirus (MCPyV) has been found to be associated with most MCC cases. The primary histologic differential diagnoses of cutaneous MCC is small cell primary bronchogenic carcinoma (SCLC); moreover, both are of neuroendocrine origin. SCLC accounts for approximately 10-15% of all primary lung cancer cases; this histologic subtype is a distinct entity with biological and oncological features distinct from non-small cell lung cancer (NSCLC). In contradistinction to MCC, SCLC is classically IHC positive for cytokeratin 7 (CK7) and transcription factor (TTF-1). Similar to SCLC, MCC cell lines may be classified into two different biochemical subgroups designated as Classic and Variant. In our review and case report, we aim to emphasize the importance of a multidisciplinary approach to the approach to this difficult differential diagnosis. We also aim to comment about features of the cells of origin of MCC and SCLC; to summarize the microscopic features of both tumors; and to review their respective epidemiologic, clinical, prognostic and treatment features. We want to emphasize the initial workup study of the differential diagnosis patient, including evaluating clinical lymph nodes, a clinical history of any respiratory abnormality, and chest radiogram. If a diagnosis of primary cutaneous MCC is confirmed, classic treatment includes excision of the primary tumor with wide margins, excision of a sentinel lymph node, and computed tomography, positron emission tomography and/or Fluorine-18fluorodeoxyglucose positron emission tomography scan studies.

Dermatoscopic vascular patterns in cutaneous Merkel cell carcinoma

Merkel cell carcinoma (MCC) is one of the most aggressive primary cutaneous malignancies. The clinical diagnosis of MCC is often delayed. Although the rarity of this skin cancer partially explains the low clinical suspicion by physicians, the absence of characteristic clinical features contributes to the delay in diagnosis. Dermatoscopy has proven a useful diagnostic tool in other cutaneous malignancies; however, the dermatoscopic features of cutaneous MCC are unknown. We performed dermatoscopy on 10 primary cutaneous MCC to describe the dermatoscopic features and correlate these findings with the histopathologic parameters. Consecutive patients with cutaneous MCC were identified and their tumors were evaluated under dermatoscopy. An 8-point MCC histopathology profile was recorded for each primary tumor in an attempt to correlate individual parameters with dermatoscopic features. All 10 tumors showed an irregular vascular pattern under dermatoscopy and demonstrated milky-red areas/globules and numerous linear irregular vessels. No correlation was noted between dermatoscopic and histopathologic features. The patients were from a single institution and tumors evaluated by a single dermatoscopic reviewer. Because of the rarity of this tumor, a small number of tumors were evaluated (10). MCC exhibits a variety of dermatoscopic vascular patterns, most commonly milky-red areas/globules, polymorphous vessels, and linear-irregular vessels. Although we found no specific dermatoscopic pattern for MCC in our series, the polymorphous vascular pattern was atypical and suggestive of a malignant process. Further studies should be done to investigate the potential correlation between dermatoscopic features and histopathologic parameters.

Acetylcholine Receptor Expression in Merkel Cell Carcinoma

Neurocrest-derived tissues express muscarinic and nicotinic acetylcholine receptors (mAChR and nAChR respectively). These receptors are critical for migration of neurocrest-derived cells to their corresponding tissues during development. Recent reports demonstrate neurocrest-derived melanoma and numerous non-Merkel cell neuroendocrine tumors express both muscarinic and nicotinic receptors. In light of the controversy surrounding the origin and pathogenesis of Merkel cell carcinoma (MCC), we investigated the immunohistochemical expression of both mAChR and nAChR in MCC. Fifteen cases of primary non-metastatic cutaneous MCC archived at a large veterans' hospital and tertiary referral dermatopathology service were retrieved by computer-assisted search. Immunohistochemistry was utilized to evaluate the presence of M3, M5 and beta 2 nAChR expression. All the cases were confirmed prior to study by a single board certified dermatopathologist (MBM). Fifteen cases of primary cutaneous MCC were diffusely positive for M3 and M5 mAChR staining. All cases lacked immunohistochemical staining for the beta 2 nAChR. Despite the limited number of cases, MCC appears to uniformly express M3 and M5 receptors. These receptors have been linked to cell proliferation and migration which may confer a potential therapeutic target.