A single center’s experience with atypical presentation of Merkel cell carcinoma positive for polyomavirus DNA detection

World Journal of Clinical Cancer Research www.directivepublications.org A single center’s experience with atypical presentation of Merkel cell carcinoma positive for polyomavirus DNA detection. Trancesco Bovino* Corresponding author Trancesco Bovino, Dipartimento di Scienze Anestesiologiche, Chirur- giche e dell’Emergenza, Seconda Università degli studi di Napoli, Italia. Email: [email protected] Received Date: October 20 2021 Accepted Date: October 24 2021 Published Date: November 26 2021 Abstract Merkel cell malignant neoplastic disease (MCC) could be a rare malig- nant neoplasm of the skin with tendency to speedy native progression and frequent unfold to regional humor nodes. during this paper 10den- cy to|we tend to} retrospectively describe the atypical presentation of five cases of Merkel cell malignant neoplastic disease determined in our surgical department within the last ten years. Four patients had cheek localization while one patient had primary nodal presentation. Since integration of Merkel cell polyomavirus (MCPyV) deoxyribo- nucleic acid into the neoplasm order is often recorded during this form of cancer, we tend to analyzed formalin-fixed paraffin embedded MCC tissue samples from our 5 patients for the presence of MCPyV deoxyri- bonucleic acid by means that of enzyme chain reaction (PCR). MCPyV deoxyribonucleic acid was gift all told 5 carcinomas. All patients were treated with wide surgical excision of the neoplasm and watcher node diagnostic assay. One patient had stage I illness, 3 patients had stage II illness, and one patient had stage III illness. Adjuvant actinother- apy was administered all told cases for native management. therapy was administered to the patient with primary nodal presentation and in stage III illness. Median time of follow-up was eighty four months. None of the patients relapsed. Despite the low range of patients ex- amined, our expertise suggests that surgery could be a necessary step whereas implementation of adjuvant medical aid, actinotherapy and therapy depends on individual risk assessment. Treatment outcome was excellent, most likely thanks to early detection of MCC. Keywords Merkel cell carcinoma; polyomavirus; DNA detection; chemotherapy Introduction Merkel cell cancer (MCC), initial delineate by Toker in 1972 [1] is associate degree aggressive system neoplasm arising within the der- mo-epidermal junction of the skin. MCC incidence will increase more and more with age. The neoplasm isn’t diagnosed in patients younger than fifty years, whereas the median age at designation is regarding sixty five years [2, 3]. MCC happens most often in Europe and North America (75- 90%) whereas solely pure gold of cases area unit re- ported in Australian patients; there area unit terribly restricted knowl- edge regarding the prevalence in Asian population [4-10]. These tumors area unit generally found on the pinnacle and neck, arms, chest, with a small feminine predominance, particularly in sun-exposed areas of the skin, and sometimes presents as an effortless bluish-red nodule [11]. inflated incidence of MCC has additionally been recorded in subjects heavily treated with methoxsalen (psoralen) and ultraviolet A (PUVA) for skin disorder, and in patients with chronic immunological disorder, as in chronic cancer of the blood, human immunological disorder infec- tion, and previous solid organ transplantation [4, 12]. within the clinical outcome. Currently, there are not any evidence- based mostly treatment modalities for MCC thanks to the low incidence of this entity. Indeed, solely single cases or little numbers of patients have to date been delin- eate within the literature. Here, we tend to contribute to the data of this neoplasm by news 5 MCPyV-DNA-positive cases with atypical presen- tation and earlier age onset ascertained at our establishment. The medical records of 5 patients with MCC ascertained and treated between 2003 and 2008 at the Surgical and medicine Department of Second University of Naples, Italy, were reviewed. Four patients had cheek presentation whereas one patient given with nodal involvement with no known primary neoplasm. Thus, all patients had associate de- gree uncommon presentation. designation was confirmed by typical he- matoxylin & fluoresceine staining and immunohistochemical staining mistreatment the subsequent markers: CK20, chromogranin, synapto- physin, neurogen- specific enolase (NSE), S100, thyroid transcription factor-1 (TTF-1), and pan-cytokeratin. customary surgical procedures were planned consistent with clinical presentation. The margins of exci- sion were a minimum of two.5 cm round the lesion. lookout man lym- phatic tissue diagnostic assay (SLNB) was performed altogether cases following designation of Merkel cell cancer except within the patient presenting with nodal involvement. Adjuvant therapy was administered if necessary, consistent with printed tips [13]. Patients were inspired to receive adjuvant treatment consisting in native actinotherapy (total dose: sixty Gy) and/ or therapy (carboplatin at United Self-Defense Group of Colombia four on day one and etoposide at eighty mg/m2 on days 1-3, perennial each 3 weeks for 4–6 cycles) consistent with the stage. All pa- tients were then enclosed in a very follow-up program consisting in total body PET-TC scan and assessment of liquid body substance levels of chromogranin A and NSE each six months for the primary 3 years so per annum for the subsequent 5 years. MCPyV ordering integration into neo- plasm polymer was investigated consistent with customary procedures. Briefly, polymer was obtained from formalin-fixed paraffin embedded neoplasm samples following deparaffinization with xylol, digestion with proteolytic enzyme K till complete tissue lysis, and phenol/chloroform extraction with Na acetate/ fermentation alcohol precipitation. PCR was performed with two hundred weight unit of genomic polymer in a very reaction mixture containing ten millimetre Tris-HCl (pH eight.3), 1.5 mM MgCl2, 50 mM KCl, two hundred two hundred dNTP, and 2.5 units of Taq polymer enzyme (Roche Diagnostics) in a very final volume five0|of fifty} l. The reaction was applied in a very poly- mer thermal cycler (Mastercycler gradient, Eppendorf, Milan, Italy). For MCPyV detection, the LT1, LT3, LT5, VP1, and M1/2 primer sets were used [6]. additionally, the LT1 and M1/2 primer sets were used for nested PCR, mistreatment thirty one cycles for every primer set. actin PCR was performed to verify suitableness of genomic polymer for PCR analysis. PCR merchandise were analyzed by ionophoresis on one.8% agarose gel in TBE. Case report Page - 01

World Journal of Clinical Cancer Research www.directivepublications.org first website of unwellness was administered following surgery. The patient was then enclosed within the follow-up program. FFPE tissue specimens were tested positive for MCPyV desoxyribonucleic acid by PCR. No repetition of unwellness was detected when a seven-year fol- low-up. Case 5 In Jan 2008, a sixty eight year-old man, with delicate hyper- tension and sort two DM, noted Associate in Nursing indolent nodular lesion on the external region of the left cheek. the most diameter of the lesion was two cm. PET-CT scan disclosed a two.5 cm left region pathology with a liquid ecstasy SUV of seven. Surgical removal of the lesion with wide margins and left region node dissection were performed. Adjuvant ra- diation was administered to the first website of unwellness and to the left region region following surgery. Concomitant therapy with carboplatin at United Self-Defense Group of Colombia four on day one and etopo- side at eighty mg/m2 on days 1-3 was given and perennial each 3 weeks for four cycles. The patient was then followed-up. FFPE tissue speci- mens were tested positive for MCPyV desoxyribonucleic acid by PCR. No repetition of unwellness was detected when a five-year follow-up. Discussion MCC is also a rare growth generally occurring in aged of us on sun-ex- posed areas like head, neck or extremities. Areas of involvement coun- sel a task for the radiation in affirmative development of health problem [14]. Indeed, terribly} very recent cohort study at the side of 195 pa- tients, eighty one in all primary MCCs occurred on ultraviolet-exposed sites; only 5 you take care of cases were localized on buttocks. In dis- tinction, all MCC cases discovered at our institution did not arise on sun-exposed areas; moreover, the median age of our patients was below that according in literature. Specifically, median age at MCC confined to humor nodes whereas not a lucid primary web site has been rarely ac- cording. To our data, the foremost necessary series has been painted by Eusebi et al. [22], UN agency according five region, 2 axillary, and one submandibular primary lymphatic tissue cases. MCC in humor nodes is additionally the results of organic process unfold from Associate in Nursing occult or regressed primary MCC. instead, humor nodes is ad- ditionally the primary web site of health problem. although this latter hypothesis is usually not accepted as a results of Merkel cells haven’t been famed in humor nodes, we’ve got an inclination to favour this hy- pothesis for three reasons. First, MCC might arise American state novo in humor nodes from tissue or stem cells of the humor crisscross sys- tem [22, 23] and Second, PET-TC failed to disclose lesions elsewhere. Third, the long disease-free survival in our patient with primary MCC nodal presentation is rare for organic process MCC. Chronic immunological disorder, as seen in HIV infection, CLL, or in- duced (organ transplantation), seems to be a vital risk issue for MCC [24]. However, in our series, none of the patients had concomitant im- munologic disorders. diagnosing of MCC remains troublesome and needs immunohistochemical confirmation (positivity for CK20, chro- mogranin, synaptophysin, and NSE; negativity for S100, TTF-1 and pan-cytokeratin). Recently, the Merkel cell polyomavirus has been in- volved within the pathological process of MCC [5, 7-9, 25-27]. MCPyV deoxyribonucleic acid has been recently detected as a possible morbific issue for MCC. within the general population, its seropreva- lence is nine you bored with youngsters younger than four years ma- ture and will increase to thirty five you interested by 4–13 years mature [27]. victimisation immunoassays, Tolstov et al., found that eightieth of healthy North yank adults (blood donors) showed proof for past MCPyV Case 1 A forty one year-old lady was named our establishment in Gregorian calendar month 2003 as a result of a body covering formation within the right area region related to moderate pain. She was in smart clinical performance; her anamnesis was outstanding just for severe high blood pressure treated with ACE inhibitors. CT scan unconcealed a solid ex- pansive oval formation of 5x6x7 cm within the right area space with well-defined contours. She was subjected to radical excision of the lesion and area humour nodes. a complete of 5 humour nodes were excised. as- sociate degreeatomy} unconcealed an intranodal MCC, with diffuse in- filtration by tumour cells that turned imunohistochemically positive for CK20, chromogranin, synaptophysin, and NSE, and negative for S100, TTF-1 and pan-cytokeratin. The remaining humour nodes were unin- volved. Physical examination, routine blood tests and total body PET/ TC scan failed to yield clues to the first website of tumour. This atypical presentation prompted North American nation to implement adjuvant therapy with carboplatin at United Self-Defense Force of Colombia four on day one and etoposide at eighty mg/ M2 on days 1-3, recurrent each twenty one days for four courses. therapy was well tolerated and no se- rious adverse events were determined. PCR analysis unconcealed the presence of MCPyV polymer in tumour samples. No repetition of mal- ady was detected once a ten-year follow-up. Case 2 In Sep 2004, a fifty seven year-old lady was seen at our establishment with associate indolent, soft, bluish-red swelling (maximum diameter of two cm) within the superior-internal quadrant of the left cheek. She was in smart clinical performance; her anamnesis was positive for moderate blood vessel high blood pressure of annual period and chronic hepa- titis C. Ultrasound unconcealed a hypoechoic nodule, with irregular margins, activity 20x8 millimetre. Surgical removal of the lesion was performed. Microscopic examination unconcealed the diagnosing of a Merkel cell malignant neoplastic disease. watch node diagnostic assay was negative. PET- CT scan was negative, and therefore the malady was categorised as stage II. The patient received associate exclusive radia- tion treatment at 60Gy. FFPE tissue specimens were tested positive for MCPyV polymer by PCR. No repetition of malady was detected once associate eight-year follow-up. Case 3 In February 2005, a fifty nine year-old man with associate indolent, soft, nodular lesion (maximum diameter of three cm) within the inferior-in- ternal quadrant of the correct cheek was visited in our patient clinic. His anamnesis disclosed severe high blood pressure. Ultrasound examina- tion unconcealed a hypoechoic nodule, with irregular margins, activity 30x6 millimetre. Wide excision and SLNB were performed. Microscopic examination showed MCC. watch node was negative. The patient was classified as having stage II malady. radiation was planned following surgery. FFPE tissue specimens were tested positive for MCPyV poly- mer by PCR. No repetition of malady was detected once a seven-year follow-up. Case 4 In could 2005, a fifty five year-old girl was seen at our establishment with Associate in Nursing indolent, soft, nodular lesion (maximum diameter of two cm) within the internal region of the left cheek. Her anamnesis was exceptional for moderate high blood pressure and chronic viral hepatitis. Ultrasound showed a hypoechoic nodule, with irregular mar- gins, mensuration 22x14 metric linear unit. Surgical excision of the lesion with wide margins and SLN dissection were performed. Micro- scopic examination discovered a MCC. SLN was negative. The patient was outlined as having stage II unwellness. Adjuvant radiation to the Case report Page - 02

World Journal of Clinical Cancer Research www.directivepublications.org exposure. per this, MCPyV was detected in eightieth of cutaneal swabs from healthy volunteers, suggesting it’s going to be a standard individu- al of the human skin [28]. though MCPyV is powerfully related to MCC and plenty of studies support its role in pathologic process, the presence of virus isn’t adequate to induce MCC carcinogenesis. MCPyV encodes an outsized T tumour matter (LT) and atiny low matter tumour (sT), that each play a job in MCC pathologic process by targeting many tumour suppressor genes [29]. Conclusion All of our patient tissue specimens were tested positive for MCPyV. above all, four tissue specimens were tested positive by the LT1 and M1/2 primer sets (nested PCR), whereas only one specimen resulted positive either by victimisation the primer sets LT1 and M1/2 or LT3. These findings, beside the notion that no case arose on sun-exposed ar- eas, could strengthen the role of MCPyV within the pathologic process of this peculiar sort of tumour. However, any studies area unit required to handle this issue. References 1. Toker C (1972) Trabecular carcinoma of the skin. Arch Der- matol 105:107–110. 2. Lemos B, Nghiem P (2007) Merkel cell carcinoma: more deaths but still no pathway to blame. J Invest Dermatol 127:2100–2103. 3. Agelli M, Clegg LX (2003) Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49:832–841. 4. Feng H, Shuda M, Chang Y, Moore PS (2008) Clonal inte- gration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096– 1100. 5. Becker JC, Houben R, Ugurel S, Trefzer U, Pföhler C, et al. (2009) MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol 129: 248–250. 6. Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M, et al. (2009) Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmo- nary neuroendocrine carcinomas. Am J Surg Pathol 33:1378– 1385. 7. Kassem A, Schöpflin A, Diaz C, Weyers W, Stickeler E, et al. (2008) Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68:5009–5013. 8. Foulongne V, Dereure O, Kluger N, Molès JP, Guillot B, et al. (2010) Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol 162: 59–63. 9. Sihto H, Kukko H, Koljonen V, Sankila R, Böhling T, et al. (2009) Clinical factors associated with Merkel cell polyoma- virus infection in Merkel cell carcinoma. J Natl Cancer Inst 101:938–945. 10. Garneski KM, Warcola AH, Feng Q, Kiviat NB, Leonard JH, et al. (2009) Merkel cell polyomavirus is more frequently pres- ent in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 129:246–248. 11. Erovic I, Erovic BM (2013) Merkel cell carcinoma: the past, the present, and the future. J Skin Cancer 2013: 929364. 12. Lunder EJ, Stern RS (1998) Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N Engl J Med 339:1247–1248. 13. http://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf 14. Andea AA, Coit DG, Amin B, Busam KJ (2008) Merkel cell carcinoma: histologic features and prognosis. Cancer 113:2549–2558. 15. Goessling W, McKee PH, Mayer RJ (2002) Merkel cell carci- noma. J Clin Oncol 20:588–598. 16. Nghiem P, McKee PH, Haynes HA (2001) Merkel cell (cu- taneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. Hamilton, Ontario: BC Decker Inc., pp.127–141. 17. Nghiem P, James N (2008) Merkel cell carcinoma. In: Wolff K, Goldsmith LA, Katz SI, et al., eds.: Fitzpatrick’s Derma- tology in General Medicine. 7th ed. New York, NY: Mc- Graw-Hill, pp.1087– 1094. 18. Eng TY, Boersma MG, Fuller CD, Goytia V, Jones WE, et al. (2007) A comprehensive review of the treatment of Merkel cell carcinoma Am J Clin Oncol 30:624–636. 19. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, et al. (2001) Multimodality treatment of Merkel cell carcino- ma: case series and literature review of 1024 cases. Ann Surg Oncol 8:204– 208. 20. Busse PM, Clark JR, Muse VV, Liu V (2008) Case records of the Massachusetts General Hospital. Case 19-2008. A 63-year- old HIV- positive man with cutaneous Merkel-cell carcinoma. N Engl J Med 358:2717–2723. 21. Rockville Merkel Cell Carcinoma Group (2009) Merkel cell carcinoma: recent progress and current priorities on etiolo- gy, pathogenesis, and clinical management. J Clin Oncol 27: 4021– 4026.

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World Journal of Clinical Cancer Research www.directivepublications.org 25. Andres C, Belloni B, Puchta U, Sander CA, Flaig MJ (2010) Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol 37:28–34. 26. Kassem A, Technau K, Kurz AK, Pantulu D, Löning M (2009) Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. Int J Cancer 125:356–361. 27. Chang Y, Moore PS (2012) Merkel cell carcinoma: a virus-in- duced human cancer. Annu Rev 7:123–144. 28. Foulongne V, Kluger N, Dereure O, Mercier G, Molès JP, et al. (2010) Merkel cell polyomavirus in cutaneous swabs. Emerg Infect Dis 16:685–687. 29. Schrama D, Peitsch WK, Zapatka M, Kneitz H, Houben R, et al. (2011) Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Derma- tol 131:1631–1638. Case report Page - 04

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