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Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm of neuroendocrine origin. It is most commonly diagnosed in elder white males. MCC patients usually present with an indurated nodule on regularly sun-exposed skin. This type of tumor is characterized by aggressive growth, high rates of recurrence and lymph node metastasis. Still, patients have a favorable prognosis if the disease is diagnosed in early stages. Advanced-stage MCC is associated with a poor prognosis.


Presentation

MCC typically present as tender, indurated nodules or plaques, and they are most frequently observed in the face or on the ears. They are also common on scalp, neck, shoulders, and arms, but rarely develop on the trunk or lower limbs [1]. According to an Australian research group, the most characteristic features of MCC are nodular morphology, sharp circumscription, cherry-red color, and opalescent surface. These qualities are each observed in >75% of all cases [2]. MCC tend to grow rapidly, but they aren't usually associated with clinical symptoms other then the presence of a discrete mass.

Lymphadenopathy
  • Positron Emission Tomography (PET)-CT -scanshowed hypermetabolic inguinal and retroperitoneal lymphadenopathies, no primary tumour. On the second dermatological examination a pink, 2 cm plaque on the anterior left knee was noted.[ncbi.nlm.nih.gov]
  • Eight months after surgery, whole-body FDG PET/CT demonstrated intensely hypermetabolic hepatic metastases and abdominal lymphadenopathy.[ncbi.nlm.nih.gov]
  • We overview the correlation between Merkel tumor and CCL, the differential diagnosis of regional lymphadenopathy and the strategies of treatment. Key words: Chronic lymphocytic leukemia, Merkel tumor, regional lymphadenopathy.[medicina-interna.ro]
  • Ultrasound hypoechoic solid nodules arising from the dermis, with variable degrees of invasion and posterior acoustic transmission CT area of high attenuation within soft tissue associated lymphadenopathy readily enhances with contrast PET FDG avid hyper-metabolic[radiopaedia.org]
Soft Tissue Mass
  • KEYWORDS: Merkel cell carcinoma; dermatologic ultrasound; neuroendocrine tumors; oncology; skin ultrasound; soft tissue masses; superficial structures[ncbi.nlm.nih.gov]
  • On MR imaging, the large soft-tissue mass was of intermediate signal intensity on T1-weighted ( Fig 1C ) and T2-weighted imaging.[ajnr.org]
  • Blacksin, Doo-Hoe Ha, Meera Hameed and Seena Aisner, Superficial Soft-Tissue Masses of the Extremities, RadioGraphics, 26, 5, (1289), (2006). L.A. Mills, A.J. Durrani and J.D.[dx.doi.org]
Agent Orange
  • Only one patient, who presented with stage III disease, was documented to have had exposure to the combination of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid (Agent Orange). Table 2.[doi.org]
Painless Jaundice
  • A 63-year-old white man with no significant previous medical or surgical history presented with painless jaundice after 3 weeks of dark urine, yellow stools, and a 9-pound weight loss.[ncbi.nlm.nih.gov]
Collapse
  • We collapsed the staging variable into 3 categories termed extent of disease, which was defined as local (stages IA, IB, IIA, and IIB), regional (stages IIIA, IIIB, and any nodal disease), and distant (stage IV and regional/distant metastasis not otherwise[doi.org]
Early Satiety
  • The investigators report a case of MCC metastatic to the stomach presenting with melena, syncope, early satiety, increasing fatigue, and unintentional weight loss.[ncbi.nlm.nih.gov]
Xerostomia
  • Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia.[ncbi.nlm.nih.gov]
Erythema
  • Other potential risk factors for Merkel cell carcinoma include erythema ab igne and congenital ectodermal dysplasia.[emedicine.com]
Skin Ulcer
  • Merkel cell carcinoma – a rare cause of non-healing skin ulcer: a case report. J. Indian Med. Assoc. 110(7), 496–498 ( 2012 ). Medline, Google Scholar 61 Grenader T, Shavit L.[doi.org]
Withdrawn
  • Indeed, MCC regression occurs when immunosuppression therapy is suspended/withdrawn ( 38 ).[doi.org]
  • Patients were not withdrawn from follow-up at the date of diagnosis of a second cancer; therefore, the analysis allowed for risk estimation of third or higher order cancers.[doi.org]
Testicular Mass
  • Ultrasound imaging confirmed a large testicular mass, and he underwent left orchiectomy. His histological examination revealed a neuroendocrine tumor with an immunostaining pattern suggesting Merkel cell carcinoma.[ncbi.nlm.nih.gov]
Testicular Swelling
  • A 66-year-old Maori man presented to our hospital with left testicular swelling. His alpha-fetoprotein and beta-human chorionic gonadotrophin levels were within normal limits. His lactate dehydrogenase concentration was elevated to 267 U/L.[ncbi.nlm.nih.gov]
Ataxia
  • A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia.[ncbi.nlm.nih.gov]
  • […] telangiectasia and Rad3 related; ATM, ataxia telangiectasia mutated; Fox04, forkhead transcription factor FoxO4; MDM2, mouse double minute 2 homolog.[doi.org]
Dysarthria
  • Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia.[ncbi.nlm.nih.gov]
Vertigo
  • A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia.[ncbi.nlm.nih.gov]

Workup

The dermoscopic assessment of skin lesion and the histological examination of tissue samples obtained by biopsy are the supporting pillars of MCC diagnosis. With regard to the former, the presence of polymorphous and linear irregular, arborizing vessels has been reported as a distinguishing feature. These vessels are of large caliber and are often poorly focused. There are milky pink and white areas, some of which are shiny and/or structureless. In general, architectural disorder may be considered a property of malignant skin tumors, so it's not unique to MCC, but regular patterns more likely indicate a benign neoplasm. Pigmentation and hyperkeratosis are not characteristic of MCC [2].

In any case, an additional microscopic and immunohistochemical characterization is required to support a tentative diagnosis of MCC [3]. These tumors are located in the dermis, but may invade the subcutis and underlying tissues such as muscle, cartilage, and bone. They rarely spread to the overlying epidermis. MCC are composed of small, round tumor cells that stain blue with hematoxylin in hematoxylin and eosin staining. The often form sheets, nests, or trabeculae, but may also aggregate in other formations. Tumor cells carry vesicular or finely granular nuclei with small nucleoli that leave little room for cytoplasm. The mitotic index is generally high. Infiltration of inflammatory cells and necrotic foci are occasionally observed [4].

Up to 90% of MCC express cytokeratin 20, a low-molecular-weight keratin to be found in Merkel cells, gastrointestinal epithelium, gastrointestinal and transitional cell carcinomas [5]. Tumors with morphological and histological features suggestive of MCC that don't express cytokeratin 20 may express neurofilament. By contrast, MCC typically test negative for cytokeratin 7 and thyroid transcription factor 1 [3].

Lymph node involvement is first assessed clinically. As indicated below, sentinel lymph node biopsies are recommended for patients who don't present clinical symptoms of lymph node metastasis. Tissue samples should also be obtained and histologically examined in cases of lymphadenopathy, and these patients should also undergo imaging procedures. Diagnostic imaging is also required if distant metastases are suspected [3].

In light of the discovery of the Merkel cell polyomavirus in 2008, serological and virological studies may now be carried out to complement the aforementioned diagnostic approach [6]. The results may be of therapeutic and prognostic relevance, but data on this matter are still scarce.

Foam Cell
  • Histopathologically, the excised specimen was indicative of MCC coincident with SCC and showed extensive necrosis in the upper portion of the tumor, numerous caspase-3-positive apoptotic cells, an accumulation of CD68-positive foam cells and vascular[ncbi.nlm.nih.gov]

Treatment

Surgical removal of the tumor and adjuvant radiotherapy are the mainstays of MCC therapy in case of localized disease. The invasive growth of the neoplasm warrants wide excision margins regardless of the size of the primary tumor. A distance of about 2 cm to the visible borders of the cutaneous lesions should be maintained [5]. A complete histological examination of the surgical margins should be carried out, especially if a rather narrow excision had to be performed. Furthermore, sentinel lymph node biopsies should be carried out to ensure the accuracy of clinical tumor staging [3].

Patients with overt lymph node involvement should undergo neck dissection and adjuvant radiotherapy. Surface-mold computer-optimized high-dose-rate brachytherapy may be offered to patients who require palliative treatment [5].

Of note, molecular targeted and immune-based therapies have not yet been approved for the treatment of MCC but are currently on trial [7]. They aim at eliminating the etiologic agent Merkel cell polyomavirus and at canceling its effects.

Prognosis

The cause-specific five-year survival rate has been estimated to 88% [1]. Overall five-year survival rates of about 50% have also been reported, but these data should be interpreted considering the mean age of MCC patients: During five-year follow-ups, rather large numbers of them die of other forms of cancer or non-related diseases. In general, mortality depends on the age of the patient (higher mortality of elder individuals), the anatomical location of the tumor and its size (larger MCC and MCC on trunk or lower limbs associated with higher risks), and tumor stage (lower survival rates in case of advanced-stage disease) [1] [3]. Fortunately, most patients present with localized disease, and advances in MCC diagnosis increasingly allow for an early recognition of the disease [3].

Etiology

Merkel cells are mechanoreceptors connected to somatosensory afferent nerve endings and are involved in the perception of touch and pressure. They are also known to produce somatostatin and other mediators exerting endocrine and paracrine effects, and have thus been classified as neuroendocrine cells. Because MCC tumor cells share important morphological and immunohistochemical features with Merkel cells, the latter have long since been assumed to be the origin of the former, and MCC are often referred to as neuroendocrine neoplasms [3]. However, epithelial cells and sarcomatous elements have repeatedly been identified in MCC, and these observations led to the hypothesis of MCC arising from a common precursor or stem cell still able to differentiate into various cell lines [8]. On the other hand, pro/pre- or pre-B cells have been proposed as possible cells of origin of MCC. This hypothesis is supported by the fact that MCC commonly express terminal deoxynucleotidyl transferase and paired box gene 5, genes whose expression is generally restricted to pro/pre- and pre-B cells [9].

Epidemiology

The annual incidence of MCC ranges between 1 and 16 per 1,000,000 inhabitants, with lowest rates calculated for Northern Europe and highest rates observed in Australia and Oceania [1]. In general, the number of MCC cases has been rising over the last few decades, but it could not yet be clarified whether this trend corresponds to a true increase of disease incidence or whether it reflects the continuous improvement of MCC diagnosis [8]. Men are affected more than twice as often as women, and individuals with white skin are much more frequently diagnosed with MCC than patients with darker skin [1] [8]. However, MCC has been diagnosed in patients of African ancestry [3]. The individual risk of developing MCC augments with age. At the time of diagnosis, about two thirds of MCC patients are older than 70 years [1].

Sex distribution
Age distribution

Pathophysiology

MCC pathogenesis likely is a multistep and multifactorial process affected by genetic, molecular, and environmental factors that have only been partially identified so far. According to current knowledge, exposure to ultraviolet radiation and immunosuppression are among the main risk factors for MCC.

The apparent relation between a patient's immune status and their predisposition for MCC development supports the hypothesis of viral pathogens being implicated in MCC pathogenesis. In fact, Feng and colleagues detected a previously unknown polyomavirus in 80% of MCC samples examined for its presence. This virus has subsequently been named Merkel cell polyomavirus and was found to be integrated within the tumor genome in a clonal pattern, indicating that the infection took place before the malignant degeneration [10]. However, an infection with Merkel cell polyomavirus doesn't seem to be able to trigger tumor development in the absence of a set of mutations that render it replication-defective [6]. The fact that cancerogenesis isn't initiated before such mutations occur may also explain why few people ever develop MCC, despite the fact that large parts of the global population are infected with Merkel cell polyomavirus: Its prevalence exceeds 80% among people aged 50 years and older [11]. Be that as it may, exposure to ultraviolet rays may induce mutations in the viral genome that finally trigger tumorgenesis. Tumor growth is then again maintained by Merkel cell polyomavirus. The virus expresses two putative oncoproteins, the large T-antigen and the small T-antigen. It has been hypothesized that the large T-antigen favors an abnormal cell cycle transit, while the small T-antigen enhances cap-dependent translation [6]. Additionally, tumor cells tend to accumulate somatic mutations. They are either induced by ultraviolet radiation or caused by the integration of the viral DNA into the host cell genome, and they cannot be corrected due to defective DNA repair systems [3].

Prevention

Risk factors for the development of MCC include exposure to ultraviolet radiation, immunosuppression, male gender, and old age [8]. While age and gender are unchangeable factors, preventive measures can be taken to minimize the exposure to ultraviolet rays and to avoid immunosuppression as far as possible. Patients should be encouraged to always use sunscreen when pursuing outdoor activities. The sun protection factor should be chosen according to personal, regional and weather-dependent requirements. In this context, maximum sun protection should be recommended for the elderly, for immunosuppressed patients, in high-risk areas such as Australia, Southern Africa, and South America, at high altitude and on days with high levels of ultraviolet radiation.

Summary

MCC is a rare and highly invasive cutaneous malignancy most commonly developing on sun-exposed areas of head and neck [3]. MCC consist of tumor cells that resemble cutaneous Merkel cells in their main histological features, which explains the designation chosen for this neoplasm. However, whether or not MCC derive from Merkel cells or a common precursor remains an issue of debate [1]. While ultraviolet radiation and immunosuppression have been identified as main risk factors in numerous epidemiological studies, Merkel cell polyomavirus has only recently been discovered and suggested as the causative agent of the disease [10]. If this viral pathogen plays an essential role in MCC tumorgenesis, immune-based therapies may be developed to complement the current range of treatment options, which is limited to surgical resection of the primary tumor and its metastases, and radiotherapy [7].

Patient Information

Merkel cell carcinoma (MCC) is a rare malignancy of the skin. It is most commonly observed in the elderly, with men being affected more frequently than women. Furthermore, individuals with fair skin are more likely to develop MCC than those with darker skin. Besides age and gender, the patients' immune status and exposure to ultraviolet radiation have been identified as risk factors. Thus, it doesn't come as a surprise that highest incidence rates have been observed in Australia and that MCC typically grows in the face or on the ears, on scalp, neck, shoulders, or arms. The regular use of sunscreen with a high sun protection factor is the most efficient measure to prevent the onset of MCC that is currently known.

MCC present as tender, indurated nodules that rapidly increase in size. Most commonly, they are of cherry-red color, have a shiny surface, and are well demarcated against surrounding tissues. They don't usually cause clinical symptoms other then the presence of a discrete mass. In order to recognize MCC, dermoscopic and histological examinations are required. In order to carry out the latter, tissue samples have to be obtained by biopsy. Sometimes, the whole node is surgically removed and subsequently examined without being biopsied before. In any case, biopsies have to be carried out, to assess the condition of the regional lymph nodes because MCC tend to metastasize to these organs.

Treatment is based on the excision of the primary tumor and affected regional lymph nodes, and subsequent radiotherapy. Most MCC are well susceptible to radiation. The patients' prognosis depends on their age, the anatomical location of the tumor and its size, and the tumor stage at the time of diagnosis. If they are diagnosed during early stages of the disease, they have a favorable prognosis. By contrast, metastatic MCC is associated with a poor prognosis.

References

Article

  1. Youlden DR, Soyer HP, Youl PH, Fritschi L, Baade PD. Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993-2010. JAMA Dermatol. 2014; 150(8):864-872.
  2. Jalilian C, Chamberlain AJ, Haskett M, et al. Clinical and dermoscopic characteristics of Merkel cell carcinoma. Br J Dermatol. 2013; 169(2):294-297.
  3. Coggshall K, Tello TL, North JP, Yu SS. Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging. J Am Acad Dermatol. 2018; 78(3):433-442.
  4. Chang Y, Moore PS. Merkel cell carcinoma: a virus-induced human cancer. Annu Rev Pathol. 2012; 7:123-144.
  5. Huber GF. Modern management of Merkel cell carcinoma. Curr Opin Otolaryngol Head Neck Surg. 2014; 22(2):109-115.
  6. Arora R, Chang Y, Moore PS. MCV and Merkel cell carcinoma: a molecular success story. Curr Opin Virol. 2012; 2(4):489-498.
  7. Tello TL, Coggshall K, Yom SS, Yu SS. Merkel cell carcinoma: An update and review: Current and future therapy. J Am Acad Dermatol. 2018; 78(3):445-454.
  8. Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010; 37(1):20-27.
  9. zur Hausen A, Rennspiess D, Winnepenninckx V, Speel EJ, Kurz AK. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res. 2013; 73(16):4982-4987.
  10. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008; 319(5866):1096-1100.
  11. Tolstov YL, Pastrana DV, Feng H, et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer. 2009; 125(6):1250-1256.

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Last updated: 2019-07-11 20:58