Merkel cell carcinoma C44.L

Cyril Toker, 1972

Rare, highly malignant, often rapidly and aggressively growing skin tumor with neuroendocrine and epithelial differentiation, high recurrence rates and a high lymphogenic metastasis tendency.

Incidence: 0.3-0.6/100,000 inhabitants/year with increasing trend. In the Federal Republic of Germany about 300 new cases per year are expected nationwide.

Unresolved.

Originally, the thesis arose that Merkel cell carcinoma derived from Merkel cells due to a common expression of epithelial cytokeratin (CK20) and neuroendocrine (synaptophysin, chromogranin A, CD56). This hypothesis is currently in doubt, also in view of significant differences in gene expression between Merkel cell carcinoma and Merkel cell (genes found in Merkel cell carcinoma (KIT, PAX-5, TdT, BCL-2) are not encountered in Merkel cell.

It is now believed, among other things, that the Merkel cell is derived from an (epi)dermal pluripotent stem cell (Sauer CM et al. 2017), so that a pluripotent stem cell is assumed to be the origin. Various arguments suggest that, at least for the intermediate type of Merkel cell carcinoma, a pre/pro B cell may also be a cell of origin. This is supported by the protein expression of several early B cell markers (early B cell factor 1, E2A). The detectable expression of various immunoglobulins (IgA,-G,-M) would also be unusual for a malignant epithelial skin tumor.

A high cumulative UV radiation exposure is considered a risk factor.

Furthermore, it occurs frequently in immunosuppression after organ transplantation (risk factor increased 13-fold in immunosuppression), in B-cell lymphomas as well as other haematological diseases and in HIV infection.

There are also clear indications that the disease is caused by a polyomavirus(Merkel cell polyomavirus - MCPyV). The viral infection causes, among other things, "epigenetic silencing" in that the infected cell expresses a histone deacetylase that leads to the formation of transcriptionally inactive heterochromatin and thus to the reduced expression of tumor suppressor proteins. This deprives the tumor of immunological control. Various immunogens can no longer become active.

To what extent the association of Merkel cell carcinoma and Lambert-Eaton myasthenic syndrome (LEMS), a rare, often paraneoplastic autoimmune disease caused by antibodies against the presynatpic voltage-gated calcium channels, plays a pathogenetic role remains to be seen (Troyanova -Slavkova S et al. 2018)

Occurs mainly in older people. The mean age at diagnosis is 75 years.

No clear gender preference.

Merkel cell carcinoma practically does not occur in children.

Particularly light-exposed areas, especially the head and neck area (49%); less frequently extremities (33%) and trunk (27%). Palms and soles of the feet are left out

Mostly solitary, often rapidly growing (within a few weeks and months), dermal, reddish or bluish, painless, hemispherical, 1.0-4.0 cm nodule or correspondingly large plaque in the area of the head or extremities (in light-exposed areas). The surface of the nodule is smooth, rarely ulcerated or crusted. At depth, an iceberg-like widening of the nodule is often found. Rarer are plaque-like variants. There is a great tendency to postoperative local recurrence!

Coincidence with other malignant epithelial tumors(squamous cellcarcinoma, basal cell carcinoma, malignancies of the salivary glands and bile ducts) is not uncommon.

• Histological classification:
  • Intermediary cell type (most frequent manifestation): Process localized in the dermis. Uniform, immature, usually blurred tumour. The tumour cells have large, monomorphic, pale nuclei surrounded by a narrow cytoplasmic border. Mitoses are numerous. Necroses are rare.
  • Trabecular type (best prognosis of all 3 types): Medium sized, monomorphic tumor cells showing a striking trabecular growth pattern.
  • Small cell type (rather aggressive growth pattern): Consists of small cells with conspicuous hyperchromatic nuclei. Frequent necroses.
• Immunohistology: The examination with antibodies against intermediary filament proteins and against neuroendocrine markers is indispensable in the diagnosis of Merkel cell carcinoma today.
  • Intermediate filament proteins include the low molecular weight cytokeratins CK-8, -18, -20 and neurofilament. The detection of CK-20 (cytokeratin-20) is the most important factor in establishing a diagnosis.
  • Neuroendocrine markers: Chromogranin A, synaptophysin, neuron-specific enolase, protein gene product 9.5, neuropeptides, neural adhesion molecule (NCAM), peripheline may be positive.
  • The thyroid transcription factor (TTF-1) is negative (important parameter in the differentiation from small cell bronchial carcinoma).

• Basal cell carcinoma
• Angioma
• Hidradenoma
• B-cell lymphoma
• Skin metastases
• Amelanotic melanoma

Due to the rapid growth of the tumor, a number of differential diagnoses can be ruled out.

Primary tumor and local recurrence:

In cases of high-grade suspicion of MCC, direct complete excision, should be preferred to a trial biopsy (Haymerle G et al. 2015).

In primary tumors without evidence of the presence of organ metastases, complete surgical excision followed by an "adequate" safety margin should be performed.

According to the current German S2k guideline for Merkel cell carcinoma (valid until December 30, 2021), excision of the primary tumor is recommended with a safety margin of 1 cm in stage I and 2 cm in stage II. In special localizations, e.g. head and neck region, a smaller safety distance must be chosen due to the anatomical conditions and the preservation of functionality.

Elective lymph node excision is no longer recommended.

For small primary tumors (< 2.0cm), excision alone seems to be a sufficient option according to a larger study (n=104 patients). Adjuvant local radiotherapy is questioned (From ML 2016).

Sentinel LC biopsy is an important diagnostic measure to evaluate lymph node status (see Prognosis below).

Lymph node metastases and lymphatic drainage metastases: Radical lymphadenectomy with adjuvant radiotherapy of the area of primary tumor and lymphatic drainage area.

In-transit metastases should also be treated surgically/radiotherapy.

Distant metastases or unresectable MCC:

Immune checkpoint inhibitors (ICIs).

In distant metastatic or unresectable stage, immune checkpoint inhibitors (ICIs) are now the first-line therapy. Unlike chemotherapies, ICIs are more tolerable and show long-lasting success. For metastatic MCC, the all-human anti-PD-L1 antibody avelumab, has been approved as an immune checkpoint inhibitor for first-line therapy since September 2017. Avelumab (Merck KGaA) selectively inhibits the PD-1/PD-L1 interaction between T cells and tumor cells. In addition, antibody-dependent cellular cytotoxicity may also contribute to the effect via the Fc portion of the IgG1 antibody. Dosage: 10mg/kgKG i.v. every 2 weeks.

Alternative: For metastatic Merkel cell carcinoma, other ICIs are available with nivolumab and pembrolizumab, two anti-PD-1 antibodies (Nghiem PT et al. 2016). However, neither ICI has yet been approved for MCC. However, positive evidence for a good response has been shown in the first prospective studies.

Chemotherapies

The literature demonstrates impressive but short-lived success. Improvement in overall survival has not been demonstrated to date. In clinical practice, chemotherapies are rarely still used for MCC due to the success of ICI. Therapeutic procedures lean toward those of small cell bronchial carcinoma. Satisfactory results are available for the CMF regimen (cyclophosphamide/methotrexate/5-fluorouracil).

• Alternative: low-dose regimen with etoposide (100 mg/day p.o.).
• Alternative: etoposide/carboplatin or etoposide/cyclophosphamide.
• Alternative: octreotide (e.g., Sandostatin). This somatostatin analogue leads to stimulation of somatostatin receptors and growth arrest of tumor cells. Dosage: 500-1000 µg s.c. 3 times/day until tumor regression.

Several studies showed that a combined surgical/radiotherapy approach is superior to excision alone. Both the surgical field and the lymphatic drainage area should be included. Retrospective studies show that this reduces the local recurrence rate. Fast electrons are suitable (ED: 5 times/week 2.0 G; GD: 50 Gy adjuvant or 60-66 Gy if tumour is detected at the edge of the incision or 70 Gy in an inoperable situation).

In a large collective (n=2093) of adult patients in stage I-III (mean age 73 years; 61.8M; 38.2w) 4 groups with different radiation modalities were formed (Patel et al 2017). The survival rates in the individual groups provide clear indications for: "low dose, low survival rate".

• Group 1 (>30-<40Gy; 3-year survival rate: 41.8%)
• Group 2 (40<50Gy; 3-year survival rate: 69%)
• Group 3 (50-55Gy; 3-year survival rate: 69.2%)
• Group 4 (>55-70Gy; 3-year survival rate: 66%)

Apparently, the diameter of the primary tumor (PT) and the tumor thickness (see TNM staging) play an important role for the clinical "outcome". With a diameter > 2cm there is a 6-7 fold increased probability of a positive sentinel lymph node. An increase in tumor thickness of 0.1 cm means a 21% increase in the probability of a positive SLN.

5-year survival rate: For a PT diameter < 2cm, this is between 66-75%; for PT > 2cm, 50-60%; in the presence of LK metastases, 5-year survival rates are reported between 42-52%, and for distant metastases around 18%.An unfavorable constellation is the combination: male, head and neck region, and an age < 60 years.

Alternative: chemotherapeutic agents. Therapy schemes with proven complete remission

• Aftercare period of at least 5 years:
• within the first year after removal of the primary tumour, close follow-up at intervals of about four to six weeks.
• After 12 months follow-up at 3-month intervals; later every six months.
• Diagnostics:
• Clinical examination with lymph node palpation and lymph node sonography, especially of the regional lymph node stations.
• Serological control of neuron-specific enolase and chromogranin A.
• Upper abdominal sonography and X-ray examination of the chest once a year.
• MRT and PET examinations depending on the clinical problem.

1. Agelli M et al (2003) Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49: 832-841
2. Beer TW et al (2008) Mast cells have a prognostic value in Merkel cell carcinoma. At J Dermatopathol 30: 27-30
3. Boccara O et al (2012) Guidelines for the diagnosis and treatment of Merkel cell carcinoma - Cutaneous Oncology Group of the French Society of Dermatology. Eur J Dermatol 22:375-379.
4. Feng H et al (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Sciencexpress.org/17 January/Page 1-5
5. Frohm ML et al (2016) Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site. JAMA Dermatol 152:1001-1007.
6. Garneski KM et al (2007) Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol 57: 166-169
7. Hauschild A, Garbe C (2006) Short guideline cutaneous neuroendocrine carcinoma (Merkel cell carcinoma). JDDG 7: 508-510
8. Haymerle G et al (2015) Management of Merkel cell carcinoma of unknown primary origin: the Vienna Medical School experience. Eur Arch Otorhinolaryngol 272:425-429
9. Kaufman HL et al(2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:1374-1385.
10. Nghiem PT et al (2016) PD-1 Blockade with pembrolizumab in advanced Merkel cell carcinoma. N Engl J Med 374: 2542-2552.
11. Patel SA et al (2017) Identifying an Optimal Adjuvant Radiotherapy Dose for Extremity and Trunk Merkel Cell Carcinoma Following Resection: An Analysis of the National Cancer Database.
12. JAMA Dermatol 153:1007-1014.
13. Raju S et al (2014) Treatment of Merkel cell carcinoma of the head and neck: a systematic review. Dermatol Surgery 40:1273-1283
14. Sauer CM et al. (2017) Merkel cell carcinoma: cutaneous manifestation of a highly malignant pre/pro B-cell neoplasia? dermatologist 68: 204-210.
15. Schwartz JL et al (2014) NCCN Guidelines implementation in the multidisciplinary Merkel Cell Carcinoma Program at the University of Michigan. J Natl Compr Canc Netw 12:434-441

16. Smith K et al (2003) Overview of Merkel cell carcinoma and recent advances in research. Int J Dermatol 42: 749-751

17. Su LD et al (2002) Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes. J Am Acad Dermatol 46: 661-666

18. Troyanakova-Slavkova S et al. (2018) A rare case of Lambert-Eaton myasthenic syndrome associated with Merkel cell carcinoma and pre-existent vitiligo. Act Dermatol 44: 109-113

19. Weiser H et al (2008) The Merkel cell carcinoma. Act Dermatol 34: 163-169