113: Merkel Cell Carcinoma

Question 1

What are the main risk factors associated with Merkel cell carcinoma (MCC)?

Answer 1

The main risk factors associated with MCC include:
- UV light exposure
- Advanced age
- Immune suppression
- Merkel cell polyomavirus (MCPyV)

Question 2

How has the incidence of Merkel cell carcinoma (MCC) changed from 1986 to 2006?

Answer 2

Between 1986 and 2006, the reported incidence of MCC quadrupled from 0.15 per 100,000 to 0.6 per 100,000 persons.

Question 3

What is the prognosis for patients with Merkel cell carcinoma (MCC) compared to those with invasive melanoma?

Answer 3

The prognosis for patients with MCC is markedly poorer, with a disease-associated mortality at 5 years of 46%, compared to 9% for invasive melanoma.

Question 4

What historical milestones contributed to the understanding of Merkel cell carcinoma (MCC)?

Answer 4

Key historical milestones include:
1. 1875 - Human Merkel cells were first described by Friedrich S. Merkel.
2. 1972 - Toker described cases of ‘trabecular cell carcinoma of the skin.’
3. 1980 - The name ‘Merkel cell carcinoma’ was first applied to this tumor.
4. 1992 - Antibodies to cytokeratin-20 were found to stain normal skin Merkel cells and most MCC tumors, aiding diagnosis.

Question 5

What demographic factors influence the incidence of Merkel cell carcinoma (MCC)?

Answer 5

Demographic factors influencing the incidence of MCC include:
- Age: More common in individuals older than 65 years.
- Race: Far more common in white individuals (0.23 per 100,000) compared to black individuals (0.01 per 100,000).
- Gender: Men are affected more than women (2:1 ratio) and tend to have a worse prognosis.

Question 6

What are the cutaneous findings that indicate a suspicion of Merkel Cell Carcinoma (MCC)?

Answer 6

89% of MCC cases exhibit at least 3 of the 5 features (AEIOU):
1. Asymptomatic (nontender, firm, red, purple, or skin-colored papule or nodule)
2. Expanding rapidly (significant growth noted within 1-3 months)
3. Immune suppression (e.g., HIV/AIDS, chronic lymphocytic leukemia)
4. Older than 50 years of age
5. Ultraviolet-exposed skin on a person with fair skin.

Question 7

What is the significance of presenting without an identifiable primary lesion in MCC patients?

Answer 7

MCC patients presenting without an identifiable primary lesion—’unknown primary’—have better outcomes than similarly staged patients with known primary tumors. This is due to immune-mediated regression of the primary lesion, allowing the immune system to recognize and respond to the disease.

Question 8

What are the common complications and outcomes for patients with Merkel Cell Carcinoma (MCC)?

Answer 8

The complications for those who do not experience metastasis depend on the therapy received:
- Surgical excision, radiation therapy, and possibly systemic therapy lead to relatively minimal complication rates and the best possible chance of cure.
- Very aggressive surgical excision, amputation, or chemotherapy for low-risk disease tend to have higher complication rates without improved outcomes.

Question 9

What is the association between Merkel Cell Carcinoma (MCC) and immune suppression?

Answer 9

MCC is strongly associated with immune suppression, with approximately 8% of MCC patients being profoundly immune suppressed, which is a 16-fold overrepresentation compared to what is expected. Conditions that increase the risk for MCC include HIV/AIDS, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and immune suppressive regimens associated with solid-organ transplantation.

Question 10

What is the significance of Merkel Cell Polyomavirus (MCPyV) in relation to MCC?

Answer 10

MCPyV is present in 80% of MCC tumors compared to only 7% of skin controls, indicating a strong association between MCPyV and MCC. It is the only known polyomavirus that integrates into the host’s DNA and is causal for human cancer, suggesting that the virus is present prior to or very early in tumorigenesis.

Question 11

What are the two mutational profiles identified in MCC tumors?

Answer 11

The two mutational profiles in MCC tumors are:
1. MCC-LO: Group of tumors with relatively low mutational burden (few single-nucleotide variants) and majority contained MCPyV (virus-positive).
2. MCC-HI: Tumors with relatively high mutational burden, virtually all were virus-negative, and mutations were almost entirely UV-induced.

Question 12

How do MCPyV and UV radiation contribute to MCC tumorigenesis?

Answer 12

MCPyV and UV radiation play distinct roles in MCC tumorigenesis:
- 80% virus-positive: Viral oncoproteins are expressed through clonal integration of viral DNA into the host genome.
- 20% virus-negative: UV-induced mutations are present at extremely high levels, with some mutations representing neoantigens visible to the immune system.

Question 13

What is the clinical significance of detecting antibodies to the MCPyV oncoprotein in MCC patients?

Answer 13

Detecting antibodies to the MCPyV oncoprotein is clinically useful for newly diagnosed MCC patients. If patients produce oncoprotein antibodies, tracking their antibody titer can help detect early MCC recurrence. Conversely, those who do not produce detectable oncoprotein antibodies have a higher risk of recurrence and require closer surveillance through clinical and radiologic examinations.

Question 14

How does the presence of an unknown primary lesion affect the outcomes for patients with Merkel Cell Carcinoma (MCC)?

Answer 14

Patients with MCC presenting without an identifiable primary lesion—termed ‘unknown primary’—have better outcomes than those with known primary tumors. This is due to immune-mediated regression of the primary lesion, allowing the immune system to recognize and respond effectively to the disease.

Question 15

What is the significance of the site of first recurrence in patients with Merkel Cell Carcinoma (MCC)?

Answer 15

The site of first recurrence is significant as it indicates the extent of disease progression:
- Local recurrences account for 21%
- Nodal recurrences (regional lymphadenopathy) account for 27%
- Distant recurrences occur at sites beyond the regional draining lymph nodes, accounting for 52%. This distribution can inform treatment strategies and prognosis.

Question 16

What is the relationship between immune suppression and the incidence of Merkel Cell Carcinoma (MCC)?

Answer 16

MCC is strongly associated with immune suppression. Approximately 8% of MCC patients are profoundly immune suppressed, which is a 16-fold overrepresentation compared to what is expected. Conditions that increase the risk for MCC include HIV/AIDS, non-Hodgkin lymphoma, and chronic treatment of autoimmune diseases.

Question 17

How does the presence of Merkel Cell Polyomavirus (MCPyV) correlate with mutational profiles in MCC tumors?

Answer 17

MCC tumors can be classified into two mutational profiles:
1. MCC-LO: Characterized by a low mutational burden and predominantly virus-positive (contain MCPyV).
2. MCC-HI: Characterized by a high mutational burden, virtually all are virus-negative, and mutations are primarily UV-induced.

Question 18

What role does the MCPyV oncoprotein play in the growth of Merkel Cell Carcinoma tumors?

Answer 18

The MCPyV oncoprotein, also known as the T-antigen, is present in approximately 80% of all MCC tumors and is critical for the growth of most MCC tumors. The presence of antibodies to the MCPyV oncoprotein can be measured using a clinically available serology test, which is useful for monitoring newly diagnosed MCC patients for recurrence.

Question 19

What are the implications of detecting antibodies to the MCPyV oncoprotein in patients with Merkel Cell Carcinoma?

Answer 19

Detecting antibodies to the MCPyV oncoprotein has significant clinical implications:
- Producing oncoprotein antibodies indicates that tracking their antibody titer can be used to detect early MCC recurrence.
- Not producing detectable oncoprotein antibodies is associated with a higher risk of recurrence, necessitating closer surveillance through clinical and radiologic examinations.

Question 20

How do the mechanisms of tumorigenesis differ between virus-positive and virus-negative Merkel Cell Carcinoma?

Answer 20

The mechanisms of tumorigenesis in MCC differ as follows:
- Virus-positive (80%): Viral oncoproteins are expressed through clonal integration of viral DNA into the host genome.
- Virus-negative (20%): Characterized by UV-induced mutations that are present at extremely high levels, with some mutations representing neoantigens visible to the immune system.

Question 21

What is the risk of recurrence in Merkel Cell Carcinoma (MCC)?

Answer 21

MCC has a higher risk of recurrence, necessitating closer surveillance through clinical and radiologic examinations.

Question 22

How do the mechanisms of tumorigenesis differ between virus-positive and virus-negative MCC?

Answer 22

In virus-positive MCC (80%), viral oncoproteins are expressed through clonal integration of viral DNA into the host genome. In virus-negative MCC (20%), UV-induced mutations are present at extremely high levels, with some mutations representing neoantigens visible to the immune system.

Question 23

What are the classic histologic features of Merkel Cell Carcinoma (MCC)?

Answer 23

• Sheets of small basophilic cells with scant cytoplasm, fine chromatin, and no nucleoli.
• Numerous mitotic figures and occasional individual necrotic cells.
• Lymphovascular invasion is common and can be found even in a ‘negative’ margin, explaining the high local recurrence rate in MCC.

Question 24

What are the three histologic patterns associated with MCC and their prognostic implications?

Answer 24

1. Intermediate type: Most common, uniform small cells with minimal cytoplasm, pale nuclei, and dispersed chromatin appearance.
2. Small cell type: Second most common, irregular hyperchromatic cells with scant cytoplasm arranged in linear patterns.
3. Trabecular type: Least common but most distinctive, described by Toker in 1972, with a lattice-like appearance.

Question 25

What is the significance of Cytokeratin-20 in the diagnosis of MCC?

Answer 25

- Cytokeratin-20 is an intermediate filament protein expressed in MCC. - It shows a 'perinuclear dot' pattern that is pathognomonic for MCC. - 10% to 20% of MCCs are cytokeratin-20 negative, which can complicate diagnosis.

Question 26

How does the Thyroid Transcription Factor-1 (TTF-1) help differentiate between MCC and small-cell lung cancer?

Answer 26

- Negative for TTF-1 indicates MCC. - Positive for TTF-1 indicates small-cell lung cancer. - This differentiation is crucial as both tumors can appear identical in routine histology.

Question 27

What is the role of the CM2B4 antibody in the diagnosis of MCC?

Answer 27

- The CM2B4 antibody tests for the MCPyV oncoprotein in MCC tumor tissue. - It is an excellent tool for determining if an MCC is virally induced. - Approximately 20% of MCCs are negative for this antibody, and viral positivity is associated with a moderately decreased risk of MCC recurrence.

Question 28

What is the significance of sentinel lymph node biopsy (SLNB) in the management of MCC?

Answer 28

- SLNB is a sensitive test for detecting MCC spread to the lymph nodes. - MCC has a higher likelihood of occult lymph node involvement (approximately 30%) compared to melanoma (~1%). - SLNB involves fewer nodes and has less morbidity than elective lymph node dissection, making it a preferred method.

Question 29

What are the key factors affecting the prognosis of MCC?

Answer 29

- Survival after a diagnosis of MCC is highly dependent on the stage at presentation. - Prognosis decreases markedly with nodal involvement and metastatic disease. - The AJCC's 8th edition staging system uses the TNM (tumor, node, metastasis) classification for evaluation.

Question 30

What other diagnostic markers can be used to confirm MCC if cytokeratin-20 is negative?

Answer 30

Other markers include CAM5.2 and MCPyV oncoprotein (CM2B4 antibody). Thyroid transcription factor-1 and cytokeratin-7 negativity can help differentiate MCC from small-cell lung carcinoma.

Question 31

What are the classic histologic features of MCC observed under a microscope?

Answer 31

- Sheets of small basophilic cells with scant cytoplasm, fine chromatin, and no nucleoli. - Numerous mitotic figures and occasional individual necrotic cells. - Lymphovascular invasion is common and can be found even in a 'negative' margin, contributing to high local recurrence rates.

Question 32

What are the three histologic patterns of MCC associated with prognosis?

Answer 32

1. Intermediate type: Most common, uniform small cells with minimal cytoplasm, pale nuclei, and dispersed chromatin appearance. 2. Small cell type: Second most common, irregular hyperchromatic cells with scant cytoplasm arranged in linear patterns. 3. Trabecular type: Least common, described by Toker in 1972, has a lattice-like appearance.

Question 33

How does the expression of Cytokeratin-20 relate to the diagnosis of MCC?

Answer 33

- Cytokeratin-20 is an intermediate filament protein expressed in MCC and is pathognomonic for it. - The 'perinuclear dot' pattern of cytokeratin is essential for diagnosis. - 10% to 20% of MCCs may be cytokeratin-20 negative, which complicates diagnosis.

Question 34

What is the significance of the Thyroid Transcription Factor-1 in differentiating MCC from small-cell lung cancer?

Answer 34

- Negative result indicates MCC. - Positive result indicates small-cell lung cancer. - This factor is useful for differential diagnosis between these two tumors that may appear identical in routine histology.

Question 35

What is the role of the CM2B4 antibody in the diagnosis of MCC?

Answer 35

- The CM2B4 antibody tests for the Merkel Cell Polyomavirus oncoprotein in MCC tumor tissue. - It is an excellent tool for determining if an MCC is virally induced. - Approximately 20% of MCCs are negative for this antibody, and viral positivity is associated with a moderately decreased risk of MCC recurrence.

Question 36

What factors influence the prognosis of a patient diagnosed with MCC?

Answer 36

- Survival is highly dependent on the stage at presentation. - Prognosis decreases markedly with nodal involvement and metastatic disease. - The AJCC's 8th edition staging system uses TNM classification and includes clinical evaluations and imaging studies.

Question 37

What is the importance of Sentinel Lymph Node Biopsy (SLNB) in the management of MCC?

Answer 37

- SLNB is a sensitive test for detecting MCC spread to lymph nodes. - Approximately 30% of MCC cases may have occult lymph node involvement, significantly higher than melanoma. - SLNB involves fewer nodes and has less morbidity compared to elective lymph node dissection, making it a preferred method.

Question 38

What is the significance of identifying microscopic lymph node disease in patients with MCC?

Answer 38

Identifying microscopic lymph node disease is critical because it is not apparent on clinical examination. 1/3 of patients with local-only disease may actually have occult nodal disease, affecting their survival.

Question 39

What are the prognostic findings on histology for MCC?

Answer 39

- Lymphovascular Invasion: Associated with worse overall survival. - Tumor Growth Pattern: Nodular is well circumscribed; infiltrative is associated with poor outcomes. - MCPyV positivity is associated with better outcomes.

Question 40

What is the initial management strategy for MCC at the primary site?

Answer 40

The initial management strategy for MCC at the primary site includes surgical excision of the tumor as the primary treatment.

Question 41

What is the role of radiation therapy in the treatment of MCC?

Answer 41

- MCC is an unusually radiosensitive tumor. - Radiation is often used as an adjuvant treatment following surgery. - Typical radiation doses range from 50 Gy to 56 Gy for a primary site.

Question 42

What imaging modality is recommended for baseline evaluation in MCC?

Answer 42

Baseline PET/CT scans are recommended for most patients except those with very low-risk disease (e.g., primary ≤1 cm and negative SLNB).

Question 43

What is the next step in management for a patient with a positive sentinel lymph node biopsy (SLNB)?

Answer 43

The draining lymph node bed should be treated, likely with radiation therapy.

Question 44

How does an infiltrative growth pattern affect prognosis in MCC?

Answer 44

An infiltrative growth pattern is associated with poor outcomes compared to a nodular growth pattern.

Question 45

How does lymphovascular invasion affect prognosis in MCC?

Answer 45

Lymphovascular invasion is associated with worse overall survival.

Question 46

Is baseline imaging recommended for a patient with a tumor diameter of 1.5 cm and negative SLNB?

Answer 46

Baseline imaging, such as PET/CT, is recommended for most patients except those with very low-risk disease (e.g., primary ≤1 cm and negative SLNB).

Question 47

How does a nodular growth pattern affect prognosis in MCC?

Answer 47

A nodular growth pattern is associated with better outcomes compared to an infiltrative growth pattern.

Question 48

How does a tumor positive for p63 affect prognosis in MCC?

Answer 48

Positive p63 is associated with a more aggressive clinical course.

Question 49

How does high CD8 lymphocyte infiltration affect prognosis in MCC?

Answer 49

High CD8 lymphocyte infiltration is independently associated with improved MCC-specific survival.

Question 50

How does downregulated intratumoral vascular E-selectin affect prognosis in MCC?

Answer 50

Downregulated intratumoral vascular E-selectin is associated with poor intratumoral CD8 lymphocyte infiltration and worse survival.

Question 51

How does MCPyV oncoprotein expression affect prognosis in MCC?

Answer 51

MCPyV oncoprotein expression is associated with better outcomes.

Question 52

What are the acute side effects of radiation therapy for MCC?

Answer 52

- Erythema at the site. - Mild-to-moderate fatigue that peaks toward the end of radiation and usually resolves within 1 to 2 months.

Question 53

What is the most significant potential side effect of radiation therapy in MCC patients?

Answer 53

Lymphedema, which is more common in lower extremities when radiation therapy is given to the inguinal lymph nodes.

Question 54

What are the recommended surveillance practices for MCC after diagnosis?

Answer 54

- Clinical examination every 3 to 6 months for the first 2 years after diagnosis, and every 6 to 12 months thereafter. - Imaging studies are recommended 'as clinically indicated.'

Question 55

What is the optimal treatment approach for MCC?

Answer 55

Optimal treatment should involve obtaining pathologically clear margins by surgery, typically with 1- to 2-cm margins if possible.

Question 56

What are the reasons against recommending adjuvant chemotherapy for MCC patients?

Answer 56

1. Mortality: 4% to 7% acute death rate from adjuvant chemotherapy. 2. Morbidity: Neutropenia occurs in 60% of patients. 3. Decreased quality of life: severe in older population. 4. Resistance to chemotherapy: MCC that recurs after chemotherapy is less responsive to later palliative chemotherapy. 5. Immunity: Chemotherapy suppresses immune function. 6. Outcomes are not improved: no survival benefit among node-positive patients who received chemotherapy.

Question 57

What percentage of patients with fever experience neutropenia?

Answer 57

Neutropenia occurs in 60% of patients with fever.

Question 58

What percentage of patients with fever experience sepsis?

Answer 58

Sepsis occurs in 40% of patients with fever.

Question 59

What are the severe quality of life effects of MCC in older populations?

Answer 59

Severe effects include fatigue, hair loss, and nausea/vomiting.

Question 60

How does chemotherapy affect resistance in MCC?

Answer 60

MCC that recurs after chemotherapy is less responsive to later palliative chemotherapy.

Question 61

What effect does chemotherapy have on immunity?

Answer 61

Chemotherapy suppresses immune function.

Question 62

Is there a survival benefit for node-positive patients receiving chemotherapy?

Answer 62

No survival benefit is observed among node-positive patients who received chemotherapy compared to those who did not.

Question 63

What are the typical radiation doses for MCC?

Answer 63

Typical radiation doses are 50-56 Gy in 2-Gy fractions, 5 times per week over 4-6 weeks.

Question 64

What are the potential acute side effects of radiation therapy for MCC?

Answer 64

Acute side effects include erythema at the site and mild-to-moderate fatigue.

Question 65

Is adjuvant radiation therapy recommended for MCC patients with a tumor diameter of 0.8 cm and negative SLNB?

Answer 65

Adjuvant radiation therapy is not recommended for MCC patients with good prognostic features.

Question 66

What is the recommended treatment for the draining lymph node bed in a patient with a 2.5 cm tumor and positive SLNB?

Answer 66

The draining lymph node bed should be treated with radiation therapy.

Question 67

What margin size is recommended for a patient with a 3 cm tumor undergoing surgery?

Answer 67

Margins of 1-2 cm are recommended, depending on the site.

Question 68

What is the local recurrence rate for a 2 cm tumor undergoing Mohs surgical excision with and without adjuvant radiation therapy?

Answer 68

The local recurrence rate is 16% for surgery alone and 0% for patients who also had adjuvant radiation therapy.

Question 69

Is adjuvant chemotherapy recommended for a patient with a 1 cm tumor and negative SLNB?

Answer 69

Adjuvant chemotherapy is not recommended for MCC patients whose disease has been treated with surgery or radiation therapy.

Question 70

What is the recommended surveillance approach for a patient with MCPyV oncoprotein antibodies?

Answer 70

Surveillance via serology may be an approach to monitoring disease burden.

Question 71

How does immune therapy affect treatment response in MCC patients with MCPyV oncoprotein antibodies?

Answer 71

Immune therapy is associated with a durable, if not curative, response.

Question 72

What is the typical duration of radiation therapy for a patient with a 2 cm tumor?

Answer 72

Radiation therapy is typically given in 2-Gy fractions, 5 times per week over 4-6 weeks.

Question 73

What is the recommended margin size for a patient with a 1.5 cm tumor undergoing surgery?

Answer 73

Margins of 1-2 cm are recommended, depending on the site.

Question 74

What is the local recurrence rate for a 2.5 cm tumor undergoing Mohs surgical excision with and without adjuvant radiation therapy?

Answer 74

The local recurrence rate is 16% for surgery alone and 0% for patients who also had adjuvant radiation therapy.

Question 75

What are the acute side effects of radiation therapy for MCC?

Answer 75

- Erythema at the site - Mild-to-moderate fatigue that peaks toward the end of radiation.

Question 76

What is the most significant potential side effect of radiation therapy in MCC patients?

Answer 76

**Lymphedema** is the most significant potential side effect.

Question 77

What are the recommended surveillance protocols for patients diagnosed with MCC?

Answer 77

- Clinical examination every 3 to 6 months for the first 2 years. - Imaging studies as clinically indicated.

Question 78

What are the key components of optimal treatment for MCC?

Answer 78

Optimal treatment should involve obtaining pathologically clear margins by surgery.

Question 79

What are the reasons against recommending adjuvant chemotherapy for MCC patients?

Answer 79

1. Mortality: 4% to 7% acute death rate. 2. Morbidity: Neutropenia occurs in 60%.

Question 80

What are the stages of Merkel Cell Carcinoma according to the AJCC 8th Edition Staging System?

Answer 80

The stages are: 0: In situ; I: ≤2 cm; II: >2 cm; IIIA: Any size, nodes positive; IIIB: Any size, confirmed nodes positive; IV: Any size, distant metastasis.

Question 81

What is the recommended treatment approach for clinically negative nodes in primary cutaneous MCC?

Answer 81

Perform a Sentinel lymph node biopsy and excision of the primary site.

Question 82

What are the treatment options for patients with positive nodes in MCC?

Answer 82

Options include fine needle aspiration and excision of the primary site.

Question 83

What are the key differences in staging between clinical and pathologic classifications for MCC?

Answer 83

Clinical classification considers nodes positive by examination; pathologic classification confirms via examination.

Question 84

What steps should be taken if nodes are clinically positive in MCC management?

Answer 84

Perform fine needle aspiration, excision of the primary site, and consider imaging studies.

Question 85

What is the recommended treatment approach for a patient with clinically negative nodes and a negative sentinel lymph node biopsy?

Answer 85

Radiotherapy to the primary site ± draining lymph node basin.