113: Merkel Cell Carcinoma Flashcards
What are the main risk factors associated with Merkel cell carcinoma (MCC)?
The main risk factors associated with MCC include:
- UV light exposure
- Advanced age
- Immune suppression
- Merkel cell polyomavirus (MCPyV)
How has the incidence of Merkel cell carcinoma (MCC) changed from 1986 to 2006?
Between 1986 and 2006, the reported incidence of MCC quadrupled from 0.15 per 100,000 to 0.6 per 100,000 persons.
What is the prognosis for patients with Merkel cell carcinoma (MCC) compared to those with invasive melanoma?
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.
What historical milestones contributed to the understanding of Merkel cell carcinoma (MCC)?
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.
What demographic factors influence the incidence of Merkel cell carcinoma (MCC)?
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.
What are the cutaneous findings that indicate a suspicion of Merkel Cell Carcinoma (MCC)?
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.
What is the significance of presenting without an identifiable primary lesion in MCC patients?
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.
What are the common complications and outcomes for patients with Merkel Cell Carcinoma (MCC)?
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.
What is the association between Merkel Cell Carcinoma (MCC) and immune suppression?
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.
What is the significance of Merkel Cell Polyomavirus (MCPyV) in relation to MCC?
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.
What are the two mutational profiles identified in MCC tumors?
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.
How do MCPyV and UV radiation contribute to MCC tumorigenesis?
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.
What is the clinical significance of detecting antibodies to the MCPyV oncoprotein in MCC patients?
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.
How does the presence of an unknown primary lesion affect the outcomes for patients with Merkel Cell Carcinoma (MCC)?
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.
What is the significance of the site of first recurrence in patients with Merkel Cell Carcinoma (MCC)?
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.
What is the relationship between immune suppression and the incidence of Merkel Cell Carcinoma (MCC)?
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.
How does the presence of Merkel Cell Polyomavirus (MCPyV) correlate with mutational profiles in MCC tumors?
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.
What role does the MCPyV oncoprotein play in the growth of Merkel Cell Carcinoma tumors?
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.
What are the implications of detecting antibodies to the MCPyV oncoprotein in patients with Merkel Cell Carcinoma?
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.
How do the mechanisms of tumorigenesis differ between virus-positive and virus-negative Merkel Cell Carcinoma?
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.
What is the risk of recurrence in Merkel Cell Carcinoma (MCC)?
MCC has a higher risk of recurrence, necessitating closer surveillance through clinical and radiologic examinations.
How do the mechanisms of tumorigenesis differ between virus-positive and virus-negative MCC?
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.
What are the classic histologic features of Merkel Cell Carcinoma (MCC)?
- 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.
What are the three histologic patterns associated with MCC and their prognostic implications?
- Intermediate type: Most common, uniform small cells with minimal cytoplasm, pale nuclei, and dispersed chromatin appearance.
- Small cell type: Second most common, irregular hyperchromatic cells with scant cytoplasm arranged in linear patterns.
- Trabecular type: Least common but most distinctive, described by Toker in 1972, with a lattice-like appearance.
What is the significance of Cytokeratin-20 in the diagnosis of MCC?
- 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.
How does the Thyroid Transcription Factor-1 (TTF-1) help differentiate between MCC and small-cell lung cancer?
- 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.
What is the role of the CM2B4 antibody in the diagnosis of MCC?
- 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.
What is the significance of sentinel lymph node biopsy (SLNB) in the management of MCC?
- 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.
What are the key factors affecting the prognosis of MCC?
- 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.
What other diagnostic markers can be used to confirm MCC if cytokeratin-20 is negative?
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.
What are the classic histologic features of MCC observed under a microscope?
- 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.
What are the three histologic patterns of MCC associated with prognosis?
- Intermediate type: Most common, uniform small cells with minimal cytoplasm, pale nuclei, and dispersed chromatin appearance.
- Small cell type: Second most common, irregular hyperchromatic cells with scant cytoplasm arranged in linear patterns.
- Trabecular type: Least common, described by Toker in 1972, has a lattice-like appearance.
How does the expression of Cytokeratin-20 relate to the diagnosis of MCC?
- 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.
What is the significance of the Thyroid Transcription Factor-1 in differentiating MCC from small-cell lung cancer?
- 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.
What is the role of the CM2B4 antibody in the diagnosis of MCC?
- 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.
What factors influence the prognosis of a patient diagnosed with MCC?
- 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.
What is the importance of Sentinel Lymph Node Biopsy (SLNB) in the management of MCC?
- 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.
What is the significance of identifying microscopic lymph node disease in patients with MCC?
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.
What are the prognostic findings on histology for MCC?
- 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.
What is the initial management strategy for MCC at the primary site?
The initial management strategy for MCC at the primary site includes surgical excision of the tumor as the primary treatment.
What is the role of radiation therapy in the treatment of MCC?
- 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.
What imaging modality is recommended for baseline evaluation in MCC?
Baseline PET/CT scans are recommended for most patients except those with very low-risk disease (e.g., primary ≤1 cm and negative SLNB).
What is the next step in management for a patient with a positive sentinel lymph node biopsy (SLNB)?
The draining lymph node bed should be treated, likely with radiation therapy.
How does an infiltrative growth pattern affect prognosis in MCC?
An infiltrative growth pattern is associated with poor outcomes compared to a nodular growth pattern.
How does lymphovascular invasion affect prognosis in MCC?
Lymphovascular invasion is associated with worse overall survival.
Is baseline imaging recommended for a patient with a tumor diameter of 1.5 cm and negative SLNB?
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).
How does a nodular growth pattern affect prognosis in MCC?
A nodular growth pattern is associated with better outcomes compared to an infiltrative growth pattern.
How does a tumor positive for p63 affect prognosis in MCC?
Positive p63 is associated with a more aggressive clinical course.
How does high CD8 lymphocyte infiltration affect prognosis in MCC?
High CD8 lymphocyte infiltration is independently associated with improved MCC-specific survival.
How does downregulated intratumoral vascular E-selectin affect prognosis in MCC?
Downregulated intratumoral vascular E-selectin is associated with poor intratumoral CD8 lymphocyte infiltration and worse survival.
How does MCPyV oncoprotein expression affect prognosis in MCC?
MCPyV oncoprotein expression is associated with better outcomes.
What are the acute side effects of radiation therapy for MCC?
- Erythema at the site.
- Mild-to-moderate fatigue that peaks toward the end of radiation and usually resolves within 1 to 2 months.
What is the most significant potential side effect of radiation therapy in MCC patients?
Lymphedema, which is more common in lower extremities when radiation therapy is given to the inguinal lymph nodes.
What are the recommended surveillance practices for MCC after diagnosis?
- 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.’
What is the optimal treatment approach for MCC?
Optimal treatment should involve obtaining pathologically clear margins by surgery, typically with 1- to 2-cm margins if possible.
What are the reasons against recommending adjuvant chemotherapy for MCC patients?
- Mortality: 4% to 7% acute death rate from adjuvant chemotherapy.
- Morbidity: Neutropenia occurs in 60% of patients.
- Decreased quality of life: severe in older population.
- Resistance to chemotherapy: MCC that recurs after chemotherapy is less responsive to later palliative chemotherapy.
- Immunity: Chemotherapy suppresses immune function.
- Outcomes are not improved: no survival benefit among node-positive patients who received chemotherapy.
What percentage of patients with fever experience neutropenia?
Neutropenia occurs in 60% of patients with fever.
What percentage of patients with fever experience sepsis?
Sepsis occurs in 40% of patients with fever.
What are the severe quality of life effects of MCC in older populations?
Severe effects include fatigue, hair loss, and nausea/vomiting.
How does chemotherapy affect resistance in MCC?
MCC that recurs after chemotherapy is less responsive to later palliative chemotherapy.
What effect does chemotherapy have on immunity?
Chemotherapy suppresses immune function.
Is there a survival benefit for node-positive patients receiving chemotherapy?
No survival benefit is observed among node-positive patients who received chemotherapy compared to those who did not.
What are the typical radiation doses for MCC?
Typical radiation doses are 50-56 Gy in 2-Gy fractions, 5 times per week over 4-6 weeks.
What are the potential acute side effects of radiation therapy for MCC?
Acute side effects include erythema at the site and mild-to-moderate fatigue.
Is adjuvant radiation therapy recommended for MCC patients with a tumor diameter of 0.8 cm and negative SLNB?
Adjuvant radiation therapy is not recommended for MCC patients with good prognostic features.
What is the recommended treatment for the draining lymph node bed in a patient with a 2.5 cm tumor and positive SLNB?
The draining lymph node bed should be treated with radiation therapy.
What margin size is recommended for a patient with a 3 cm tumor undergoing surgery?
Margins of 1-2 cm are recommended, depending on the site.
What is the local recurrence rate for a 2 cm tumor undergoing Mohs surgical excision with and without adjuvant radiation therapy?
The local recurrence rate is 16% for surgery alone and 0% for patients who also had adjuvant radiation therapy.
Is adjuvant chemotherapy recommended for a patient with a 1 cm tumor and negative SLNB?
Adjuvant chemotherapy is not recommended for MCC patients whose disease has been treated with surgery or radiation therapy.
What is the recommended surveillance approach for a patient with MCPyV oncoprotein antibodies?
Surveillance via serology may be an approach to monitoring disease burden.
How does immune therapy affect treatment response in MCC patients with MCPyV oncoprotein antibodies?
Immune therapy is associated with a durable, if not curative, response.
What is the typical duration of radiation therapy for a patient with a 2 cm tumor?
Radiation therapy is typically given in 2-Gy fractions, 5 times per week over 4-6 weeks.
What is the recommended margin size for a patient with a 1.5 cm tumor undergoing surgery?
Margins of 1-2 cm are recommended, depending on the site.
What is the local recurrence rate for a 2.5 cm tumor undergoing Mohs surgical excision with and without adjuvant radiation therapy?
The local recurrence rate is 16% for surgery alone and 0% for patients who also had adjuvant radiation therapy.
What are the acute side effects of radiation therapy for MCC?
- Erythema at the site
- Mild-to-moderate fatigue that peaks toward the end of radiation.
What is the most significant potential side effect of radiation therapy in MCC patients?
Lymphedema is the most significant potential side effect.
What are the recommended surveillance protocols for patients diagnosed with MCC?
- Clinical examination every 3 to 6 months for the first 2 years.
- Imaging studies as clinically indicated.
What are the key components of optimal treatment for MCC?
Optimal treatment should involve obtaining pathologically clear margins by surgery.
What are the reasons against recommending adjuvant chemotherapy for MCC patients?
- Mortality: 4% to 7% acute death rate.
- Morbidity: Neutropenia occurs in 60%.
What are the stages of Merkel Cell Carcinoma according to the AJCC 8th Edition Staging System?
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.
What is the recommended treatment approach for clinically negative nodes in primary cutaneous MCC?
Perform a Sentinel lymph node biopsy and excision of the primary site.
What are the treatment options for patients with positive nodes in MCC?
Options include fine needle aspiration and excision of the primary site.
What are the key differences in staging between clinical and pathologic classifications for MCC?
Clinical classification considers nodes positive by examination; pathologic classification confirms via examination.
What steps should be taken if nodes are clinically positive in MCC management?
Perform fine needle aspiration, excision of the primary site, and consider imaging studies.
What is the recommended treatment approach for a patient with clinically negative nodes and a negative sentinel lymph node biopsy?
Radiotherapy to the primary site ± draining lymph node basin.
