Radiation Oncology: A Question-Based Review

Merkel Cell Carcinoma

John P. Christodouleas and Benjamin D. Smith

image Background

What is the annual incidence of Merkel cell carcinoma (MCC) in the U.S.?

~500 cases/yr of MCC in the U.S.

What is the median age of Dx for MCC?

The median age of Dx is ~74 yrs (90% >50 yrs).

What is the cell type of origin for MCC?

Neuroendocrine (dermal sensory cells)—aka trabecular or “small cell” cancer of the skin.

What is the prognosis of MCC as compared to other skin cancers?

Of skin cancers, MCC has the worst prognosis (even worse than melanoma).

What % of pts have LN involvement at Dx?

20% have LN involvement at Dx.

DMs develop in what % of pts with MCC?

50%–60% of MCC pts develop DMs.

Is MCC a radiosensitive or radioresistant tumor?

MCC is considered radiosensitive.

What demographic group does MCC affect predominantly?

Elderly whites are primarily affected by MCC.

Where do most MCCs arise anatomically?

H&N region (50%) > extremities (33%)

MCC tumors at which sites have a particularly poor prognosis?

Vulva and/or perineum MCC is associated with a particularly poor prognosis.

To what tumor type is the histologic appearance of MCC similar?

The histologic appearance of MCC is similar to small cell carcinoma of the lung.

What are the histologic subtypes of MCC?

Histologic subtypes of MCC:

1.     Small cell

2.     Intermediate cell

3.     Trabecular

What histologic subtype of MCC has the best prognosis?

Trabecular MCC has the best prognosis.

What are 2 important prognostic factors in MCC?

Prognostic factors in MCC:

1.     Thickness/DOI

2.     LN status

image Workup/Staging

What is the workup for MCC?

MCC workup: H&P, CBC, CMP, CT C/A/P, and MRI or PET for H&N primaries to assess nodal status

What imaging is required at a min for MCC staging?

CT chest/abdomen is required for staging.

Why is chest imaging paramount in the staging of MCC?

Chest imaging is important to r/o mets and the −possibility of small cell lung cancer with mets to the skin as an etiology.

Outline the informal staging system commonly utilized by various institutions for MCC.

Informal staging system for MCC:

1.     Stage I: localized

2.     Stage II: LN+

3.     Stage III: DMs

Outline the latest AJCC TNM staging for MCC.

1.     T1: ≤2 cm

2.     T2: >2 cm and ≤5 cm

3.     T3: >5 cm

4.     T4: invades bone, muscle, fascia, or cartilage

5.     N1a: micromets

6.     N1b: macromets

7.     N2: in-transit mets (between primary and nodal basin or distal to primary)

8.     M1a: mets to skin, SQ tissue, or distant LN

9.     M1b: mets to lung

10. M1c: mets to all other visceral sites

What is the definition of in-transit mets or N2 Dz per the latest AJCC classification?

N2 Dz is defined as tumor distinct from the primary tumor and either between the primary and the nodal basin or distal to the primary.

Outline the latest AJCC stage groupings for MCC.

1.     Stage IA: T1pN0

2.     Stage IB: T1cN0

3.     Stage IIA: T2-3pN0

4.     Stage IIB: T2-3cN0

5.     Stage IIC: T4N0

6.     Stage IIIA: any TN1a

7.     Stage IIIB: any TN1b-2

8.     Stage IV: M1

image Treatment/Prognosis

What is the Tx paradigm for MCC?

MCC Tx paradigm: surgery/WLE with sentinel LN Bx +/− LND +/− adj RT +/− adj chemo

What are some commonly used chemo agents for MCC?

Agents used in MCC: cisplatin or carboplatin with etoposide or irinotecan

What surgical margins are recommended?

Surgical margins of 3–4 cm are recommended.

When is adj RT indicated for MCC?

Historically, adj RT has been included in the Tx course for the majority of MCC pts. A recent study by Allen et al. (JCO 2005) suggested that adj RT was of no benefit in margin− pts with surgically staged low-risk nodal Dz. Strong indications for RT include:

1.     Tumor >2 cm

2.     + /Close margins

3.     Angiolymphatic invasion

4.     LN + or no LN evaluation

5.     Immunocompromised pts

Per the NCCN, what RT doses are commonly used for MCC?

Commonly used total doses for MCC:

1.     Negative margins50–56 Gy

2.     Positive margins56–60 Gy

3.     Gross residual or unresectable60–66 Gy

What RT margins are typically used for MCC?

For MCC, the typical RT margin is 5 cm around the primary tumor (i.e., not the scar).

When are regional LNs covered in the RT volume for MCC?

Regional LNs are typically covered for all MCC pts. Retrospective data suggests that the inclusion of regional LNs in the RT field is associated with superior outcomes (Jabbour J et al., Ann Surg Oncol 2007Eich HT et al., Am J Clin Oncol 2002). However, the role of LN coverage in sentinel LN Bx–negative or LND-negative pts is controversial.

What is the evidence for concurrent CRT after surgery for MCC?

Data on concurrent CRT for MCC are limited. Phase II trials have shown that CRT is tolerable (Poulsen MG et al., IJROBP 2006), but no trials have established superior efficacy over RT alone.

What is the historical LF rate after surgery alone and with adj RT?

Historical rates are 45%–75% with surgery alone and 15%–25% with adj RT.

Estimate the 3-yr OS for MCC by informal staging.

3-yr OS by informal staging:

1.     Stage I (localized): 70%–80%

2.     Stage II (LN+): 50%–60%

3.     Stage III (DM): 30%

image Toxicity

What specific follow-up studies do MCC pts require?

Frequent CXR imaging, consideration of serum −neuron-specific enolase testing for recurrence, and total skin exam for life (high rates of 2nd skin cancers)

What follow-up intervals are recommended by the NCCN for MCC?

MCC recommended follow-up schedule: H&P and clinically indicated imaging q1–3mos for yr 1, q3–6mos for yr 2, and annually thereafter.

What are the major toxicities in pts receiving CRT for MCC?

Skin (grade 3–4) toxicity is ~60% and neutropenia is ~40%. (Poulsen M et al., IJROBP 2001)