Hematology/OncologyGrand Rounds

September 3, 2004

Merkel Cell CarcinomaPresented by Coy Heldermon

CC: Bleeding bottomHPI: 57yo WM fell in his backyard while getting off of a

ladder and bruised his R buttock. Hematoma formed and over several days the skin broke down and he noticed bleeding. He presented to his PCP who cauterized the bleeding sites and took biopsies.

PMH: prostatectomy tonsillectomy/adenoidectomy mononucleosis as teen

FH: Aunt – Br Ca, Uncle – Lung CaSH: Married, 3 grown children, remote 14pyh of cigarettes,

social ETOH use.ROS: Negative except pain and bleeding at R buttockPE: remarkable only for necrosis at 2cm hematoma site on

mid R buttock

Clinical Course

June 02 – pathology read as small cell neoplasm at an OSH and referred to BJH with final reading of Merkel cell carcinoma. Pt underwent local excision at R buttock with iliac lymph node dissection and spermatic cord excision.

- Surgical margins were positive and 3/3 lymph nodes had disease.- CT chest, abdomen, pelvis demonstrated no evidence of metastatic

disease.October 02 – Pt. referred to BJH Oncology. Pt received 3 cycles

vincristine/adriamycin/cytoxan followed by radiation therapy and concurrent cisplatin/etoposide.

September 03 – CT/PET reveals metastatic disease in the lungs, pancreas, L femoral neck, scapula, iliac and sacral lymph node chains, chest wall and a bone lesion at S4.

- Pt underwent 5 cycles of cisplatin/irinotecan. May 04 – CT - Resolution of chest wall lesion and decreased size of

remaining lesions.The patients therapy was only complicated by the expected periodic

nausea and cytopenias with persistent anemia.

Merkel Cell

• So what is a Merkel cell?

- identified in 1875 by Friedrich Sigmund Merkel, President of University of Rostock, professor of anatomy & physician. Dr. Merkel identified the cell as a component of the “touch receptor”

Arch Mikrosc Anat 11:636-652, 1875

Merkel Cell

- Nondendritic, nonkeratinocytic epidermal cell near the basal layer, usually directly associated with nerve terminals especially near hair follicles and sweat gland ridges.

- Some may be in the dermis but not associated with nerve cells.Figure of Sinus Hair Follicle: G-sebaceous gland, B- hair bulb, T- nerve terminus, M- merkel cell

Anat Rec. Mar;271A(1):225-39, 2003

Merkel Cell- Slow adapting type I

mechanoreceptor- Contain dense core

granules similar to neurosecretory granules.

- Thought to release glutamate (among other things) in response to mechanical stimulation.

- Likely of neural crest origin.

- Possibly not the cell of origin of Merkel cell carcinoma.

Figure of Merkel cell (M) nerve ending (T) demonstrating dense core granules.

Anat Rec. Mar;271A(1):225-39, 2003

Merkel Cell Carcinoma

• 1st described by Toker in 1972 as a trabecular cancer of the dermis with high lymphatic metastatic risk and found mainly in elderly patients. (Arch Dermatol 1972;105:107-110)

• U.S. Annual Incidence is ~0.4/100,000• U.S. Median age is ~70 years• 90% are found in caucasians, ~80% are in men.• 80% are <2cm with 40% on the head & neck,

40% on arms & legs and 20% on the trunk.• ~50% have spread at diagnosis.• Risk factors: sun & immunosuppression

Merkel Cell Carcinoma

• Presentation is usually with a painless raised discolored nodule.

• Metastatic spread is usually first to local lymph nodes> liver> lung> bones> brain

J Clin Onc 20(2): 588-598, 2002

Int J Derm 42:669-676, 2003

Merkel Cell Carcinoma

Work-up:

- CT to assess regional lymph node involvement.

- CXR to evaluate for lung metastases.

- Sentinel node biopsy to evaluate lymphatic extension and thus efficacy of local therapy.

Merkel Cell Carcinoma Pathology

Pathology is of three types often in combination.

Solid (50%)– irregular nests of intermediate sized basophilic cells in dense fibrous connective tissue.

Diffuse (42%)- small irregular hyperchromatic cells in diffusely infiltrating sheets.

Trabecular (8%)- irregular cords or ribbons of basophilic cells.

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J Clin Onc 20(2): 588-598, 2002

Merkel Cell Carcinoma

• Tumor often is necrotic and preferentially invades vascular and perineural spaces.

• Invasion beyond the dermis is a predictor of metastases - 78% metastatic vs 29% metastatic in those with tumor confined to dermis.

Merkel Cell Carcinoma

Cells typically have prominent ovoid nuclei, dispersed chromatin, sparse cytoplasm, conspicuous nucleoli, and multiple neurosecretory granules

Int J Derm 42:669-676, 2003

Merkel Cell Carcinoma

• Histochemistry is positive for CK8, CK 18, CK20, somatostatin receptor, chromogranin A(from neuroendocrine granules), neuron specific enolase, & synaptophysin(from the pre-synaptic vesicles)

• CK7 and TTF-1(thyroid transcription factor) are negative, distinguishing MCC from SCLC

Merkel Cell Carcinoma

CK 18 Stain CK20 Stain

Int J Derm 42:669-676, 2003J Clin Onc 20(2): 588-598, 2002

Merkel Cell Carcinoma Staging

• Two staging systems are commonly used, The AJCC system and the Yiengpruksawan system (used more often)

• Y’s system is - Stage I for no nodal dz- Stage II for nodal disease- Stage III for systemic

metastases

AJCC for Skin Cancers

Merkel Cell Carcinoma Treatment

Stage

Treatment Recommendations

I Localized disease Surgery: local excision with > 2 cm margin, sentinel lymph node biopsy Radiation therapy: adjuvant treatment after resection with 45-50 Gy Chemotherapy: little experience for adjuvant chemotherapy

IA 2 cm

IB > 2 cm

II Lymph node involvement

Surgery: local excision with > 2 cm margin, lymph node dissection Radiation therapy: adjuvant therapy to both primary site and lymph node region Chemotherapy: no chemotherapy trials but rational to treat

III

Distant metastases

Radiation therapy: palliative use of radiation Chemotherapy: CAV or EP most commonly used

J Clin Onc 20(2): 588-598, 2002

Merkel Cell Carcinoma Treatment OptionsDrugs Dosage Repeat Reference

Inoperable stage I

Cyclophosphamide 600 mg/m2 i.v. day 1 Repeat every 3 weeks

Ferrau et al. (1994) 46

Epidoxorubicin 75 mg/m2 i.v. day 1

Etoposide 150 mg/m2 i.v. days 1 + 2

Stages II and III

Cisplatin 50 mg/m2 i.v. days 1 + 7

Repeat every 3-4 weeks

Etoposide 170 mg/m2 i.v. days 3-5

Cyclophosphamide 600 mg/m2 i.v. days 1 + 8

Repeat on day 28 Fenig et al. (1993) 53 : CR 4/5 patients, PR 1/5 patients

Methotrexate 40 mg/m2 i.v. days 1 + 8

5-Fluorouracil 600 mg/m2 i.v. days 1 + 8

VP-16 150 mg/m2 i.v. days 1 + 2

Repeat on day 22 Azagury et al. (1993) 54 : CR 1 patient

Cisplatin 150 mg/m2 i.v. days 1 + 2

Doxorubicin 150 mg/m2 i.v. day 1

Bleomycin 150 mg/m2 i.v. day 1

Int J Derm 42:669-676, 2003

Merkel Cell Carcinoma Treatment Options

• Other regimens in the literature include:- cyclophosphamide, doxorubicin, vincristine- cyclophosphamide, epirubicin, vincristine- cyclophosphamide, doxorubicin, vincristine + prednisone- cyclophosphamide, doxorubicin, vincristine alternating with cisplatin

& etoposide- doxorubicin, ifosfamide- cisplatin +/- doxorubicin- doxorubicin- mitoxantrone

Cyclophosphamide, anthracyclines and cisplatin are the most commonly used drugs in the literature.

Response rates for multidrug regimens are reported at 60-70%.

Merkel Cell Carcinoma Survival

Stage

Median Survival (months)

5-Year Survival (%)

I Localized disease 64 / 75

IA 2 cm 30

IB > 2 cm 26

II Lymph node involvement

18 47 / 49

III

Distant metastases

5

0 / 25

J Clin Onc 20(2): 588-598, 2002

Merkel Cell Carcinoma Future Directions

• TNF-alpha

• interferon-alpha-2a/b

• Bcl-2 antisense

Bibliography• Halata Z, Grim M, Bauman KI. Friedrich Sigmund Merkel and his "Merkel cell",

morphology, development, and physiology: review and new results. Anat Rec. 2003 Mar;271A(1):225-39

• Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States.J Am Acad Dermatol 2003; 49:832-841

• Mendenhall WM, Mendenhall CM, Mendenhall NP. Merkel Cell Carcinoma. Laryngoscope 2004; 114:906-910

• Yiengpruksawan A, Coit DG, Thaler HT, et al. Merkel cell carcinoma. Prognosis and management. Arch Surg 1991; 126:1514-1519

• Mott RT, Smoller BR, Morgan MB. Merkel cell carcinoma: a clinicopathologic study with prognostic implications. J Cutan Pathol 2004; 31:217-223

• Krasagakis K, Tosca AD. Overview of Merkel cell carcinoma and recent advances in research. Int J Derm 2003; 42:669-676

• Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Onc 2002; 20:588-598

• George TK, di Sant’agnese PA, Bennett JM. Chemotherapy for metastatic Merkel cell carcinoma. Cancer 1985; 56:1034-1038

• Tai PTH, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, Gilchrist J. Chemotherapy in Neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Onc 2000; 18:2493-2499