HematologyOncology Grand Rounds September 3, 2004

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Hematology/OncologyGrand RoundsSeptember 3, 2004

• Merkel Cell Carcinoma

Presented by Coy Heldermon
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• CC Bleeding bottom
• HPI 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 Ca
• SH Married, 3 grown children, remote 14pyh of
  cigarettes, social ETOH use.
• ROS Negative except pain and bleeding at R
  buttock
• PE remarkable only for necrosis at 2cm hematoma
  site on mid R buttock

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• 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.

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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 11636-652, 1875
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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. Mar271A(1)225-39, 2003
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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. Mar271A(1)225-39, 2003
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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 1972105107-110)
• 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 lt2cm with 40 on the head neck, 40 on
  arms legs and 20 on the trunk.
• 50 have spread at diagnosis.
• Risk factors sun immunosuppression

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Merkel Cell Carcinoma

• Presentation is usually with a painless raised
  discolored nodule.
• Metastatic spread is usually first to local lymph
  nodesgt livergt lunggt bonesgt brain

Int J Derm 42669-676, 2003
J Clin Onc 20(2) 588-598, 2002
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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.

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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
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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.

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Merkel Cell Carcinoma

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

Int J Derm 42669-676, 2003
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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

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Merkel Cell Carcinoma
CK20 Stain
CK 18 Stain
J Clin Onc 20(2) 588-598, 2002
Int J Derm 42669-676, 2003
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Merkel Cell Carcinoma Staging
AJCC for Skin Cancers

• Two staging systems are commonly used, The AJCC
  system and the Yiengpruksawan system (used more
  often)
• Ys system is
• Stage I for no nodal dz
• Stage II for nodal disease
• Stage III for systemic metastases

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Merkel Cell Carcinoma Treatment
J Clin Onc 20(2) 588-598, 2002
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Merkel Cell Carcinoma Treatment Options
Int J Derm 42669-676, 2003
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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.

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Merkel Cell Carcinoma Survival
J Clin Onc 20(2) 588-598, 2002
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Merkel Cell Carcinoma Future Directions

• TNF-alpha
• interferon-alpha-2a/b
• Bcl-2 antisense

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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 Mar271A(1)225-39
• Agelli M, Clegg LX. Epidemiology of primary
  Merkel cell carcinoma in the United States.J Am
  Acad Dermatol 2003 49832-841
• Mendenhall WM, Mendenhall CM, Mendenhall NP.
  Merkel Cell Carcinoma. Laryngoscope 2004
  114906-910
• Yiengpruksawan A, Coit DG, Thaler HT, et al.
  Merkel cell carcinoma. Prognosis and management.
  Arch Surg 1991 1261514-1519
• Mott RT, Smoller BR, Morgan MB. Merkel cell
  carcinoma a clinicopathologic study with
  prognostic implications. J Cutan Pathol 2004
  31217-223
• Krasagakis K, Tosca AD. Overview of Merkel cell
  carcinoma and recent advances in research. Int J
  Derm 2003 42669-676
• Goessling W, McKee PH, Mayer RJ. Merkel cell
  carcinoma. J Clin Onc 2002 20588-598
• George TK, di Santagnese PA, Bennett JM.
  Chemotherapy for metastatic Merkel cell
  carcinoma. Cancer 1985 561034-1038
• 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 182493-2499