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Hematology/ Oncology Grand RoundsÂ


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Hematology/ Oncology Grand RoundsÂ

  1. 1. Hematology/Oncology Grand Rounds September 3, 2004 Merkel Cell Carcinoma Presented by Coy Heldermon
  2. 2. 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
  3. 3. 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.
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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.
  10. 10. 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. s d t J Clin Onc 20(2): 588-598, 2002
  11. 11. 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.
  12. 12. 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
  13. 13. 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
  14. 14. Merkel Cell Carcinoma CK 18 Stain CK20 Stain Int J Derm 42:669-676, 2003 J Clin Onc 20(2): 588-598, 2002
  15. 15. 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
  16. 16. 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
  17. 17. Merkel Cell Carcinoma Treatment Options Drugs 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/m 2 i.v. days 1 + 7 Repeat every 3-4 weeks Etoposide 170 mg/m2 i.v. days 3-5 Cyclophosphamide 600 mg/m 2 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/m 2 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
  18. 18. 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%.
  19. 19. 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
  20. 20. Merkel Cell Carcinoma Future Directions • TNF-alpha • interferon-alpha-2a/b • Bcl-2 antisense
  21. 21. 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