Premalignant and Malignant Non-Melanoma Skin … and Malignant Non-Melanoma Skin Cancer Elise...

Premalignant and Malignant

Non-Melanoma Skin Cancer

Elise Grgurich, D.O. and Lanny Dinh, D.O.

Lehigh Valley Health Network/PCOM

Department of Dermatology

American Osteopathic College of Dermatology

March 6, 2017

No Disclosures

Objectives

•Briefly review disease pathogenesis, presentation, and treatment options

•Discuss updates in the literature in regard to the various premalignant and

malignant lesions

•Introduce ongoing research and future studies in the field of non-melanoma

skin cancers

Premalignant Lesions

Actinic Keratosis •Most common precancerous lesion

–Can progress to SCC

•0.1-0.6% per lesion-year

•Treatment options:

–Cryotherapy

–Topical treatments:

•5-Fluorouracil (0.5-5%)

•Imiquimod 5% cream

•Ingenol mebutate

•Diclofenac

–Photodynamic therapy

–Destructive/Surgical management

Dermatology 3ed.

Actinic Keratosis

•5-FU, imiquimod, ingenol mebutate and diclofenac are similarly efficacious but have

different adverse effects and cosmetic outcomes

•Use dependent on patient preferences, prior physician and patient experience, and

cost

Actinic Keratosis

•Single course of 5% fluorouracil cream effectively reduces AK counts and need for

spot treatment for longer than 2 years

•Fewer hypertrophic AKs in the treatment group at 6 months

Malignant lesions

Basal Cell Carcinoma•Most common type of skin cancer

–2 million Americans affected every year

•Metastasis is extremely rare

–0.0028-0.55% metastatic rate

–50% of deaths from BCC result from direct extension into vital structure rather than

metastases

Dermatology 3ed.

Basal Cell Carcinoma

•Pathogenesis

–Arise from pluripotent cells

associated with hair follicle

–Mutations that activate

hedgehog signaling pathway

cell growth

•Sonic hedgehog

•Patched 1 - most common

•Smoothened

Basal Cell Carcinoma

•Pathogenesis

–Arise from pluripotent cells

associated with hair follicle

–Mutations that activate

hedgehog signaling pathway

cell growth

•Sonic hedgehog

•Patched 1 - most common

•Smoothened

Basal Cell Carcinoma

•Pathogenesis

–Arise from pluripotent cells

associated with hair follicle

–Mutations that activate

hedgehog signaling pathway

cell growth

•Sonic hedgehog

•Patched 1 - most common

•Smoothened

Basal Cell Carcinoma

•Pathogenesis

–Arise from pluripotent cells

associated with hair follicle

–Mutations that activate

hedgehog signaling pathway

cell growth

•Sonic hedgehog

•Patched 1 - most common

•Smoothened

Basal Cell Carcinoma

•Treatment options:

–Surgical

•Excision

•Mohs Micrographic surgery (MMS)

•Curettage and electrodessication

–Radiation

–Topical treatments: Imiquimod, 5-FU

–Hedgehog pathway inhibitors (HPIs)

Basal Cell Carcinoma

•Treatment options:

–Surgical

•Excision

•Mohs Micrographic surgery (MMS)

•Curettage and electrodessication

–Radiation

–Topical treatments: Imiquimod, 5-FU

–Hedgehog pathway inhibitors (HPIs)

•Vismodegib (2012) and sonidegib (2015)

Charles M. Rudin Clin Cancer Res 2012;18:3218-3222

©2012 by American Association for Cancer Research

Basal Cell Carcinoma

• Follow up of 104 patients with locally

advanced or metastatic BCC from the pivotal

ERIVANCE study

• Median duration of vismodegib exposure was

12.9 months

• Increased response rates

–Metastatic disease - 30.3% to 33.3%

–Locally advanced – 42.9% to 47.6%

• Median duration of response improved from

7.6 – 9.5 months for locally advanced disease

• No change in side effect profile or new

emerging safety signals

Basal Cell Carcinoma

• 8 articles (704 patients ) systematically

reviewed to evaluate clinical experience

with hedgehog pathway inhibitors

•Vismodegib

–significant, consistent effect on

locally advanced and metastatic BCC

–Superior responses for metastatic

BCC compared to traditional treatment

•Not enough data to review sonidegib since

its approval in 2015

Basal Cell Carcinoma

•Treatment options:

–Surgical

•Excision

•Mohs Micrographic surgery (MMS)

•Curettage and electrodessication

–Radiation

–Topical treatments: Imiquimod, 5-FU

–Hedgehog pathway inhibitors (HPIs)

•Vismodegib (2012) and sonidegib (2015)

•Itraconazole

Basal Cell Carcinoma

• 29 patients enrolled in open-label study

–Cohort A: 200mg twice daily x 1 month

–Cohort B: 100mg twice daily x 2.5 months

•Reduced tumor size and promoted re-epithelialization in 8 patients

•None of the BCCs completely cleared

•Average tumor reduction with lower dosage (Cohort B) was comparable to higher dosage (Cohort A)

Squamous Cell Carcinoma (SCC)

•Second most common skin cancer in the United States

•700,000 cases annually

Dermatology 3ed. Skindropbox.com

Squamous Cell CarcinomaStage Union for International Cancer Control (UICC) 2010 Brigham and Women’s

Hospital (BWH) 2013

T1 Tumor <2 cm in greatest dimension 0 high-risk factors*

T2 Tumor >2cm in greatest dimension 0 high-risk factors*

T2a 1 high-risk factors*

T2b 2-3 high-risk factors*

T3 Tumor with invasion of deep structures (muscle, cartilage, bone) >4 high-risk factors* or bony

invasion

T4 Tumor with invasion of axial skeleton or direct perineural invasion of skull

base

* BWH high-risk factors: tumor diameter >2cm, poorly differentiated histology, perineural invasion >0.1mm, tumor

invasion beyond fat

Squamous Cell Carcinoma

•National comprehensive cancer network (NCCN) high-risk features:

–Tumor location- mucosal surfaces, genitalia, periorbital, nose, lips, chin, ears,

temples, sites of prior burn scars or radiation

–Tumor diameter >2cm

–Tumor depth >2mm ( Clark level >IV)

–Perineural invasion

–Lymphovascular invasion

–Poorly differentiated histopathology

–Immunosuppression

•Solid organ transplant (particularly kidney) > bone marrow transplant

Squamous Cell Carcinoma

•National comprehensive cancer network (NCCN) high-risk features:

–Tumor location- mucosal surfaces, genitalia, periorbital, nose, lips, chin, ears,

temples, sites of prior burn scars or radiation

–Tumor diameter >2cm

–Tumor depth >2mm ( Clark level >IV)

–Perineural invasion

–Lymphovascular invasion

–Poorly differentiated histopathology

–Immunosuppression

•Solid organ transplant (particularly kidney) > bone marrow transplant

Squamous Cell Carcinoma

•Additional management considerations for high risk SCC:

–Sentinel lymph node biopsy (SLNB)

•2015 meta-analysis recommends considering SLNB for patients with T2

lesions

–Radiographic imaging to assess disease burden for high risk patients

•CT, MRI, PET

–Biomarkers for characterization of aggressive SCC

•Matrix-metalloproteinases, p300, nuclear IKK

Squamous Cell Carcinoma

•Immunotherapy for metastatic SCC

–Metastatic SCC has elevated expression of epidermal growth factor

receptor (EGFR)

•Cetuximab - EGFR inhibitor

•Pantimumab - monoclonal antibody against EGFR

–Combination therapy of cetuximab, fluorouracil, carboplatin, or

cisplatin

–PD-1 inhibitors

–CTLA-4 inhibitor

Squamous Cell Carcinoma•Chemoprevention

– 2 or more NMSC + 10 or more AKs

•Acitretin – 0.2-0.4mg/kg/day

–4 month up taper

–CBC, CMP, lipids, LFTs q3mo

–Continued indefinitely

•Nicotinamide (niacinamide or nicotinic acid) –

500mg BID

–23% fewer people had NMSC

–Lower side effect profile and no lab

monitoring

Cutaneous T-Cell Lymphoma

• T cell non-Hodgkin’s lymphomas

• Average of 6 years from presentation to diagnosis

– Clinically and histopathologically can resemble benign inflammatory disorders including psoriasis and atopic dermatitis

Cutaneous T-Cell Lymphoma

• High-throughput TCR sequencing (HTS) detected T cell clones in 46/46 CTCL patients• More sensitive and specific than TCRγ PCR• Successfully discriminated CTCL from benign inflammatory diseases• Demonstrated hematogenous spread of small numbers of malignant T

cells in patients with new skin lesions

Cutaneous T-Cell Lymphoma

• High-throughput TCR sequencing (HTS)• Accurately assessed responses to therapy and facilitated diagnosis of

disease recurrence• Diagnosed CTCL in all stages• Provided insights into the cell of origin and location of malignant CTCL

cells in skin

Cutaneous T-Cell Lymphoma

• Largest cohort of patients with advanced MF/SS from 29 international sites• 1,275 patients

• Identifies prognostic values to help stratify advanced-stage patients

Cutaneous T-Cell Lymphoma

• Independent poor prognostic markers for stage IV:– Increasing age > 60– Elevated LDH– Large cell transformation in the skin as independent poor prognostic

markers

Cutaneous T-Cell Lymphoma

• Interleukin (IL-31), Th2 cytokine• Increased in serum of CTCL patients

• Found in IL-31 may play a role in CTCL pruritus by exerting indirect effects on sensory nerves through epidermal neoplastic T cells and keratinocytes to transmit itch

Merkel Cell Carcinoma

• Neuroendocrine carcinoma

• Linked to UV exposure and Merkel cell polyomavirus

• In the United States, the age-adjusted incidence is estimated at 0.24 per 100,000 person-years

http://www.nature.com/nrclinonc/journal/v6/n9/fu

ll/nrclinonc.2009.109.html

Merkel Cell Carcinoma

• Review of Treatment

– Wide local excision is the mainstay of tx (NCCN) + SLN

– Immunotherapy with PD-1/PD-L1 inhibitors is a promising treatment

option for advanced or metastatic disease

– Clinical trials are currently in progress to further evaluate these novel

therapeutic agents

Merkel Cell Carcinoma

• A case of metastatic MCC with a significant response to nivolumab

–humanized IgG4 monoclonal PD-1 inhibitor

Merkel Cell Carcinoma

Merkel Cell Carcinoma

• 26 adults with advanced Merkel-cell carcinoma without previous systemic

treatment

• Pembrolizumab, PD-1 inhibitor, dosed at 2mg/kg for 3 weeks

• Objective response rate was 56%, 4 patients had a complete response, and

10 had a partial response

Summary

•Topicals remain a viable option for chemoprevention and treatment of AKs

•Hedgehog pathway inhibitors, especially itraconazole, continue to be studies for

advanced BCC

•Staging for invasive SCC continues to be utilized to help determine prognosis

•High throughput sequencing is a new diagnostic tool for CTCL

•PD-1 inhibitors may be a potential treatment option for MCC in the future

References (AKs and BCC)

• Elston DM, Ferringer T, Ko CJ, Peckham SM. Dermatopathology. 2nd ed. Edinburgh, United Kingdom: Saunders (W.B.) Co; December 3, 2013.

• Jacobsen AA, Aldahan AS, Hughes OB, Shah VV, Strasswimmer J. Hedgehog pathway inhibitor therapy for locally advanced and Metastatic Basal cell carcinoma. JAMA Dermatology. 2016;152(7):816. doi:10.1001/jamadermatol.2016.0780.

• James WD, Elston DM, Berger TG. Andrews’ diseases of the skin: Clinical Dermatology - expert consult - online and print. 11th ed. London: Elsevier Health Sciences; May 19, 2015.

• Patel G, Armstrong AW, Eisen DB. Efficacy of Photodynamic therapy vs other interventions in Randomized clinical trials for the treatment of Actinic Keratoses. JAMA Dermatology. 2014;150(12):1281. doi:10.1001/jamadermatol.2014.1253.

• Pomerantz H, Hogan D, Eilers D, et al. Long-term efficacy of topical Fluorouracil cream, 5%, for treating Actinic Keratosis. JAMA Dermatology. 2015;151(9):952. doi:10.1001/jamadermatol.2015.0502.

• Sekulic A, Migden MR, Lewis K, et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. Journal of the American Academy of Dermatology. 2015;72(6):1021–1026.e8. doi:10.1016/j.jaad.2015.03.021.

References (SCC)

• Cheng J, Yan S. Prognostic variables in high-risk cutaneous squamous cell carcinoma: a review.

Journal of Cutaneous Pathology. Apr 2016.

• Fu T, Aasi SZ, Hollmig ST. Management of high-risk squamous cell carcinoma of the skin. Current

Treatment Options in Oncology. Jul 2016.

• Ruiz ES, Karia P, Morgan F, Schmults C. The positive impact of radiologic imaging on high-stage

cutaneous squamous cell carcinoma management. Journal of the American Academy of Dermatology.

Oct 2016.

• Skulsky SL, O’Sullivan B, McArdle O, et al. Review of high-risk features of cutaneous squamous cell

carcinoma and discrepancies between the American Joint Committee on Cancer and NCCN clinical

practice guidelines in oncology. Head and Neck. Aug 2016.

References (EMPD)

• Azmahani, Abdullah et al. Androgen receptor, androgen-producing enzymes and their transcription factors in

extramammary Paget disease. Human Pathology. 46(11), 1662 - 1669.

• Tanaka, Ryota et al. Concordance of the HER2 protein and gene status between primary and corresponding

lymph node metastatic sites of extramammary Paget disease. Clinical & Experimental Metastasis. 2016.

33(7), 687-697.

• Plaza, Jose et al. HER-2/neu expression in extramammary Paget disease: A clinicopathologic and

immunohistochemistry study of 47 cases with and without underlying malignancy. Journal of Cutaneous

Pathology. 2009. 36(7), 729-733.

• Cown, Renee et al. A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary

Paget’s disease. Gynecologic Oncology. 2016. 142, 139-143.

References (MPD)

• Bouzaiene, H., Mezghani, B., Slimane, M., Goucha, A., Ariane, A., Naija, L., ... & Rahal, K. (2016). Paget’s Disease of the Female Breast: Clinical Findings and Management in 53 Cases at a Single Institution. Middle East Journal of Cancer, 7(3), 145-159.

• Chu, Peiguo., Wu, Emerald., Weiss, Lawrence. Cytokeratin 7 and Cytokeratin 20 Expression in Epithelial Neoplasms: A Survey of 435 Cases. Modern Pathology. 2000;. 13(9), 962-972.

• Ugur Ozerdem, Jennifer McNiff, Fattaneh Tavassoli. Cytokeratin 7-negative Mammary Paget’s Disease: A diagnostic Pitfall. Pathol Res Pract. 2016. 212(4), 279-281.

References (CTCL)• Kirsch IR, Watanabe R, O’Malley JT, et al. “ TCR sequencing facilitates diagnosis and identifies mature T

cells as the cell of origin in CTCL.” Sci Transl Med. 2015; 7(308). Online. doi:10.1126/scitranslmed.aaa9122

• Scarisbrick JJ, Prince HM, Vermeer MH, et al. “Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model.” J Clin Oncol. 2015; 33(32): 3766-3773.

• Nattkemper LA, Martinez-Escala E, Gelman AB, et al. “Cutaneous T-cell lymphoma and pruritus: the expression of IL-31 and its receptors in the skin.” Acta Derm Venereol; 96:894-898.

References (MCC)

• Oram C, Bartus CL, Purcell SM. “Merkel cell carcinoma: a review.” Cutis. 2016;97:290-295.

• Walocko FM, et al. “Metastatic merkel cell carcinoma response to nivolumab.” J ImmunoTherapy Cancer. 2016; 4:79.

• Nghiem, PT et al. “PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma.” N Engl J Med. 2016;374:2542-52.

Thank You

•Stephen Purcell, D.O.

•Tanya Ermolovich, D.O.

•Resident Team

–Veronica Rutt, D.O.

–Kelly Quinn, D.O.

–Carl Barrick, D.O.

–Claire Dorfman, D.O.