Cutaneous Signs of Internal Malignancy Ted Rosen, MD Professor of Dermatology Baylor College of Medicine Disclosure/Conflict of Interest ▪ No relevant disclosures ▪ No conflicts of interest Objectives ▪ Recognize common disorders associated with internal malignancy ▪ Manage cutaneous disorders in the context of associated internal malignancy ▪ Differentiate cutaneous signs of leukemia and lymphoma ▪ Understand spidemiology of cutaneous metastases Cutaneous Signs of Internal Malignancy ▪ General physical examination ▪ Pallor (anemia) ▪ Jaundice (hepatic or cholestatic disease) ▪ Fixed erythema or flushing (carcinoid) ▪ Alopecia (diffuse metastatic disease) ▪ Itching (excoriations) Anemia: Conjunctival pallor and Pale skin Jaundice 1-12% of hepatocellular, biliary tree or pancreatic cancer PRESENT with jaundice, but up to 40-60% eventually develop it World J Gastroenterol 2003;9:385-91 For comparison CAN YOU TELL JAUNDICE FROM NORMAL SKIN? JAUNDICE Alopecia Neoplastica Most common report w/ breast CA Lung, cervix, desmoplastic mm Hair loss w/ underlying induration Biopsy = dermis effaced by tumor Ann Dermatol 26:624, 2014 South Med J 102:385, 2009 Int J Dermatol 46:188, 2007 Acta Derm Venereol 87:93, 2007 J Eur Acad Derm Venereol 18:708, 2004 Gastric Adenocarcinoma: Alopecia Ann Dermatol 2014; 26: 624–627 Pruritus: Excoriation ▪ Overall risk internal malignancy presenting as itch LOW. OR =1.14 ▪ CTCL, Hodgkin’s & NHL, Polycythemia vera ▪ Biliary tree carcinoma Eur J Pain 20:19-23, 2016 Br J Dermatol 171:839-46, 2014 J Am Acad Dermatol 70:651-8, 2014 Non-specific (Paraneoplastic) Specific (Metastatic Disease) Paraneoplastic Signs “Curth’s Postulates” ▪ Concurrent onset (temporal proximity) ▪ Parallel course ▪ Uniform site or type of neoplasm ▪ Statistical association ▪ Genetic linkage (syndromal) Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, Rees TD, eds. Cancer of the Skin. Philadelphia: WB Saunders; 1976:1308-1309 Paraneoplastic Dermatoses ▪ Acanthosis nigricans ▪ Ichthyosis (acquired) ▪ Bazex syndrome ▪ Paget’s disease of the breast ▪ Clubbing of nails ▪ Paget’s disease ▪ Dermatomyositis (extramammary) ▪ Erythema gyratum (and ▪ Paraneoplastic pemphigus other figurate erythemas) ▪ Porphyria cutanea tarda (PCT) ▪ Exfoliative erythroderma ▪ Pyoderma gangrenosum ▪ Glucagonoma ▪ Scleromyxedema ▪ Hyperpigmentation ▪ Sign of Leser-Trélat ▪ Hypertrichosis lanuginosa ▪ Sweet’s Syndrome Acanthosis Nigricans ▪ Velvety pigmentation (ASx) ▪ Neck or axilla typical ▪ Neoplastic (~20%): Rapid onset ▪ Adenocarcinoma (90%) GI & GU; MOST COMMONLY GASTRIC ▪ 60% concurrent, 20% before and 20% after cancer dx ▪ Also seen in obesity and insulin- resistant diabetes and in purely hereditary form Arch Dermatol 66:80, 1952 Cancer 15:364, 1962 Indian Online Derm J 5:239, 2014 Acanthosis Nigricans IGF = Insulin-like growth factor Adapted from: Dermatol Online J. 14(9):2, 2008 IGF = Insulin-like growth factor In malignancy TGF-α Adapted from: Dermatol Online J. 14(9):2, 2008 Acanthosis Nigricans ▪ In children, typically not due to malignancy (obesity) ▪ Ethnic predilection (children): Native Americans, Blacks: High Hispanics: Moderate Caucasians: Low Illustrative Case ▪ 45 year-old female ▪ CC: Rash under arms ▪ Overweight ▪ Not diabetic, not hypertensive, no dyslipidemia ▪ No meds; good health ▪ No systemic or localizing signs or symptoms ▪ Negative Family history ▪ + Mammogram: ASx ductal carcinoma found Dermatomyositis ▪ Heliotrope (30-60%) ▪ Positive auto-antibodies ▪ Gottron’s papules (70%) ▪ Nondestructive ▪ Erythema + scale elbow/knee arthralgia/arthritis ▪ Proximal muscle weakness ▪ Fever ▪ Elevated CPK ▪ Elevated ESR ▪ Elevated aldolase ▪ Calcinosis cutis ▪ Muscle pain ▪ Pathologic biopsy = ▪ Abnormal EMG skeletal muscle myositis Dermatomyositis ▪ Malignancy in adult DM, not juvenile DM ▪ 7-30% DM assoc w/ malignancy Clin Dermatol 24:363, 2006; G Ital Dermatol Venereol 149:525-37, 2014 ▪ Relative risk of malignancy is 6.5x greater if DM present, than if not Curr Rheum Rep 4415, 2002 ▪ “Real” risk increases with: ↑age, male gender, dysphagia Br J Dermatol. 2013;169:838-4 ▪ Most often: Ovarian, Breast, Lung, Gastric ▪ Lymphoma also rarely reported ▪ May relate to cross-reacting auto-antibodies Curr Opin Rheumatol 18:620, 2006 Dermatomyositis Dermatomyositis: Malignancy Illustrative Case ▪ 61 year-old ▪ Acute onset weakness ▪ Concurrent rash on torso, knees, elbows ▪ Elevated CPK and ESR ▪ Work up: abnormal chest x-ray ▪ Biopsy: bronchogenic carcinoma Dermatomyositis Workup ▪ EXCLUDE: Ichthyosis vulgaris and Xerosis - IV starts early in life - Xerosis starts late in life; itchy ▪ Medication Hx, Examine for muscle weakness ▪ Examine for adenopathy ▪ Biopsy skin; Screening labs: CBC, SMAC, Fasting glucose, HIV, TSH, PTH, ANA, CPK, CXR, age-sex appropriate cancer screen (age >40) ▪ CT scans, HTLV titers, SPEP ▪ J Am Acad Dermatol 55:647, 2006 Dermatomyositis Workup: Auto-Antibodies ▪ anti-TIF1γ, NXP2, SAE, MDA5, Jo-1, Mi2, PL-7, PL-12, MJ ▪ 96% specific and 67% sensitive ▪ Helps rule-out genetic or toxic myopathy ▪ Anti-TIF1γ & NXP-2 especially associated w/ malignancy ▪ Anti-TIF1γ + (50-75% cancer) and NXP-2+ (13.6% cancer) USA: Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e172 Europe: Autoimmun Rev. 2014;13:1211-9 Japan: Curr Opin Rheumatol. 2016;28:636-44 Reactive Patterns ▪ Urticaria (hives) ▪ Erythema multiforme ▪ Erythema annulare centrifugum ▪ Erythema gyratum repens ▪ Exfoliative erythroderma Urticaria ▪ COMMON: 15% all Americans ▪ “Acute” Food/drug (usually obvious) ▪ “Chronic” Daily, > 6 weeks ▪ NO cause found in 80-90% ▪ Lymphoma (B-cell) Leukemia (CLL) Thyroid carcinoma ▪ Hepatitis (HBV, HCV) ▪ RA, SLE, JRA ▪ Abscess, sinusitis, otitis, Trichomonas, Candida, Parasites J Investig Allergol Clin Immunol 17:192, 2007 Ann Dermatol 24:453, 2012 Urticaria: Valid Association? ▪ In one large prospective study (1155 patients) with chronic urticaria, no association with any type of visceral or hematological malignancy was found. ▪ Br J Dermatol 123:453–6, 1990 Erythema Gyratum Repens ▪ Concentric erythema, trailing edge scales ▪ Mild pruritus ▪ “Wood Grain” morphology ▪ Trunk primary site ▪ Rash usually precedes cancer diagnosis (80%) ▪ Variable sites/types of malignancy, but lung is the most common ▪ Rare but reliable sign of cancer Am J Med Sci 321:302, 2001 JAAD 54:745, 2006 ▪ 85-100% association BMJ Case Rep. 2016; Mar 7; pii: bcr2016214665 69 year-old male 3 month itchy rash 100 pack-yr smoker w/ symptomatic COPD Denies weight loss, hemoptysis, dyspnea or cough Dx: Erythema gyratum CT scan + lesion RUL T4N2M0 bronchogenic CA Eur J Dermatol 18:197, 2008 69 year-old male 3 month itchy rash 100 pack-yr smoker w/ symptomatic COPD Denies weight loss, hemoptysis, dyspnea or cough Dx: Erythema gyratum CT scan + lesion RUL T4N2M0 bronchogenic CA Eur J Dermatol 18:197, 2008 Erythema Annulare Centrifugum ▪ Annular, arcuate and polycyclic ▪ Erythema, scale (min) ▪ DDx: Tinea, SCLE ▪ Internal cancer: Lung most common ▪ Myeloma; Leukemia (various) ▪ Tuberculosis ▪ Dental abscess ▪ Drug & Food allergy EAC: CLL Derm Online J 12(6):11, 2006 ▪ 58 year-old female ▪ 3 month hx serpiginous erythema with scale ▪ W/U revealed stromal smooth muscle cancer of the stomach: resected ▪ Rash resolved ▪ 3 months later: rash resumed and then nodules appeared ▪ Bx nodule = original cancer ▪ Patient refused further Rx and died 1 year later of metz Exfoliative Erythroderma ▪ Widespread red and then scaly skin ▪ ITCHY ▪ Complications Dehydration Protein loss High output CHF Local infection Septicemia Nail shedding Rosen T, et al Am Fam Phys 59:625, 1999 Exfoliative Erythroderma Pre-existing skin 50% disease (eg Psoriasis) Drug reaction 10% Malignancy 10% (may be occult) Idiopathic 30% Dermatol Clin 18:405, 2000 Exfoliative Erythroderma CTCL Hodgkins Illustrative Case ▪ 63 year-old with 2 mo history of red, scaly, itchy skin ▪ No prior skin disorder, no meds, good health, nl labs ▪ Skin biopsy nonspecific ▪ Workup unproductive ▪ Repeated evaluations: 6 mo Colonic adenoCA discovered ▪ Resection: erythroderma resolved Rosen T, Chappell R, Drucker C. Exfoliative dermatitis: presenting sign of visceral internal malignancy. South Med J. 72:652-3, 1979 Exfoliative Erythroderma: Due to Rx ▪ All EGRF-inhibitors ▪ Chlorambucil ▪ Denileukin diftitox ▪ Interferon ▪ Thalidomide ▪ Pentostatin ▪ Cisplatin ▪ Therapeutic arsenic ▪ Erythropoietin Glucagonoma Syndrome ▪ “Necrolytic migratory erythema” ▪ Intertrigo-like: raw and scaling groin; face, extremities ( pigment) ▪ Glossitis, cheilitis ▪ Weight loss ▪ Hyperglycemia ▪ Personality changes ▪ Islet-cell pancreatic tumor Eur J Endocrinol 151:531, 2004 Hepatobiliary Pancreat Dis Int 3:473, 2004 J Eur Acad Dermatol Venereol 30:2016-22, 2016 Glucagonoma Eur J Endocrinol 151:531-7, 2004 Hypertrichosis Lanuginosa ▪ “Malignant down” ▪ 66 total cases as of 2007 ▪ 10:1 = Female:Male ▪ Age 40-70 ▪ Abundant fine hair growth on face; rarely elsewhere ▪ Lung, colon and prostate primary malignancies ▪ Different from hirsutism: terminal hair growth all over ▪ Actas Dermosifiliogr 96:459-61, 2005 ▪ Br J Dermatol 157:1087, 2007 J Cutan Med Surg 19:507-10, 2015 Hypertrichosis Lanuginosa Hypertrichosis Lanuginosa Ichthyosis (Acquired) ▪ Rhomboidal scales ▪ Extremities ▪ Resembles very severe dry skin Hypothyroidism, ESRD Sarcoidosis, SLE, DM, HIV+ (25%), Diabetes (50%), TB, Hansen’s, Medications Cancer: Hodgkin’s (70%), KS, Non-Hodgkin’s Lymphomas, T- cell lymphoma, myeloma, Rare: CA ovary, breast, lung, Cx Am J Clin