Residency · Residency · Dermatology
Dermatologic Manifestations of Systemic Disease
Introduction
The skin serves as a window to internal disease, and dermatologists are frequently the first to identify cutaneous signs that herald systemic pathology. Recognizing these associations enables early diagnosis and treatment of underlying conditions ranging from malignancy to autoimmune disease to metabolic disorders. This lecture reviews the most clinically significant skin-systemic disease connections.
Cutaneous Signs of Internal Malignancy
Paraneoplastic Dermatoses
Malignant acanthosis nigricans presents with sudden onset, rapidly progressive, extensive velvety hyperpigmented plaques involving atypical sites such as the oral mucosa and palms (tripe palms). It is most commonly associated with gastric adenocarcinoma and other GI and lung cancers. The sign of Leser-Trelat manifests as an explosive onset of multiple seborrheic keratoses, associated with GI malignancy and often co-occurring with malignant acanthosis nigricans.
Paraneoplastic pemphigus causes painful mucosal erosions and a polymorphous cutaneous eruption, associated with lymphoproliferative disorders including non-Hodgkin lymphoma, CLL, and Castleman disease. It is characterized by anti-plakin antibodies (envoplakin, periplakin) and may lead to fatal bronchiolitis obliterans. Bazex syndrome, or acrokeratosis paraneoplastica, presents as violaceous psoriasiform plaques on acral sites (ears, nose, fingers, toes) and is associated with upper aerodigestive tract squamous cell carcinoma.
Erythema gyratum repens features concentric, woodgrain-patterned erythema with fine scale and is most frequently associated with lung cancer, with approximately 80% of cases having an underlying malignancy. Necrolytic migratory erythema produces annular, erosive, crusted plaques with centrifugal spread in perioral and intertriginous distribution, and is pathognomonic for glucagonoma (pancreatic alpha-cell tumor), forming part of the associated triad of diabetes, weight loss, and necrolytic migratory erythema.
Sweet syndrome (acute febrile neutrophilic dermatosis), when presenting in an atypical or bullous form, is associated with acute myeloid leukemia and myelodysplastic syndrome. Dermatomyositis in adults carries an association with malignancy in 15 to 30% of cases (ovarian, lung, GI, breast, nasopharyngeal), warranting age-appropriate cancer screening plus CT of the chest, abdomen, and pelvis.
<image>Clinical photograph montage of paraneoplastic dermatoses: malignant acanthosis nigricans with tripe palms, erythema gyratum repens showing woodgrain pattern, necrolytic migratory erythema with perioral erosions, and Bazex syndrome with acral violaceous keratoderma</image>
| Paraneoplastic Dermatosis | Cutaneous Findings | Most Common Malignancy |
|---|---|---|
| Malignant acanthosis nigricans | Extensive velvety plaques, tripe palms, oral involvement | Gastric adenocarcinoma |
| Sign of Leser-Trelat | Explosive onset of seborrheic keratoses | GI malignancy |
| Paraneoplastic pemphigus | Painful mucosal erosions, polymorphous eruption | NHL, CLL, Castleman disease |
| Bazex syndrome | Violaceous acral psoriasiform plaques | Upper aerodigestive tract SCC |
| Erythema gyratum repens | Concentric woodgrain-patterned erythema | Lung cancer (~80%) |
| Necrolytic migratory erythema | Annular erosive perioral/intertriginous plaques | Glucagonoma |
| Sweet syndrome (atypical) | Tender pseudovesicular plaques, fever | AML, MDS |
| Dermatomyositis (adult) | Heliotrope rash, Gottron papules | Ovarian, lung, GI, breast (15–30%) |
Cancer-Associated Genodermatoses
Gardner syndrome is characterized by epidermal inclusion cysts, osteomas, and desmoid tumors resulting from an APC gene mutation, with colorectal polyposis and adenocarcinoma. Muir-Torre syndrome produces sebaceous neoplasms (adenomas, carcinomas) and keratoacanthomas associated with visceral malignancy (colorectal, genitourinary) through MSH2/MLH1 mismatch repair gene mutations, making it a Lynch syndrome variant. Cowden syndrome presents with trichilemmomas, oral papillomas, and acral keratoses due to PTEN mutation, with increased risk of breast, thyroid, and endometrial carcinoma. Peutz-Jeghers syndrome manifests with mucocutaneous lentigines on the lips, buccal mucosa, and fingers due to STK11/LKB1 mutation, with hamartomatous GI polyps and increased risk of GI, breast, ovarian, and pancreatic cancer.
Endocrine and Metabolic Diseases
Diabetes Mellitus
Necrobiosis lipoidica presents as yellow-brown atrophic plaques with telangiectasias on the pretibial area, associated with diabetes but not exclusively, and may ulcerate. Diabetic dermopathy -- brown atrophic macules on the shins known as "shin spots" -- is the most common cutaneous manifestation of diabetes. Generalized granuloma annulare (annular plaques with palisading granulomas) has a stronger association with diabetes than the localized form. Scleredema diabeticorum produces thickened, indurated skin of the upper back and neck in poorly controlled type 2 diabetes. Eruptive xanthomas appear as crops of yellow papules on extensor surfaces and buttocks in the setting of severe hypertriglyceridemia, which may signal uncontrolled diabetes. Benign acanthosis nigricans, a marker of insulin resistance, produces velvety hyperpigmentation of the axillae, neck, and intertriginous areas.
Thyroid Disease
Pretibial myxedema (thyroid dermopathy) presents as firm, non-pitting, waxy plaques on the pretibial area associated with Graves disease, occurring with or after hyperthyroidism treatment. Hypothyroidism causes diffuse hair loss with coarse, brittle hair and lateral eyebrow loss (Queen Anne sign), as well as generalized myxedema with non-pitting edema, dry coarse skin, and a yellowish hue from carotenemia. Hyperthyroidism may produce Plummer nails (onycholysis), and autoimmune thyroid disease is associated with chronic spontaneous urticaria.
Adrenal Disease
Addison disease produces diffuse hyperpigmentation, especially of palmar creases, buccal mucosa, scars, and sun-exposed areas, because elevated ACTH stimulates melanocortin receptors. Cushing syndrome causes facial plethora, moon facies, buffalo hump, purple striae, easy bruising, acne, hirsutism, and skin fragility.
Connective Tissue Diseases
Systemic Lupus Erythematosus
The malar (butterfly) rash features erythema over the cheeks and nasal bridge with sparing of the nasolabial folds. Discoid lupus produces scarring, atrophic plaques with follicular plugging and dyspigmentation. Photosensitivity occurs in more than 80% of patients, and oral ulcers are typically painless and located on the hard palate. Lupus hair describes diffuse non-scarring alopecia with frontal hairline broken hairs. Anti-Ro/La antibodies are associated with subacute cutaneous lupus (annular polycyclic or papulosquamous photodistributed lesions) and neonatal lupus.
Dermatomyositis
The heliotrope rash presents as violaceous erythema of the periorbital skin with edema, while Gottron papules appear as violaceous papules over the MCPs, PIPs, DIPs, elbows, and knees. The V-sign and shawl sign represent photodistributed poikiloderma. Mechanic's hands describe fissured, hyperkeratotic skin of the lateral and palmar fingers, and the holster sign refers to poikiloderma of the lateral thighs. Periungual changes include cuticular overgrowth (Samitz sign) and dilated nailfold capillary loops.
Systemic Sclerosis (Scleroderma)
Raynaud phenomenon is usually the first manifestation, featuring the classic triphasic color change. Sclerodactyly produces tightening and thickening of digital skin. Nailfold capillaroscopy reveals dilated loops with dropout areas (giant capillaries). Additional findings include digital pitting scars and ulcers from ischemic vascular disease, calcinosis cutis with calcium deposits in skin (CREST syndrome), mat telangiectasias of the face and hands, and salt-and-pepper dyspigmentation, particularly on the trunk.
<image>Nailfold capillaroscopy comparison showing normal capillary architecture versus systemic sclerosis pattern with dilated giant capillary loops, avascular areas (dropout), and microhemorrhages, alongside dermatomyositis pattern with bushy/tortuous capillaries</image>
| Genodermatosis | Gene/Mutation | Skin Findings | Associated Malignancy |
|---|---|---|---|
| Gardner syndrome | APC | Epidermal cysts, osteomas, desmoid tumors | Colorectal adenocarcinoma |
| Muir-Torre syndrome | MSH2/MLH1 | Sebaceous neoplasms, keratoacanthomas | Colorectal, genitourinary |
| Cowden syndrome | PTEN | Trichilemmomas, oral papillomas, acral keratoses | Breast, thyroid, endometrial |
| Peutz-Jeghers syndrome | STK11/LKB1 | Mucocutaneous lentigines (lips, buccal, fingers) | GI, breast, ovarian, pancreatic |
Gastrointestinal Disease
Inflammatory Bowel Disease
Pyoderma gangrenosum is most commonly associated with ulcerative colitis. Erythema nodosum produces tender red nodules on the shins that correlate with IBD disease activity, especially Crohn disease. Oral aphthous ulcers are recurrent and correlate with disease activity. Perianal disease with fissures, fistulae, and abscesses is characteristic of Crohn disease, and metastatic Crohn disease produces non-caseating granulomatous skin lesions at sites distant from the GI tract.
Celiac Disease
Dermatitis herpetiformis presents as intensely pruritic, grouped vesicles on extensor surfaces (elbows, knees, buttocks, scalp) with granular IgA deposits at the dermal papillae on direct immunofluorescence. It is associated with gluten-sensitive enteropathy in more than 90% of cases.
Hepatic Disease
Pruritus is common in cholestatic liver disease such as primary biliary cholangitis and primary sclerosing cholangitis. Spider angiomas are estrogen-mediated with upper body distribution, and more than five suggest liver disease. Palmar erythema involves the thenar and hypothenar eminences. Jaundice causes scleral icterus and generalized yellowish discoloration. Porphyria cutanea tarda is associated with hepatitis C, alcohol, hemochromatosis, and HIV.
Sarcoidosis
Cutaneous involvement occurs in 25 to 35% of sarcoidosis cases and may be the presenting sign. Morphologies include papules, plaques, nodules, annular lesions, and lupus pernio (violaceous plaques on the nose, cheeks, and ears). Scar sarcoidosis, in which old scars develop granulomatous infiltration, is highly suggestive of the diagnosis. Erythema nodosum occurs in acute sarcoidosis as part of Lofgren syndrome, which includes bilateral hilar lymphadenopathy, erythema nodosum, fever, and polyarthralgia. Histology reveals non-caseating (naked) granulomas without significant surrounding lymphocytic infiltrate.
Clinical Pearls
Sudden-onset extensive acanthosis nigricans with tripe palms in an adult warrants urgent GI malignancy workup. Dermatomyositis in adults older than 40 requires age-appropriate cancer screening plus CT of the chest, abdomen, and pelvis at diagnosis and for 3 to 5 years afterward. Dermatitis herpetiformis is pathognomonic for celiac disease, diagnosed by biopsy showing granular IgA at the dermal papillae, and treated with dapsone and a gluten-free diet. Nailfold capillaroscopy is a simple, non-invasive tool that can distinguish connective tissue diseases from primary Raynaud phenomenon. Necrolytic migratory erythema should prompt measurement of serum glucagon and pancreatic imaging.
References
- Callen JP. Skin signs of internal malignancy. In: Bolognia JL, et al., eds. Dermatology. 4th ed. Elsevier; 2018.
- Dourmishev LA, Dourmishev AL. Dermatologic Signs of Systemic Disease. Springer; 2009.
- Sontheimer RD. Skin manifestations of systemic autoimmune connective tissue disease: diagnostics and therapeutics. Best Pract Res Clin Rheumatol. 2004;18(3):429-462.
- Thiers BH, Sahn RE, Callen JP. Cutaneous manifestations of internal malignancy. CA Cancer J Clin. 2009;59(2):73-98.
