9.4 Cutaneous Manifestations of Systemic Disease
Key Takeaways
- Rapid onset of acanthosis nigricans accompanied by tripe palms (hyperkeratosis of the palms) is a classic paraneoplastic marker associated with underlying gastrointestinal adenocarcinoma in over 90% of cases, predominantly gastric carcinoma.
- Necrolytic migratory erythema—characterized by painful, pruriginous annular erythematous plaques with central bullae and erosions in flexural and perineal areas—is pathognomonic for a glucagonoma, an alpha-cell pancreatic neuroendocrine tumor.
- Over 80% of cases of erythema gyratum repens, which presents with rapidly migrating concentric erythematous bands resembling 'wood grain,' are associated with internal malignancy, most commonly lung cancer.
- Pyoderma gangrenosum manifests as a rapidly enlarging, painful ulcer with a violaceous, undermined border; it is non-infectious, demonstrates pathergy in 30% of patients, and is associated with inflammatory bowel disease (IBD) in 50% of presentation cases.
- Porphyria cutanea tarda (PCT) is caused by a deficiency in uroporphyrinogen decarboxylase (UROD) and presents with cutaneous fragility, subepidermal bullae, and hypertrichosis on sun-exposed skin; active hepatitis C virus (HCV) infection is present in up to 70% of affected individuals.
9.4 Cutaneous Manifestations of Systemic Disease
Cutaneous signs frequently serve as the diagnostic harbinger of severe internal systemic pathology, including occult visceral malignancies, systemic necrotizing vasculitides, autoimmune connective tissue diseases, reactive erythemas, and metabolic disorders. Mastery of these dermatological-systemic correlations is highly tested in MRCPI General Medicine Part I.
Cutaneous Paraneoplastic Syndromes
Cutaneous paraneoplastic syndromes arise from tumor-derived cytokines, growth factors, or cross-reactive autoantibodies produced by distant internal malignancies. Recognizing these skin markers allows early diagnosis of underlying occult cancers.
| Paraneoplastic Skin Condition | Clinical Appearance & Morphology | Primary Associated Internal Malignancy | Underlying Pathophysiological Mechanism |
|---|---|---|---|
| Acanthosis Nigricans (Malignant) | Rapidly progressive, velvety hyperpigmented hyperkeratotic plaques in intertriginous areas (axillae, neck, groin), accompanied by Tripe Palms (velvety hyperkeratosis of palmar dermatoglyphics). | Gastric Adenocarcinoma (>60%); other gastrointestinal carcinomas (pancreatic, colon). | Secretion of Transforming Growth Factor-alpha (TGF-α) by tumor cells acting on epidermal growth factor receptors (EGFR). |
| Erythema Gyratum Repens | Rapidly migrating concentric, polycyclic erythematous bands with trailing scale, resembling a "wood-grain" pattern (advancing up to 1 cm/day). | Bronchogenic Carcinoma (Lung) (>50%); esophageal, breast, bladder cancer (>80% associated with malignancy). | Tumor antigen cross-reactivity with epidermal basement membrane structures. |
| Necrolytic Migratory Erythema (NME) | Pruriginous, painful annular erythematous plaques that develop central flaccid bullae, erosion, and crusting, localized to the perineum, groin, buttocks, and distal extremities. | Glucagonoma (alpha-cell neuroendocrine tumor of the pancreas). | Associated with the 4D Syndrome: Dermatosis (NME), Diabetes mellitus, Deep vein thrombosis, Depression, plus anemia, weight loss, glossitis. Elevated glucagon (>500 pg/mL). |
| Sign of Leser-Trélat | Sudden eruptive appearance of multiple seborrheic keratoses over weeks to months, typically on an inflamed, pruriginous base. | Gastrointestinal Adenocarcinomas (gastric, colorectal), Lymphoma, Leukemias. | Eruptive proliferation driven by circulating tumor-secreted growth factors (EGF, TGF-α). |
| Dermatomyositis | Heliotrope rash (violaceous periorbital edema), Gottron's papules (flat-topped violaceous papules over MCP/IP joints), Shawl sign, Holster sign, periungual telangiectasias, proximal muscle weakness. | Ovarian, Lung, Gastric, Colorectal Carcinomas, and Non-Hodgkin Lymphoma. | Autoimmune microvasculopathy. Anti-TIF1-γ antibodies confer a 50-70% risk of underlying cancer in adults aged >50. |
| Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis) | Abrupt onset of painful, tender, "juicy" erythematous papules, plaques, or nodules on face, neck, and upper limbs; accompanied by high fever, neutrophilia, and elevated CRP/ESR. | Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS) (20% paraneoplastic). | Hypersensitivity reaction driven by G-CSF and IL-6 leading to dermal neutrophilic infiltration without vasculitis. |
MRCPI Exam Pearl: Benign acanthosis nigricans develops insidiously in insulin-resistant states (type 2 diabetes, obesity, PCOS). In contrast, malignant acanthosis nigricans presents with sudden, extensive eruption, involvement of mucosal surfaces (oral lips/tongue), and tripe palms, mandating immediate endoscopy and CT imaging of the abdomen.
Systemic Vasculitis & Connective Tissue Disease Markers
Cutaneous Manifestations of Vasculitis
Systemic small-vessel vasculitis presents characteristically with Palpable Purpura—non-blanching, raised, purple-red macules and papules located predominantly on dependent lower extremities.
• IgA Vasculitis (Henoch-Schönlein Purpura): IgA-mediated immune complex small-vessel vasculitis presenting with the classic clinical tetrad:
- Palpable purpura (buttocks and lower legs)
- Arthralgia or non-erosive arthritis (knees and ankles)
- Colicky abdominal pain (risk of ileo-ileal intussusception)
- IgA Nephropathy (microscopic hematuria, proteinuria, renal failure) Skin biopsy: Demonstrates leukocytoclastic vasculitis with direct immunofluorescence showing vascular IgA deposition.
• Granulomatosis with Polyangiitis (GPA / Wegener's): Palpable purpura, necrotic cutaneous ulcers, and pyoderma-like gangrenous lesions. Strongly associated with PR3-ANCA (c-ANCA), upper/lower respiratory tract necrotizing granulomas, and crescentic glomerulonephritis.
• Eosinophilic Granulomatosis with Polyangiitis (EGPA / Churg-Strauss): Palpable purpura, subcutaneous nodules, severe adult-onset asthma, allergic rhinitis, peripheral blood eosinophilia (>1.5 x 10⁹/L), and positive MPO-ANCA (p-ANCA) in 40-50%.
Connective Tissue Disease Cutaneous Signs
• Systemic Lupus Erythematosus (SLE): • Acute Cutaneous Lupus (ACLE): Malar "butterfly" rash across nasal bridge and cheeks, characteristically sparing the nasolabial folds. Strongly associated with systemic disease activity, ANA, and anti-dsDNA positivity. • Subacute Cutaneous Lupus (SCLE): Non-scarring, annular polycyclic or papulosquamous erythematous plaques in photo-distributed areas (shoulders, upper chest). Strongly associated with Anti-Ro/SSA antibodies and drug triggers (hydrochlorothiazide, terbinafine, diltiazem, anti-TNF agents). • Discoid Lupus (DLE): Scarring indurated erythematous plaques with follicular plugging, central atrophy, and telangiectasia. <15% develop systemic SLE.
• Systemic Sclerosis (Scleroderma): • Limited Cutaneous Systemic Sclerosis (lcSSc / CREST): Calcinosis cutis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly (skin thickening restricted to distal hands/feet and face), Telangiectasias. Associated with Anti-Centromere antibodies and long-term risk of pulmonary arterial hypertension (PAH). • Diffuse Cutaneous Systemic Sclerosis (dcSSc): Rapidly progressive skin thickening extending proximal to elbows/knees and involving the trunk. Associated with Anti-Scl-70 (anti-topoisomerase I) and Anti-RNA Polymerase III antibodies (the latter carrying a high risk of Scleroderma Renal Crisis).
Reactive Erythemas & Inflammatory Dermatoses
Pyoderma Gangrenosum
• Clinical Morphology: Rapidly expanding, agonizingly painful ulceration featuring a violaceous, ragged, undermined border with a surrounding zone of erythema. The ulcer bed contains purulent, necrotic tissue. • Key Feature (Pathergy): Demonstrates pathergy in 30% of cases—development of new ulcers or dramatic worsening of existing lesions following minor trauma, skin biopsy, or surgical debridement. • Systemic Associations:
- Inflammatory Bowel Disease (IBD): Ulcerative Colitis (>Crohn's disease) in 50% of cases.
- Rheumatoid Arthritis & Seronegative Spondyloarthropathies
- Hematological Malignancies: Acute Myeloid Leukemia, Myelodysplastic Syndrome, Multiple Myeloma. • Management: Systemic high-dose corticosteroids (Prednisolone 1 mg/kg) or Cyclosporine. Infliximab (anti-TNF) is highly effective for IBD-associated cases. Surgical debridement is strictly contraindicated due to pathergy.
Erythema Nodosum
• Clinical Presentation: Erythematous, tender, warm, non-ulcerating nodules located symmetrically on the anterior pretibial surfaces of the lower legs. Histology demonstrates a septal panniculitis without vasculitis. • Common Etiologies: • Sarcoidosis: Löfgren Syndrome triad: Erythema Nodosum, Bilateral Hilar Lymphadenopathy, and Migratory Polyarthritis (excellent prognosis). • Infections: Streptococcal pharyngitis (most common cause in children), Primary Tuberculosis, Deep fungal infections (Coccidioidomycosis). • Inflammatory Bowel Disease: Crohn's disease and Ulcerative Colitis. • Drugs: Sulfonamides, Combined Oral Contraceptives, Penicillins.
Erythema Multiforme
• Clinical Presentation: Acute, self-limiting eruption of targetoid (iris-like) lesions characterized by three concentric zones: a central dark purpuric/bullous center, a pale edematous middle ring, and an outer erythematous halo. Distributed acrally on hands, feet, and extensor surfaces. • Triggers: Herpes Simplex Virus (HSV-1/2) causes >70-80% of recurrent cases. Other causes include Mycoplasma pneumoniae infection and drugs (NSAIDs, sulfonamides, anticonvulsants).
Metabolic & Storage Skin Manifestations
Porphyria Cutanea Tarda (PCT)
• Pathophysiology: The most common porphyria, caused by hepatic deficiency of the enzyme uroporphyrinogen decarboxylase (UROD), leading to accumulation of photosensitive porphyrins. • Clinical Presentation: Marked cutaneous fragility, subepidermal tense bullae, erosions, and scarring on sun-exposed areas (dorsum of hands, forearms, face), accompanied by facial hypertrichosis (excessive hair growth) and hyperpigmentation. • Precipitating Factors & Associations:
- Chronic Hepatitis C Virus (HCV) Infection: Present in up to 70% of PCT cases worldwide.
- Hereditary Hemochromatosis / Iron Overload: Homozygosity for C282Y HFE mutation.
- Alcohol Excess & Estrogen Therapy • Diagnostics & Management: Urine under Wood's lamp displays coral-red fluorescence; markedly elevated urinary uroporphyrins. Management involves treatment of Hepatitis C with direct-acting antivirals (DAAs), repeated venesection (phlebotomy) to deplete hepatic iron stores, or low-dose oral Hydroxychloroquine (100 mg twice weekly).
A 56-year-old man presents with a 3-month history of a severely itchy, painful rash affecting his groin, perineum, and buttocks. On examination, there are extensive annular erythematous plaques with central flaccid bullae, erosion, and crusting. Laboratory tests show a hemoglobin of 9.8 g/dL, fasting blood glucose of 11.2 mmol/L, and a plasma glucagon level of 850 pg/mL (normal <100 pg/mL). Abdominal CT scan reveals a 3 cm hypervascular mass in the tail of the pancreas. What is the diagnosis for this patient's cutaneous manifestation?
A 38-year-old woman with a 6-year history of Ulcerative Colitis presents with a rapidly expanding, extremely painful ulcer on her left shin that began 4 days ago after she bumped her leg against a coffee table. On examination, the ulcer measures 6 x 4 cm, has a purulent necrotic base, and features a characteristic dark violaceous, ragged, undermined border surrounded by intense erythema. What is the most appropriate management strategy for this skin lesion?
A 52-year-old man presents with a 6-month history of fragile skin on the dorsum of both hands. He notes that minor trauma causes tense fluid-filled blisters that break easily, leaving slow-healing erosions and dark scars. On examination, there are multiple crusted erosions, small milia, hyperpigmentation, and noticeable hypertrichosis (increased hair growth) over his cheeks and temples. Urinalysis under a Wood's lamp demonstrates coral-red fluorescence. Which underlying infection should be routinely screened for in this patient?