Skin Markers of Internal Malignancy

Introduction

1. Specific markers — where the skin lesion is histologically identical to the primary tumor (e.g., metastases, Paget disease)
2. Non-specific / paraneoplastic markers — reactive cutaneous changes secondary to tumor-derived factors

I. Obligate Paraneoplastic Dermatoses

1. Acanthosis Nigricans (Malignant Type)

• Lesion: Velvety, hyperpigmented, papillomatous plaques at flexures (axillae, neck, groin), mucous membranes, and palms ("tripe palms")
• Malignancy: Predominantly gastric adenocarcinoma (~60%); also GI, uterine, ovarian carcinomas
• Mechanism: Tumor-secreted TGF-α, EGF, and IGF-1 stimulate keratinocyte proliferation via EGF receptors
• Key feature: Malignant AN tends to be more extensive, rapid-onset, involves atypical sites (lips, tongue), often accompanied by the sign of Leser-Trélat
• Tripe Palms: Rugose, velvety thickening of palmar skin resembling tripe; associated with malignancy in >90% of cases; lung and gastric cancer are the most common associations

2. Acrokeratosis Paraneoplastica (Bazex Syndrome)

• Lesion: Violaceous, psoriasiform (erythematous scaly) plaques over acral sites — tips of fingers/toes, ears (helices), nose; nail dystrophy (subungual hyperkeratosis, onycholysis, ridging); palmoplantar keratoderma sparing central volar surfaces
• Malignancy: Squamous cell carcinoma of the upper aerodigestive tract (pharynx, larynx, esophagus) or metastatic cervical lymph nodes; almost exclusively in men >60 years
• Stages:
  • Stage I: Nail changes + acral plaques (before tumor symptoms)
  • Stage II: More extensive plaques with tumor symptoms
  • Stage III: Trunk/elbows/knees involvement; bullae may appear
• Pathogenesis: Immunological cross-reactivity between tumor antigens and keratinocytes; EGF overproduction
• Distinguishing feature: Ear helix involvement is almost pathognomonic

3. Necrolytic Migratory Erythema (Glucagonoma Syndrome)

• Lesion: Cyclic eruption of erythematous blistering plaques → erosions → crusted/hyperpigmented lesions; begins periorificially (groin, perineum, mouth) and spreads centrifugally
• Malignancy: Glucagon-secreting α-cell tumor of pancreas (glucagonoma)
• Associated features: Weight loss, glucose intolerance/diabetes, anemia, glossitis, angular stomatitis, diarrhea
• Mechanism: Hypoaminoacidemia → epidermal necrolysis; glucagon excess causes essential fatty acid deficiency
• Histology: Superficial necrolysis (upper epidermal pallor and necrosis)

4. Erythema Gyratum Repens

• Lesion: Rapidly migrating, concentric, serpiginous erythematous bands with trailing scale — producing a "wood grain" or "zebra stripe" pattern; may move up to 1 cm/day
• Malignancy: Associated with underlying malignancy in nearly 100% of cases — lung, breast, esophageal, and bladder carcinomas; considered the most specific paraneoplastic dermatosis
• Mechanism: Type III hypersensitivity reaction to tumor antigens

5. Sign of Leser-Trélat

• Lesion: Sudden eruptive increase in number and size of seborrheic keratoses, often pruritic, predominantly on trunk/extremities
• Malignancy: GI adenocarcinomas (most common), lymphoproliferative malignancies, breast carcinoma
• Pathogenesis: Tumor-derived TGF-α stimulates keratinocyte and sebocyte proliferation
• Key associations: Frequently co-exists with malignant acanthosis nigricans; may occur in younger patients
• Controversy: Large epidemiologic studies have not definitively confirmed this as a true paraneoplastic sign, though anecdotal evidence is compelling

II. Facultative / Non-Specific Paraneoplastic Markers

6. Dermatomyositis

• Lesion: Heliotrope rash (periorbital violaceous erythema), Gottron papules (knuckles), shawl sign, V-sign, mechanic's hands, periungual telangiectasias
• Malignancy association: Up to 25% of adults with dermatomyositis have an underlying malignancy; risk highest in patients >40 years; nasopharyngeal carcinoma (Southeast Asia), ovarian, lung, GI, breast carcinomas
• Note: Juvenile dermatomyositis has NO malignant association; malignancy workup mandatory in adult-onset DM

7. Hypertrichosis Lanuginosa Acquisita ("Malignant Down")

• Lesion: Sudden growth of profuse, soft, fine, nonpigmented lanugo hairs — face and ears first, then trunk; eyebrows/lashes may grow to inches; palms, soles, and genitalia spared
• Malignancy: Lung and colorectal carcinoma in men; colorectal followed by lung and breast carcinoma in women; lymphoma, leukemia
• Associated findings: Glossitis, hypertrophy of tongue papillae, acanthosis nigricans, weight loss, adenopathy
• Mechanism: Unknown; possibly related to EGF or IGF-1 signaling

8. Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

• Lesion: Tender, well-demarcated, red/purple papules and plaques (pseudovesicular surface); fever; leukocytosis; may show ulceration, bullae, or oral mucosal involvement in malignancy-associated cases
• Malignancy: ~21% of cases — hematologic (15%, mostly acute myeloblastic leukemia) > solid tumors (6%; breast, GI, genitourinary)
• Malignancy-associated features: No female predominance, no preceding respiratory infection, concurrent anemia and thrombocytopenia, neutropenia possible
• Recurrence of Sweet syndrome may signal relapse of underlying malignancy

9. Paraneoplastic Pemphigus

• Lesion: Painful hemorrhagic oral erosions (earliest and most constant finding) + polymorphous skin eruptions — pemphigus-like, bullous pemphigoid-like, erythema multiforme-like, lichen planus-like, and GVHD-like lesions
• Malignancy: Non-Hodgkin lymphoma, CLL, Castleman disease, thymoma (most are lymphoproliferative)
• Pathogenesis: Autoantibodies against desmoplakin I & II, periplakin, envoplakin, BPAG1, and desmoglein 1/3; both humoral and cellular immunity implicated
• Prognosis: High mortality; worse with malignant tumors; relatively better with benign tumors (thymoma, Castleman)

10. Other Important Facultative Markers

III. Specific Skin Involvement

• Cutaneous metastases: Firm, flesh-colored/violaceous dermal nodules; "Sister Mary Joseph nodule" (umbilical metastasis) from GI/pelvic malignancy; "carcinoma en cuirasse" (breast carcinoma)
• Mammary/extramammary Paget disease: Eczematous well-demarcated plaques on nipple-areola or anogenital region; intraepidermal adenocarcinoma cells (Paget cells = large pale cells with abundant cytoplasm, mucin-positive)

Summary Table

• Fitzpatrick's Dermatology, 9th ed., Ch. 134 (Paraneoplastic Dermatoses)
• Andrews' Diseases of the Skin, Ch. 28 (Paraneoplastic Syndromes)
• Dermatology 2-Volume Set, 5th ed. (Dermatomyositis, Sweet Syndrome sections)