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Dermatologic Manifestations of Internal Malignancy
Key Points
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Internal malignancy can involve the skin either directly or indirectly.
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Direct involvement is defined as tumor metastatic to the skin.
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Indirect involvement refers to changes in the skin that suggest the possibility of an underlying malignancy.
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Patients with direct involvement should be assumed to have an underlying neoplasm and must be evaluated accordingly.
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Patients with indirect involvement may not have an underlying neoplasm when first evaluated, but must be monitored for its possible future development.
Introduction
The skin, the largest organ in the body, often mirrors changes occurring within the organism it envelops. A wide spectrum of inflammatory, proliferative, metabolic, and neoplastic diseases may affect the skin in association with an underlying malignancy. This chapter will focus on these changes, known collectively as the skin signs of internal malignancy. Internal cancer may affect the skin both directly and indirectly. Direct involvement may be defined as the actual presence of malignant cells within the skin and includes neoplasms that often first become manifested in the skin, but eventually affect internal organs (such as mycosis fungoides), visceral neoplasms metastatic to the skin (such as the Sister Joseph nodule of gastric carcinoma), and tumors arising within or below the skin that ultimately spread to the cutaneous surface (such as mammary and extramammary Paget disease). Indirect involvement of the skin in cancer patients implies the absence of tumor cells within the skin. This group includes (1) inherited syndromes associated with skin manifestations and an increased incidence of systemic neoplasia, (2) cutaneous changes resulting from hormone secretion by tumors, and (3) a wide spectrum of proliferative and inflammatory disorders occurring in conjunction with internal malignancy.
History
In the original text Cancer of the Skin , Curth outlined a set of criteria that could be used to analyze the relationship between an internal malignancy and a cutaneous disorder. Curth's postulates, as Callen has subsequently labeled them, consist of five characteristics: (1) a concurrent onset – the malignancy is discovered when the skin disease occurs; (2) a parallel course – if the malignancy is removed or successfully treated, the skin disease remits, and when the malignancy recurs, the cutaneous disease also recurs; (3) a uniform malignancy – there is a specific tumor cell type or site associated with the skin disease; (4) a statistical association – based on sound case-control studies there is a significantly more frequent occurrence of malignancy in a patient with a cutaneous disease; and (5) a genetic association. These criteria are extremely useful and should be satisfied before a link between an internal neoplasm and a specific skin change can be assumed.
Inherited syndromes associated with internal malignancy
Many familial cancer syndromes have prominent dermatologic features. When characteristic skin findings are encountered, a thorough review of systems and family history should be undertaken. Genetic testing and counseling is a central component of patient management. Multidisciplinary care is often required. This topic has been extensively reviewed elsewhere and is summarized in Table 34.1 .
Table 34.1
Inherited Syndromes Associated with Internal Malignancy
| Disease | Inheritance, Genetic Defect | Clinical Findings | Associated Malignancy * |
|---|---|---|---|
| Cowden syndrome | AD, PTEN | Tricholemmomas ( Fig. 34.1 ), ‘cobblestone’ oral papillomas, acral keratoses, macrocephaly, fibrocystic breast disease | Breast, thyroid |
| Gardner syndrome | AD, APC (adenomatous polyposis coli) | Epidermoid cysts ( Fig. 34.2 ), osteomas, congenital hypertrophy of retinal pigment, gastrointestinal adenomatous polyps | Colorectal |
| Peutz–Jeghers syndrome | AD, STK11 (serine/threonine kinase 11) | Brown-black macules ( Figs 34.3 , 34.4 ) on lips, oral mucosa, nails, palms, soles, hamartomatous gastrointestinal polyps, intussusception | Gastrointestinal, reproductive organs, breast, pancreas |
| Muir–Torre syndrome | AD, MSH-2, MLH-1 | Sebaceous gland tumors ( Fig. 34.5 ) | Gastrointestinal, genitourinary |
| Howel–Evans syndrome | AD, TOC (tylosis (o)esophageal cancer) | Palmoplantar hyperkeratosis over pressure points | Esophageal |
| Birt–Hogg–Dubé syndrome | AD, BHD | Fibrofolliculomas ( Fig. 34.6 ), trichodiscomas, achrocordons, pulmonary cysts, spontaneous pneumothorax | Renal |
| Hereditary leiomyomatosis renal cell cancer syndrome | AD, FH (fumarate hydratase) | Cutaneous and uterine leiomyomas | Renal (papillary renal cell) |
| Multiple mucosal neuromas syndrome (MEN 2b) | AD, RET | Lip and oral cavity neuromas ( Fig. 34.7 ), thick lips, marfanoid habitus, megacolon, pheochromocytoma | Thyroid (medullary) |
| Multiple endocrine neoplasia type 1 (Werner syndrome) | AD | Collagenomas, lipomas, angiofibromas, hypopigmented ‘confetti-like’ macules, CALMs, benign neoplasms of the pituitary, parathyroid, and pancreas | Pancreatic |
| Multiple endocrine neoplasia type 2a (Sipple syndrome) | AD | Notalgia paresthetica, macular/lichen amyloidosis, benign parathyroid tumors or hyperplasia, pheochromocytoma | Thyroid (medullary) |
| Bloom syndrome | AR, RecQL3 helicase | Photosensitivity ( Fig. 34.8 ), telangiectasia, CALMs, cheilitis, immunodeficiency | Leukemia, lymphoma, gastrointestinal |
| Ataxia-telangiectasia | AR, ATM | Skin and bulbar telangiectasia ( Fig. 34.9 ), ataxia, elevated prenatal alpha-fetoprotein, immunodeficiency, sinopulmonary infections | Lymphoma, breast (heterozygote carriers) |
| Wiskott–Aldrich syndrome | X-linked AR, WAS | Eczematous dermatitis, petechiae, recurrent infections, bloody diarrhea, immunodeficiency | Lymphoma |
| Chédiak–Higashi syndrome | AR, LYST | Silvery light hair, light grayish skin, immunodeficiency, recurrent infections | Lymphoma, lymphoma-like phase |
| Griscelli syndrome | AR, myosin5a, Rab27a | Pigmentary loss, immunodeficiency, recurrent infections | Lymphoma-like phase |
| Werner syndrome | AR, RecQL2 helicase | Sclerodermoid, hyperkeratosis and ulcerations over bony prominences, accelerated aging | Fibrosarcoma, osteosarcoma |
| Rothmund–Thomson syndrome | AR, RecQL4 helicase | Photosensitivity, poikiloderma, acral keratoses, skeletal abnormalities | Osteosarcoma, fibrosacoma |
| Nevoid basal cell syndrome | AR, PTCH1 | Multiple basal cell carcinomas, palmoplantar pits, odontogenic cysts, calcified falx cerebri | Fibrosarcoma, medulloblastoma |
| Neurofibromatosis type I | AD | CALMs, axillary freckling, neurofibromas, Lisch nodules | Rhabdomyosarcoma, neurofibrosarcoma, Wilms' tumor, juvenile myelomonocytic leukemia (in children with concomitant juvenile xanthogranulomas) |
AD, autosomal dominant; AR, autosomal recessive; CALMs, café-au-lait macules.
* Those listed represent only the most common associated malignancies.
Skin changes resulting from hormone-secreting tumors
Ectopic humoral syndromes are best understood in context of the APUD cell system (i.e. cells with a capacity of a mino p recursor u ptake and d ecarboxylation). These cells, which may have a common origin from the neural crest, can secrete a variety of biologically active amines and polypeptide hormones. Neoplastic proliferation of these cells may result in characteristic symptom complexes associated with specific cutaneous changes.
Ectopic ACTH-producing tumors
Ectopic ACTH-producing tumors account for 10–15% of cases of Cushing syndrome, presenting with many typical signs of the syndrome, including hypertension, hypokalemia, and myasthenia gravis-like profound proximal muscle weakness. However, intense hyperpigmentation ( Fig. 34.10 ), occurring in only 6–10% of patients with Cushing's disease, is especially common in the setting of ectopic ACTH production and should alert the clinician to the possibility of a hormone-secreting tumor. Although the cause of hyperpigmentation
is unclear, it may be related to tumor production of the peptide β-lipotropin, which contains within its sequence of 91 amino acids, the 22 amino acid sequence of β-melanocyte stimulating hormone (MSH). Serum ACTH levels are usually very elevated. Bronchopulmonary tumors, particularly oat cell carcinoma, are most often associated with ectopic ACTH production, although other malignancies have been reported.
Carcinoid syndrome
The carcinoid syndrome is another example of a humoral syndrome associated with a non-endocrine tumor. Elevated serotonin levels are characteristic, but multiple vasoactive molecules contribute to the syndrome's numerous systemic symptoms. The most striking cutaneous manifestations are episodes of flushing, initially lasting 10 to 30 minutes and involving only the upper half of the body; as the flush resolves, gyrate and serpiginous patterns may be noted. With successive attacks, more extensive areas may be affected and the redness takes on a cyanotic quality, eventually leading to a more permanent facial cyanotic flush with associated telangiectasia, resembling rosacea ( Fig. 34.11 ). Persistent edema and erythema of the face may result in leonine facies. A pellagra-like picture that has been noted in some patients may be due to abnormal tryptophan metabolism. Systemic symptoms associated with cutaneous flushing include abdominal pain with explosive watery diarrhea, shortness of breath, palpitations, and hypertension.
Carcinoid tumors are usually found in the appendix or small intestine; extraintestinal carcinoids may arise in the bile ducts, pancreas, stomach, ovaries, testis, or bronchi. The carcinoid syndrome occurs primarily with intestinal carcinoids metastatic to the liver or with extraintestinal tumors; flushing attacks can be provoked by palpation of hepatic or abdominal metastases or by alcohol ingestion, enemas, emotional stress, or sudden changes in body temperature. When the syndrome is associated with bronchial adenomas of the carcinoid variety, the flushing is more prolonged and often associated with fever, marked anxiety, disorientation, sweating, salivation and lacrimation. Elevated 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, is a useful marker for diagnosis. The somatostatin analog, octreotide, may be used for symptomatic control.
Glucagonoma syndrome
The glucagonoma syndrome is associated with an APUDoma involving the glucagon-secreting alpha cell of the pancreas. The characteristic cutaneous eruption, necrolytic migratory erythema, usually occurs on the abdomen, perineum, thighs, buttocks ( Fig. 34.12 ), and groin, and may be mistaken for intertrigo. Patches of intense erythema with irregular outlines expand and coalesce, resulting in circinate or polycyclic configurations. Superficial vesicles on the surface rupture quickly to form crusts, but new vesicles may continue to develop along the active margins. An eczema craquelé-like appearance may be noted. Angular cheilitis and glossitis are additional features. Patients may be hyperglycemic and ill-appearing. The syndrome shares features with acrodermatitis enteropathica; deficiency of zinc, amino acids, and essential fatty acid levels occurs in some cases. Nutritional supplementation can improve cutaneous involvement; however, complete tumor resection is necessary for cure. The overall prognosis is poor as approximately 50% of cases are metastatic at the time of diagnosis.
The three clinical patterns of familial multiple endocrine neoplasia discussed above are also examples of polyglandular endocrine disorders involving the APUD cell system.
Proliferative and inflammatory dermatoses associated with internal maligancy ( Table 34.2 )
Many of the conditions discussed in this section are non-specific and have been reported both in association with and in the absence of underlying malignant disease. Malignancy is most often only one of a number of possible provoking factors.
Table 34.2
Proliferative and Inflammatory Dermatoses Associated with Internal Malignancy
| Dermatoses | Findings | Associated Malignancy * |
|---|---|---|
| Hypertrichosis lanuginosa acquisita | Extensive lanugo hair | Women – colorectal, lung, breast Men – lung, colorectal |
| Acanthosis nigricans | Flexural velvety hyperpigmentation, oral cavity papillomatous change, +/- tripe palms | Intra-abdominal adenocarcinoma, gastric most commonly |
| Tripe palms | Diffuse palmar ridging | Lung gastric adenocarcinoma if in setting of acanthosis nigricans |
| Sign of Leser–Trélat | Sudden-onset multiple seborrheic keratoses | Gastrointestinal |
| Bazex syndrome (acrokeratosis paraneoplastica) | Violaceous psoriasiform plaques on fingers, toes, nose, helices Nail dystrophy |
Aerodigestive tract |
| Primary systemic amyloidosis | Protein AL deposition in multiple organs, facial perioroficial waxy papules, ‘pinch purpura’, macroglossia | Multiple myeloma |
| Scleromyxedema | IgG lambda paraprotein Waxy lichenoid papules on face, neck, upper trunk, upper extremities Multiorgan system involvement |
Multiple myeloma |
| Sweet syndrome (acute febrile neutrophilic dermatoses) | Violaceous pseudovesicular plaques on face, neck, upper extremities Fever Neutrophilia |
Hematologic, particularly acute myelogenous leukemia |
| Pyoderma gangrenosum | Deep ulcerations with undermined dusky border, pseudovesicular plaques | Hematologic, particularly acute myelogenous leukemia |
| Paraneoplastic pemphigus | Polymorphous cutaneous eruption that may be lichenoid, bullous, or erosive Mucosal involvement Bronchiolitis obliterans |
Non-Hodgkin lymphoma, chronic lymphocytic leukemia |
| Anti-epiligrin cicatricial pemphigoid | Painful mucosal erosions, eyes and oral cavityScarring, blindness | Solid tumors |
| Dermatomyositis | Heliotrope rash, Gottron's papules, photosensitivity, periungual erythema, cuticular overgrowth, poikiloderma Proximal muscle weakness |
Women – ovarian, breast. Men… lung, prostate |
| Extramammary Paget disease | Erythematous scaly plaque, erosions, involving groin, axillae, perianal areas | Gastrointestinal, urogenital, apocrine carcinoma |
| Multicentric reticulohistiocytosis | Flesh-colored to brownish nodules involving hands and face Destructive polyarthritis |
Cervical, gastric, breast, bronchial, hematologic |
| Necrobiotic xanthogranuloma | Yellow-orange noduloplaques, periorbital, trunk, extremities IgG kappa paraprotein Multisystem disorder |
Myeloma, leukemia, lymphoma |
| Erythema gyratum repens | Figurate erythema with scaly ‘wood-grain’ appearance | Bronchial carcinoma > breast, uterine, prostate, gastrointestinal, myeloma |
| Exaggerated insect bite reaction | Papulonodular or vesiculobullous Exposed sites |
Chronic lymphocytic leukemia |
* Those listed represent only the most common associated malignancies.
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