Bartosz Chmielowski, Dennis A. Casciato, and Richard F. Wagner Jr
I. METASTASES TO THE SKIN
A. Incidence and pathology. Skin is not an uncommon metastatic site of solid tumors. Of patients with metastatic disease, 2% to 10% develop skin metastases. In men, the most common internal malignancies leading to cutaneous metastases are lung cancer (24%), colon cancer (19%), melanoma (13%), squamous cell carcinoma of the oral cavity (12%), and renal cell carcinoma (6%). In women, these are breast cancer (69%), colon cancer (9%), melanoma (5%), lung cancer (4%), and ovarian cancer (4%). Cutaneous involvement by cancer can occur both as a metastatic process and as a direct extension of the tumor to the skin.
B. Natural history. Metastases to the skin may be delayed 10 to 15 years after the initial surgical treatment of primary melanoma, breast carcinoma, and renal cancer or may be the first indication of an internal malignancy.
1. Breast cancer represents almost 75% of female patients with cutaneous metastases. It shows eight distinct clinicopathologic types of cutaneous involvement:
a. Inflammatory (erysipelas-resembling erythematous patch or plaque with active border, usually affecting the breast; but other skin sites can also be involved)
b. En cuirasse (a diffuse morphea-like induration)
c. Telangiectatic (papules with violaceous hue caused by accumulation of blood in vascular channels)
d. Nodular (usually multiple firm papulonodules, sometimes ulcerated)
e. Alopecia neoplastica (painless, well-demarcated, pinkish oval plaques of alopecia caused by hematogenous spread of breast carcinoma), which can occur with other neoplasms as well
f. Paget disease (a sharply demarcated, scaling plaque on the nipple or areola representing cutaneous infiltration of cancer)
g. Breast carcinoma of the inframammary crease (a cutaneous nodule that may resemble basal cell carcinoma)
h. Histiocytoid nodule of the eyelid (presents as a painless eyelid swelling with induration)
2. Lung cancer. Cutaneous metastases from lung cancer may appear on any surface, but they are most common on the chest wall and the posterior abdomen; small cell lung cancer metastasizes most frequently to the skin of the back. Between 1.5% and 16% of patients with lung cancer develop skin metastases; in half of these patients, it is a presenting sign of the disease. Lung cancer also has a rare but peculiar tendency to metastasize to the anal area, fingertips, or toes.
3. Gastrointestinal (GI) tract cancers. Skin metastases from colon cancer and rectal cancer usually develop after malignancy has been recognized. Abdominal wall and the perineal area are the most common sites. They may appear as sessile or pedunculated nodules, vascular nodules, scalp cysts, inflammatory carcinoma, or persistent fistulation after appendectomy. Cutaneous metastasis of gastric cancer is rare, and most cutaneous metastases are typically solitary, nodular, have a firm consistency, and are red or hyperpigmented but may present as dermatitis. Anal cancer metastases to skin involve unusual sites, such as the scalp, eyelid, nose, or legs.
4. Melanoma. Both cutaneous and extracutaneous melanoma can produce skin metastasis. They usually present as multiple pigmented nodules, but they can also be erythematous or apigmented.
5. Urologic malignancies. Of all urologic malignancies, renal cell carcinoma metastasizes to the skin most frequently, but skin metastases from bladder, prostate, and testicular cancer have also been reported. These metastases are frequently the first sign of renal cell carcinoma, and they can appear very late, up to 10 years after diagnosis. Both clinically and histologically, they may resemble common dermatologic disorders, which lead occasionally to incorrect diagnosis.
6. Subungual metastases. Malignant lesions in the nail unit can be classified into three groups: metastatic lesions from a distant primary, cutaneous involvement of a hematopoietic or lymphoproliferative malignancy, and primary cancer at this location. Lung cancer is the most common type of malignancy that can metastasize to the nail bed, followed by genitourinary, breast, head and neck cancers, and sarcomas. Subungual metastases typically present as erythematous enlargement, swelling of the distal digit, or a violaceous nodule. They are frequently painful, but they can also bleed or be hot, pulsa-tile, and fluctuant. These lesions can be mistaken for infection or trauma; in almost half of affected persons, they are a presenting sign of malignancy.
7. Umbilical metastasis (Sister Mary Joseph nodule) is encountered in 1% to 3% of patients with abdominopelvic malignancy. The term Sister Mary Joseph nodule was assigned to the Mayo brothers’ surgical nurse who recognized that umbilical metastasis denoted incurable disease when the patient underwent laparotomy. The most common origins are GI (52%), gynecologic (28%), stomach (23%), and ovarian (16%) cancer. Survival in these patients, which depends on the type of tumor and treatment modalities, can range from 2 to 18 months.
C. Prognosis. Skin metastases usually indicate advanced disease and carry a poor prognosis. The average survival time from the recognition of skin metastases is 3 months, but it can be years for lymphomas, melanoma, and breast cancer.
D. Diagnosis is based on biopsy results, especially in patients who have not previously been diagnosed with malignancy.
E. Management. Most skin metastases are treated symptomatically, and they tend to regress when the primary tumor responds to systemic therapy. Occasionally, these lesions require treatment with local radiation therapy, surgery, cryotherapy, or photodynamic therapy. Intralesional injections of thiotepa (30 mg), bleomycin, or cisplatin, or electrochemotherapy (in which the effect of intralesional chemotherapy is enhanced by electroporation) have also been utilized.
II. CUTANEOUS PARANEOPLASTIC SYNDROMES
Cutaneous paraneoplastic syndromes comprise a heterogeneous group of dermatologic syndromes describing skin lesions that do not contain malignant cells, but they appear in the presence of underlying malignancy.
A. Acanthosis nigricans is characterized by hyperpigmented, velvety plaques on the neck, in the axilla, groin, and antecubital fossa. In most cases, it reflects metabolic disturbances seen in patients with obesity, metabolic syndrome, or diabetes. If the lesions appear abruptly and progress rapidly, or they are associated with tripe palms or mucous membrane involvement, they can reflect underlying malignancy, mainly adenocarcinoma of the GI tract (in >50% of cases, gastric cancer). Benign causes of acanthosis nigricans include
1. Acromegaly, gigantism
2. Adrenal insufficiency
3. Hyperthyroidism, hypothyroidism
4. Lipodystrophy
5. Diabetes mellitus
6. Syndrome with hirsutism, obesity, and amenorrhea
7. Inherited abnormality in humans (and Swedish dachshunds)
B. Amyloidosis secondary to nonmalignant disease rarely involves skin. Patients with multiple myeloma or, less commonly, Waldenström macroglobulinemia may develop “pinch purpura” (ecchymoses or purpuric patches occurring spontaneously or with minor trauma). The lesions are primarily in flexural areas, paranasal skin, anogenital regions, the neck, and around the eyes.
C. Bazex syndrome (acrokeratosis paraneoplastica) consists of psoriasiform lesions in the acral areas (ears, nose, nails, hands, feet, elbows, knees). In 18% of cases, lesions can be pruritic. This syndrome is universally associated with malignancy, mainly carcinoma of the upper aerodigestive tract, but also prostate carcinoma, hepatocellular carcinoma, lymphoma, and bladder carcinoma. In nearly two-thirds of cases, cutaneous lesions precede the diagnosis of malignancy.
D. Dermatomyositis and polymyositis belong to a group of idiopathic inflammatory myopathies. Between 15% and 25% of cases of dermatomyositis and about 10% of polymyositis are associated with malignancy. Almost any type of malignancy has been reported in patients with dermatomyositis, but ovarian carcinoma and lung and breast cancer are the most common. Dermatomyositis may precede development of the neoplasm for up to 5 years. Treatment of the malignancy results in symptom improvement, and worsening of symptoms may herald tumor recurrence.
These myopathies are typified by proximal muscle weakness with or without tenderness. Patients typically report that they are not able to brush their hair. Flat-topped erythematous papules over the phalangeal joints (Gottron papules) and pinkish-purple discoloration around the eyes (a heliotrope rash) are pathognomic signs of dermatomyositis. Other signs include periungual telangiectasias; patchy discoloration of the skin; red, scaly scalp rash; and photosensitivity. Laboratory work commonly reveals elevated creatinine kinase level, although the cases with normal level of creatinine kinase have been reported, and possibly they are more frequently associated with malignancy.
E. Ectopic Cushing syndrome is caused by the secretion of an adrenocorticotrophic hormone (ACTH) prohormone or ACTH, most commonly by small cell lung carcinoma and bronchial carcinoids, and occasionally by thymoma, islet cell tumor, non–small cell lung carcinoma, and pheochromocytoma. It presents as proximal muscle wasting, hypertension, hypokalemia, usually weight loss (not weight gain), and, because an ACTH prohormone contains pro-opiomelanocortin, frequently with hyperpigmentation.
F. Erythema gyratum repens is characterized by an extensive eruption of erythematous, scaly, rapidly progressing, ring-forming, wood-grain–resembling lesions over most of the body, sparing the hands, feet, and face. It is frequently accompanied by severe pruritus. It is almost always a representation of underlying malignancy, and it precedes the detection of malignancy by 1 to 24 months. Lung cancer is most commonly reported, followed by esophageal and breast cancer. The treatment consists of surgical removal of the primary tumor, but some improvement can sometimes be observed after therapy with systemic steroids, radiotherapy, and azathioprine.
G. Exfoliative erythroderma syndrome is a generalized erythema of the skin accompanied by a variable degree of scaling. It is frequently accompanied by severe pruritus and generalized lymphadenopathy. Malignancy accounts for 5% to 12% of cases, and it is most frequently associated with cutaneous T-cell lymphoma, rarely with solid tumors or acute myelogenous leukemia.
H. Hypertrichosis lanuginosa acquisita (“malignant down”) refers to the development of fine, unpigmented hair predominantly localized to the head and neck. It has been associated with lung and colon cancer, but it can also occur in conjunction with shock, thyrotoxicosis, porphyria, and cyclosporine, minoxidil, phenytoin, and penicillin ingestion. Treatment should be directed toward the removal of malignancy.
I. Ichthyosis. Acquired ichthyosis is manifested by symmetric scaling ranging in severity from minor roughness and dryness to dramatic desquamation of white-to-brown scales. The diameter of the scales can range from <1 mm to >1 cm. It primarily affects the trunk and limbs. The lesions are usually more accentuated on extensor surfaces. It should be differentiated from the late-onset ichthyosis vulgaris, xerosis, and Refsum disease. Hodgkin lymphoma is the most common malignancy associated with acquired ichthyosis, but it can also occur in patients with a cutaneous T-cell lymphoma or carcinomas of the breast, lung, or bladder. It may be also a result of nonmalignant disease (e.g., autoimmune syndromes, endocrinologic disorders, nutritional abnormalities, infectious diseases, and finally a drug reaction).
J. Multicentric reticulohistiocytosis is characterized by pink, brown, gray papules appearing initially on the hands and then spreading to the face. The lesions can be also present on the knees, elbows, ankles, shoulders, feet, or hips, and they may have pathognomic coral-bead appearance. Approximately 20% to 25% of multicentric reticulohistiocytosis cases are associated with malignancy, including hematologic, breast, ovarian, gastric, and cervical neoplasms.
K. Necrolytic migratory erythema (NME) is an uncommon inflammatory dermatosis usually associated with glucagonoma and rarely with nonneoplastic conditions, such as liver disease, inflammatory bowel disease, pancreatitis, and malabsorption disorders. The postulated mechanism for NME involves a combination of zinc, amino acid, and fatty acid deficiencies. The clinical features of NME include transient eruptions of irregular erythematous lesions in which a central bulla develops, subsequently erodes, and heals with hyperpigmentation. The lesions follow a periorificial distribution, or they are located in the areas subject to greater pressure and friction (i.e., the perineum, buttocks, groin, lower abdomen, and lower extremities).
L. Necrotizing leukocytoclastic vasculitis is a rare representation of malignancy. It appears as a palpable purpura, typically in dependent areas. This vasculitis is more common with hematologic malignancies than with solid tumors. Occasionally, it can also be a complication of antineoplastic therapy.
M. Pachydermoperiostosis exhibits thickening of skin and creation of new skin folds (leonine facies). The scalp, forehead, lids, ears, and lips are the typical sites. The tongue, thenar and hypothenar eminences, elbows, and knees may be enlarged. The fingers are clubbed. Biopsy shows thickening of the horny layer and hypertrophy of the sweat and sebaceous glands.
The familial form of pachydermoperiostosis is not usually associated with malignant tumors. The acquired variety occurs almost exclusively in patients with undifferentiated lung cancer. Clubbing and hypertrophic osteoarthropathy are also associated with a variety of nonmalignant disorders.
N. Paget disease. Extramammary Paget disease is a nonhealing neoplasm occurring in the apocrine gland–bearing areas, mainly axilla and the perineum. It can be associated with either contiguous or a distant cancer. Surgical excision is the primary treatment for the skin lesions. It can also respond to topical 5-fluorouracil or imiquimod.
O. Palmoplantar hyperkeratosis is characterized by yellowish, symmetric thickening of palms and soles. It occurs in hereditary and nonhereditary forms. Acquired form can be associated with Hodgkin lymphoma, leukemia, breast cancer, and gastric cancer. Familial forms are strongly associated with squamous cell carcinoma of the esophagus, breast, and ovarian carcinoma. In familial forms, the development of malignancy is delayed >30 years after the appearance of hyperkeratosis. Arsenic exposure can predispose to punctuate palmar hyperkeratosis and higher cancer risk.
P. Papillomatosis. Florid cutaneous papillomatosis describes the sudden appearance of multiple acuminate keratotic papules that morphologically resemble viral warts. They initially develop on hands and wrists, and later spread on the entire body and the face. This syndrome always reflects underlying malignancy, most commonly gastric adenocarcinoma.
Q. Pemphigus. Paraneoplastic pemphigus is a rare autoimmune bullous mucocutaneous disorder that presents typically with painful mucosal erosive lesions and pruritic papulosquamous eruptions that often progress to blisters. Immunofluorescence testing reveals IgG autoantibodies and C3 deposited intercellularly in the epidermis and in a linear fashion along the dermal–epidermal junction. The most common underlying neoplasms include non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman disease.
R. Pityriasis rotunda manifests as round, scaly hyperpigmented lesions on the trunk, buttocks, and thighs. It is very rarely diagnosed in whites. In 6% of cases, it develops in patients with malignancies, mainly hepatocellular carcinoma and gastric carcinoma.
S. Pruritus. Refractory pruritus, in patients without liver disease, can be associated with iron deficiency, thyroid disorders, renal insufficiency, and also with malignancy, most commonly lymphoma, myeloproliferative disorders, multiple myeloma, leukemia, and carcinoids.
T. Pyoderma gangrenosum is an idiopathic neutrophilic dermatosis. It presents classically as tender, fluctuant pustules or nodules, which expand peripherally to form ulcers with sharp, raised edges. Of cases, 50% to 70% are associated with underlying systemic disease, including ulcerative colitis, Crohn disease, diverticulitis, hematologic and rheumatologic conditions, hepatopathies, visceral carcinomata, and immunodeficiency states. The associated hematologic disorders include acute lymphoid and myeloid leukemia, myeloproliferative diseases, myeloma, Waldenström macroglobulinemia, and Hodgkin and non-Hodgkin lymphomas. It has been also reported in patients with colon, bladder, prostate, breast, bronchus, ovary, and adrenocortical carcinoma.
U. Sweet syndrome (acute febrile neutrophilic dermatosis) presents as an acute eruption of tender, erythematous plaques or nodules with irregular surfaces. The lesions can occur anywhere on the body but are most common on the face and the trunk. Histologic examination reveals dense neutrophilic infiltration. The rash is usually accompanied by fever, peripheral blood neutrophilia, arthritis, and conjunctivitis. Approximately 10% of patients have underlying malignancy, and acute myelogenous leukemia has been reported most frequently. Therapy with prednisone appears to be most effective.
V. The sign of Leser-Trélat is ominous of internal malignancy, and it is described as the sudden eruption of multiple pruritic seborrheic keratoses. These lesions have, frequently, an inflammatory base. The sign of Leser-Trélat has to be differentiated from the presence of multiple benign seborrheic keratoses. The predominant types of malignancy are GI adenocarcinomas, lymphoproliferative disorders, and cancers of the lung or breast.
W. Urticaria pigmentosa is a presenting feature in 55% to 100% of patients with systemic mastocytosis. The primary lesion is a hyperpigmented macule or papule that transforms into a wheal when irritated mechanically (Darier sign). In some cases, lesions can be pigmentless, telangiectatic, and nodular.
X. Vitiligo is the hypopigmentation of skin caused by the loss of melanocytes, and it frequently occurs in individuals with malignant melanoma. It is thought that vitiligo is the consequence of the immune-mediated response against antigens shared by normal melanocytes and melanoma cells. The appearance of vitiligo in patients with melanoma is associated with better prognosis.
Y. Miscellaneous cutaneous paraneoplastic disorders
1. Alopecia mucinosa can develop during the course of lymphoreticular neoplasms as a consequence of mucinous degeneration of collagen around hair follicles and sebaceous glands. The resultant alopecia is unrelated to therapy.
2. Circinate erythemas. Erythema figuratum perstans is a circular elevation of the skin that remains stable for weeks to months. Erythema annulare centrifugum initially is a small erythematous area that slowly enlarges, leaving a central circle of normal-appearing skin. Lesions may be pruritic.
Circinate erythemas are associated most commonly with nonmalignant diseases (especially collagen vascular syndromes, angiitides, and infections). Many cases are idiopathic. Less commonly, they are associated tumors that include lymphoma and, occasionally, visceral cancer.
3. Erythromelalgia presents as painful, warm extremities (particularly the digits) that appear erythematous. Myeloproliferative diseases are the most common associated malignancies. Aspirin provides relief.
4. Pigmentation of the skin
a. Gray discoloration of the skin because melanosis may develop in patients with extensive malignant melanoma
b. Periorbital purplish discoloration can develop in patients who have amyloid deposition in the eyelids from infiltration and purpura. The syndrome of postproctoscopic palpebral purpura is well described in these patients.
5. Porphyria cutanea tarda (PCT) is a blistering disease that appears in skin exposed to sunlight. Hepatocellular carcinoma and metastatic liver tumors are occasionally associated with paraneoplastic PCT.
6. Tripe palms resemble bovine foregut and appear as thickened palmar skin with exaggerated dermatoglyphics. More than 90% of patients with tripe palms have associated malignancy, most frequently of the lung, stomach, and genitourinary tract.
III. INHERITED MALIGNANCY-ASSOCIATED SYNDROMES
Several genetic syndromes involving the skin predispose to internal malignancy without having a paraneoplastic association.
A. Ataxia telangiectasia is an autosomal-recessive disorder caused by mutations in the ATM gene, which has a crucial role in the cellular response to DNA damage. The syndrome is characterized by progressive neurodegeneration, ocular and cutaneous telangiectasias, immunodeficiency, and premature aging. These individuals are at high risk for development of hematologic malignancies, including Hodgkin and non-Hodgkin lymphoma, and leukemia.
B. Basal cell nevus syndrome (Gorlin syndrome) (see Chapter 16).
C. Cowden disease (multiple hamartoma–neoplasia syndrome) is an autosomal-dominant genodermatosis with incomplete penetrance characterized by multiple trichilemmomas (adnexal tumors), mucocutaneous papules, and high risk for malignancy. It is caused by an inactivation of PTEN (phosphatase and tensin homolog deleted on chromosome 10), a dual-phosphatase tumor suppressor gene. Patients with loss of wild-type PTEN expression from one allele carry an increased risk of malignant breast, thyroid, endometrial, and brain tumors.
D. Cronkhite-Canada syndrome is a rare, acquired, nonfamilial GI polyposis syndrome associated with protein-losing gastroenteropathy, alopecia, nail dystrophy, and hyperpigmentation. Patients are at high risk for the development of gastric, colon, and rectal carcinomas.
E. Gardner syndrome is a variant of familial adenomatous polyposis (FAP) with extracolonic symptoms; it is caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). It is an autosomal-dominant disease characterized by the presence of colonic polyposis, osteomas, and mesenchymal tumors of the skin and soft tissues. In most patients, cutaneous and bone abnormalities develop approximately 10 years before polyposis. The most common skin manifestations of Gardner syndrome are epidermoid or sebaceous cysts (66%), which are found on the face, scalp, and extremities. Other skin manifestations are fibromas, neurofibromas, lipomas, leiomyomas, and pigmented skin lesions. The patients are at high risk for development of colon cancer and desmoid tumors.
F. Howel-Evans syndrome is a rare familial syndrome that links focal nonepidermolytic palmoplantar keratoderma (tylosis) with the early onset of esophageal squamous cell carcinoma. The locus has been located on chromosome 17q25 (TOC gene).
G. Muir-Torre syndrome is a rare genodermatosis associated with mutations in mismatch repair proteins, hMSH-2 and hMLH-1. It is most often diagnosed by the synchronous or metachronous occurrence of at least one sebaceous gland neoplasm and at least one internal malignancy. The syndrome is characterized by an autosomal-dominant inheritance pattern with variable penetrance and expression. The visceral malignancies include colorectal carcinoma or carcinoma of the urogenital system.
H. Peutz-Jeghers syndrome is an autosomal dominant disorder caused by germline mutations or epigenetic silencing of the serine/threonine kinase LKB1 (also known as STK11). It is characterized by skin and mucosal hyperpigmentation (perioral blue-black freckling) and development of multiple intestinal polyps that can transform into GI adenocarcinoma.
I. Von Recklinghausen disease (neurofibromatosis type 1) is inherited as an autosomal-dominant condition caused by mutations in the tumor suppressor gene NF1. About one-half of affected individuals inherit the gene from an affected parent with the remainder of cases caused by spontaneous mutation. Hyperpigmented, oval-shaped macules with smooth borders (café au lait spots) are seen in the early childhood. Other skin lesions include freckling in non–sunexposed areas, iris hamartomas, and cutaneous neurofibromas. Individuals with von Recklinghausen disease have an increased risk of malignancy compared with the general population. A 10% lifetime risk exists of malignant peripheral nerve sheath tumors. Other malignancies (pheochromocytoma, urogenital rhabdomyosarcoma, astrocytoma, brainstem glioma, and juvenile chronic myelogenous leukemia) are seen less frequently.
J. Werner syndrome is an autosomal recessive disorder caused by mutations in the WRN gene, which is involved in abnormal telomere maintenance. It is characterized by premature aging and by early onset of age-related pathologies (alopecia, ischemic heart disease, osteoporosis, cataracts diabetes mellitus, hypogonadism) and cancer (especially sarcomas).
K. Wiskott-Aldrich syndrome is an X-linked immunodeficiency disease caused by mutations in the WAS gene, which has a key role in actin polymerization. Its clinical phenotype includes thrombocytopenia with small platelets, typical in appearance and distribution eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies. The most frequent malignancy reported is B-cell lymphoma, often positive for Epstein-Barr virus.
IV. ADVERSE CUTANEOUS EFFECTS OF RADIATION THERAPY (RT)
Despite continuous improvement in methods of delivery of RT, >90% of patients experience a different degree of skin reactions. The severity of skin reactions is influenced by both treatment-related and patient-related factors. Treatment-related factors include a larger treatment volume per field, a larger total dose, a large fraction size, longer duration of treatment, and type of energy used. Patient risk factors include radiation to skin areas of increased moisture and friction (axilla, breast, perineum), poor skin hygiene, concurrent chemotherapy, older age, comorbid conditions, compromised nutritional status, smoking, and chronic sun exposure.
A. Early effects are usually defined as side effects occurring within 90 days from the initiation of therapy. Erythema, dryness, epilation, and pigmentation changes occur between the second and the fourth week. Dry desquamation can develop between weeks 3 and 6 of treatment. It can also be followed by moist desquamation, which usually occurs after week 5. Finally, skin damage may progress to dermal necrosis and secondary ulceration.
B. Late effects are associated with injury to the dermis. The list includes dermal atrophy, telangiectasias, and invasive fibrosis. There may be permanent loss of nails and skin appendages, alopecia, and decreased or absent sweating. Patients treated with RT are at higher risk for development of secondary cutaneous malignancy, especially squamous cell carcinoma.
C. Prophylaxis of skin damage. To decrease the risk of skin damage, patients should wash the skin gently with lukewarm water and mild soap to keep the irradiated area clean and to decrease the risk of superimposed bacterial infection. Moreover, they should avoid rubbing the skin, should not use skin irritants or metallic-based topical agents (zinc oxide–based creams, aluminum-containing deodorants), should wear loose cotton clothing, and avoid extreme temperatures.
D. Management of skin reactions. Patients with erythema and dry desquamation benefit from use of nonscented, lanolin-free hydrophilic or moisturizing creams. These creams should not be applied to skin breakdowns. Petroleum jelly–based products containing skin irritants such as alcohol, perfume, other additives, and alpha hydroxyl acids should be avoided, but Vaseline or white petrolatum is generally well tolerated. Patients should also avoid swimming in chlorinated pools, hot tubs, and lakes and exposure to extremes of hot and cold. Low-dose steroids (1% hydrocortisone, mometasone furoate) decrease the degree of inflammation and pruritus. Other products (e.g., aloe vera gels, biafine, hyaluronic acid) are of no proven benefit.
No standard recommendations on treatment of moist desquamation exist, but the general principle that wounds heal more rapidly in moist environment is usually applied. The affected area should be cleaned with room temperature normal saline; moisture retentive protective barrier ointment can be applied. Hydrocolloid dressings and hydrogels in a form of sheets or amorphous gel are frequently utilized, but no compelling evidence suggests they are better than gentian violet (often not accepted esthetically) or dry dressings.
Atrophic skin has a high predisposition for ulcers and skin breakdowns; it is mainly treated with use of ointments and avoidance of trauma. The goal of treatment of chronic ulcers is to control the amount of secretions and prevent superimposed bacterial infections. These patients may require surgical intervention. Chronic fibrosis is the most difficult complication to treat, but some responses were seen with use of pentoxifylline and liposomal superoxide dismutase.
V. ADVERSE CUTANEOUS EFFECTS OF CHEMOTHERAPY
A. Alopecia induced by chemotherapy usually begins 1 to 2 weeks after the initial treatment, and it becomes most prominent in 1 to 2 months. In most cases, it is reversible and hair frequently regrows with a change of color and structure. The use of cranial prostheses (wigs) and scarves should be encouraged.
B. Hypersensitivity reactions have been documented with almost all chemotherapeutic agents. The types of reaction can range from urticaria, pruritus, angioedema, through erythema multiforme, up to toxic epidermal necrolysis. Cutaneous vasculitis, contact dermatitis, and exanthematous drug rashes are also not uncommon.
Asparaginase can cause reactions ranging from urticaria to anaphylactic shock in 25% of patients, and an intradermal skin testing with two units of the drug before the initial administration is generally recommended.
Taxanes (paclitaxel, docetaxel, and cabazitaxel) are routinely administered together with steroids, H1 and H2 blockers. In the case of paclitaxel, the reaction may be owing to polyoxyethylated castor oil that is used to solubilize the drug.
Chimeric and humanized monoclonal antibodies, such as rituximab, cetuximab, alemtuzumab, and trastuzumab, are given together with diphenhydramine and acetaminophen to reduce the incidence of infusion-related reactions. Panitumumab and ipilimumab, fully human antibodies, have been reported to cause hypersensitivity reactions in <1% of patients, but infusion reactions are very common (up to 45%) in patients treated with another fully human antibody, ofatumumab.
C. Hyperpigmentation can occur locally in the infusion site, or diffusely throughout the skin; it can also affect nails and mucous membranes. Busulfan is known to cause “busulfan tan,” a dusky diffuse hyperpigmentation that may resemble Addison disease. Bleomycin is a cause of flagellate hyperpigmentation, linear, band-like streaks of discoloration in areas of trauma predominantly on the trunk and the proximal extremities. Repetitive administration of fluorouracil results in serpentine supravenous hyperpigmentation of the skin overlying veins. Methotrexate given weekly can cause the “flag sign,” the hyperpigmented bands alternating with the normal color of the patient’s hair. Other drugs that can result in hyperpigmentation include cisplatin, cyclophosphamide, dactinomycin, daunorubicin, doxorubicin, etoposide, hydroxyurea, ifosfamide, nitrosoureas, paclitaxel, plicamycin, procarbazine, thiotepa, and vinca alkaloids.
D. Hand–foot syndrome (acral erythema, palmar–plantar erythrodysesthesia) presents initially with tingling and burning of the palms and soles that progress to severe pain, tenderness, edema, and development of well-demarcated, symmetric erythematous plaques. The lesions can spread to the dorsum of the hands and feet. Areas of pallor progress into formation of vesicles and bullae that desquamate. This syndrome is traditionally associated with use of high-dose cytarabine, fluorouracil, and liposomal doxorubicin. Currently, newer agents, such as capecitabine, which causes hand–foot syndrome of various degree in >50% of patients, and multikinase inhibitors, such as sorafenib and sunitinib, are the main causes.
Hand–foot syndrome is generally treated by cessation of the chemotherapeutic agent or a decrease in the dose. Patients are recommended to wear cotton socks or gel inserts and to avoid pressure points, to soak the affected skin in lukewarm water mixed with Epsom salts, to use urea-containing creams to remove callus buildup (prophylactic callus removal may decrease the risk of the development of hand–foot syndrome), and to apply moisturizing creams to prevent skin hardening. Application of cold during infusion of chemotherapy may prevent acral erythema. In patients treated with liposomal doxorubicin (Doxil), oral dexamethasone and topical 99% dimethyl sulfoxide (DMSO) applied four times daily for 14 days attenuated the symptoms of hand–foot syndrome.
E. Extravasation of chemotherapeutic agents describes the process of leakage or direct infiltration of a chemotherapeutic drug into tissue. The agents are divided into three groups, based on their potential to cause local tissue injury: vesicant drugs (they induce the formation of blisters and ulcers and cause tissue destruction); irritant drugs (they cause pain at the extravasation site or along the vein, with or without inflammatory response; if a large amount is extravasated they can cause ulcers, too); and nonvesicant drugs (they rarely produce reactions). The group of vesicant agents includes drugs with a high vesicant potential (actinomycin D, amsacrine, daunorubicin, doxorubicin, epirubicin, idarubicin, mechlorethamine, mitomycin C, vinblastine, vincristine, vindesine, vinorelbine) and with a low vesicant potential (cisplatin, dacarbazine, docetaxel, etoposide, fluorouracil, liposomal doxorubicin, mitoxantrone, oxaliplatin, paclitaxel). Irritant drugs include bleomycin, carboplatin, cyclophosphamide, carmustine, gemcitabine, ifosfamide, irinotecan, melphalan, pentostatin, plicamycin, streptozocin, and topotecan.
1. Prevention. All vesicant chemotherapeutics should be administered through the central line whenever possible. Central lines significantly reduce, but do not eliminate, the chance of drug extravasation. If peripheral lines have to be used, they should be used only for short infusions under direct monitoring of nursing staff. The dorsum of the hand and the areas near joints should be avoided because extravasation can cause significant functional damage. When an IV line is placed, the vein should be accessed using a single approach and the entry site should not be covered by tape. Line patency is checked by gently withdrawing blood and administering IV fluids before a cytotoxic agent is started. Patients are asked to report any discomfort promptly.
2. Clinical presentation. Extravasation usually causes immediate pain, which is followed by erythema and edema within a few hours and increasing induration over a period of several days. Skin ulceration and necrosis can occur within the next 1 to 3 weeks. Necrosis can involve underlying tendon, fascia, and periosteum. Occasionally, extravasation is painless, and it may be detected late, resulting in worsening of tissue damage.
3. Management. As soon as extravasation is noted, the drug infusion must be stopped and the affected extremity elevated. The IV catheter should not be removed immediately; it should be used for aspiration of the fluid from the site and administration of a possible antidote. If no antidote is available, the catheter can be removed.
Never flush the line and avoid applying pressure to the area. Intermittent cooling for 24 to 48 hours with ice or cold packs is recommended in all cases of extravasation, except the vinca alkaloids and epipodophyllotoxins (etoposide). Warm compresses are used for drugs from these two groups. Most clinicians also use cold compresses for paclitaxel and docetaxel extravasation, but some recommend treatment with heat.
Patients who develop nonhealing ulcers and tissue necrosis are treated surgically. A limited number of specific antidotes are available.
a. Sodium thiosulfate is used as antidote for mechlorethamine, cisplatin, and dacarbazine: 4 mL of 10% sodium thiosulfate solution is mixed with 6 mL sterile water, and 2 mL for each milligram of mechlorethamine or 100 mg of cisplatin is injected through the existing IV line, followed by SC injection of 1 mL around the area of extravasation.
b. Hyaluronidase (150 to 900 U through the IV line and around the site) is used for treatment of extravasation of vinca alkaloids, paclitaxel, ifosfamide, and epipodophyllotoxins.
c. Dimethyl sulfoxide (DMSO): 1 to 2 mL of 50% DMSO is applied topically and allowed to air-dry in patients with extravasation of anthracyclines, or mitomycin C.
d. Dexrazoxane has been reported as a part of successful treatment of anthracycline extravasation.
e. Corticosteroids. Despite the common use of corticosteroids, they are most probably ineffective. Hydrocortisone is recommended for the treatment of doxorubicin-induced venous flare reactions, which are more common than extravasation, and it may be helpful in cases of oxaliplatin extravasation.
F. Acneiform rash. Both small molecules (erlotinib) and monoclonal antibodies (cetuximab, panitumumab) that target epidermal growth factor receptor (EGFR) are associated with the development of a unique acneiform rash in up to 90% of patients. Typical lesions consist of pruritic maculopapular eruptions that may evolve into pustules. The rash has predilection to the seborrheic areas (upper trunk, face, scalp, neck).
As acneiform rash prophylaxis, minocycline (100 mg daily) or doxycycline (100 mg twice daily) can be used. These should be combined with 1% hydrocortisone, application of emollients, and the use of the broad-spectrum sunscreen creams. In patients who develop the rash, avoidance of sun exposure and use of moisturizing or colloidal oatmeal lotions are recommended. Topical clindamycin or erythromycin might be helpful, and corticosteroid use is usually discouraged. Similar rash can also be seen with imatinib and the new mTOR inhibitors, such as temsirolimus and everolimus.
G. Squamoproliferative lesions. The development of keratoacanthomas and cutaneous squamous cell carcinomas has been described in about 5% of patients treated with sorafenib. The frequency of these lesions increased significantly upon introduction of the second generation of BRAF inhibitors, such as vemurafenib and GSK2118436. Patients treated with these agents should be under a regular dermatologic surveillance.
H. Oral Complications include mucositis, dysgeusia, and infection. Infection may be caused by oral bacteria that may become pathogenic following immunosuppression, yeast (candidiasis), or viruses (herpes simplex virus, varicellazoster virus, cytomegalovirus, or Epstein-Barr virus, which is associated with oral hairy leukoplakia [OHL]).
Mouthwash containing chlorhexidine reduces bacterial counts. Palifermin (recombinant human keratinocyte growth factor) may be used for the treatment of mucositis. Vitamin D (cholecalciferol, 2000 IU) daily may be beneficial for stomatitis and dysgeusia. OHL may respond to topical over-the-counter gentian violet.
I. Radiation reactions
1. Photosensitivity can be observed in patients receiving dacarbazine, dactinomycin, fluorouracil, hydroxyurea, methotrexate, mitomycin, procarbazine, and vinblastine.
2. Enhancement of skin toxicity caused by RT has been associated with bleomycin, dactinomycin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, and paclitaxel.
3. Radiation recall (i.e., inflammatory reaction of a previously radiated area after exposure to a chemotherapeutic agent) has been described with bleomycin, capecitabine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, hydroxyurea, lomustine, methotrexate, melphalan, paclitaxel, tamoxifen, and vinblastine.
4. Reactivation of UV light–induced erythema has been associated with methotrexate, gemcitabine, and taxanes.
J. Nail dystrophies. Nails are commonly affected by chemotherapy. Bleomycin, cyclophosphamide, and doxorubicin can be responsible for development of Beau lines, transverse ridgings that move distally and disappear in the treat ment-free intervals. Mees lines, multiple white lines whose number correlates with the number of cycles of chemotherapy, are associated with daunorubicin. Onycholysis can result from therapy with docetaxel, doxorubicin, fluorouracil, and mitoxantrone.
K. Neutrophilic eccrine hidradenitis has a distinct histopathology consisting of neutrophilic infiltrates in eccrine glands with areas of necrosis. It appears as an erythematous eruption of hemorrhagic nodules, pustules, and plaques typically confined to the head, neck, trunk, or extremities. The rash usually presents 2 to 3 weeks after chemotherapy, and it was most frequently described with use of cytarabine, but also bleomycin, chlorambucil, daunorubicin, doxorubicin, and mitoxantrone. The eruption clears spontaneously without scar formation.
L. Eccrine squamous syringometaplasia is a rare chemotherapy-related skin eruption characterized by squamous metaplasia of the eccrine ducts, which presents as wellcircumscribed erythematous macules or papules that can coalesce. It is usually located in the intertriginous areas.
Suggested Reading
Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol 2006;54:28.
Sabir S, James WD, Schuchter LM. Cutaneous manifestations of cancer. Curr Opin Oncol 1999;11:139.
Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol 1995;33:161.
Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 1999;40:367.