Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section A – Symptom Management and Palliative Care

Chapter 41 – Alopecia and Cutaneous Complications

Leslie Robinson-Bostom,John Kawaoka,
Reena Rupani,
Charles J. McDonald

SUMMARY OF KEY POINTS

  

 

The human skin that serves as the interface between the living organism and the external environment is in fact the largest and most complex human organ. Its complexity is directly related to the myriad of specialized cells, tissue types, and structures that allow the skin to carry out many vital functions including maintenance of body temperature and protection against the ingress of infectious organisms and noxious chemicals, as well as the egress of vital tissue fluids. It is highly probable that the complex anatomy and physiology of the skin make it a major target of chemotherapy-induced toxicity.

Incidence

  

 

Cutaneous reactions are among the most common adverse drug reactions to occur in patients undergoing medical treatment for cancer. The incidence and severity of such reactions vary depending on the class of agent or agents, the route and frequency of administration, the dosage of drug or drugs given, and the specific tissue type involved. Some agents may cause toxicity only after the patient has been exposed to one more additional physical agent, such as ultraviolet light or x-ray emissions.

Etiology of Complication

  

 

Causes of adverse cutaneous reactions to cancer chemotherapeutic drugs are quite varied but tend to be characteristic and often unique to a particular agent or category of agents. Some reactions, such as those seen as a result of infiltration of drug during infusions, are caused by direct toxicity of the drug on any and all involved tissues. These reactions are often associated with regimens using the alkylating agents, the vinca alkaloids, and the antibiotics. Other reactions occur as a result of the specific tissue-targeted effect of an agent, such as alopecia associated with a variety of mitotic inhibitors, or the “pustular-like” eruption so commonly associated in epidermal growth factor receptor (EGFR)–targeted therapy. Cutaneous “hypersensitivity reactions” are also fairly common.

Evaluation of the Patient

  

 

Because the number and types of cutaneous reactions to cancer chemotherapy are large and quite variable, each having its own unique set of cutaneous and histopathologic findings, there are no well-established guidelines that may be commonly adhered to in patient evaluation. Patient skin signs and overall symptoms are one's best guides to evaluation and treatment. Histopathologic examination of skin specimens is often helpful as well.

Grading of the Complication

  

 

Unlike grading of complications in other organ systems, grading of cutaneous complications associated with cancer chemotherapeutic drugs has until recent years been poor, inconsistent, and often not addressed even in conjoint studies of a single agent. Interest in a more precise dermatologic examination and better grading of the severity of cutaneous eruptions has been stimulated by several recent reports that show a correlation between the extent and severity of the cutaneous eruption caused by a group of EGFR antagonists, and disease response and patient survival. It should be noted that at this point in time there is not universal acceptance of this concept ( Table 41-1 ).


Table 41-1   -- National Cancer Institute and Eastern Cooperative Oncology Group Grading System for Dermatologic Toxicities

Toxicity Grade

National Cancer Institute

Eastern Cooperative Oncology Group

1

Maculopapular rash or erythema and no associated symptoms

Maculopapular rash or erythema and no associated symptoms

2

Maculopapular eruption or erythema, associated pruritus, or other symptoms; <50% of body surface area coverage or localized desquamation or other lesions covering <50% of the body surface area

Scattered maculopapular eruption or erythema with pruritus or other associated symptoms

3

Symptomatic generalized erythroderma or macular, papular, or vesicular eruption or desquamation covering >50% of the body surface area

Generalized symptomatic macular, papular, or vesicular eruption

4

Generalized exfoliative dermatitis, ulcerative dermatitis

Exfoliative dermatitis or ulcerating dermatitis

 

 

Treatment

  

 

Treatment approaches to the large variety of cutaneous responses to cancer chemotherapeutic drugs are as varied as there are reactions and teams of investigators addressing these reactions. To reduce patient morbidity and assure early initiation of the most appropriate treatment plan, it is most appropriate and beneficial to the patient to obtain dermatologic and surgical consultation, if needed, at the earliest stage of the reaction.

INTRODUCTION

As with other pharmacologic agents used in the treatment of human disease, the administration of most cytotoxic or cancer chemotherapeutic agents can result in toxic side effects. Moreover, as with other pharmacologic agents, toxicity is often manifested in the skin. Some toxic side effects occur at ordinary therapeutic drug dosages, whereas others occur as an extension of a therapeutic drug effect at higher dose levels. Toxic drug reactions in the skin may occur as idiosyncratic or allergic drug reactions.

Cancer chemotherapeutic drugs produce many common skin conditions, such as pruritus, urticaria, and angioedema. They also cause cutaneous reactions that are not shared by any other agent or class of agents—for example, the sclerotic effect that bleomycin can have on the skin.

A description of all the cutaneous reactions to cancer chemotherapeutic agents is beyond the scope of this book. Instead, we have elected to highlight a group of reactions that are fairly common and yet unique to cancer chemotherapy. Some reactions are associated with fairly severe sequelae and might direct the ultimate course of chemotherapy; others might appear severe upon occurrence but can be treated symptomatically, with no effect on the outcome of the treatment regimen. For completeness, Table 41-2 lists the various categories of cancer treatment agents and the dermatologic conditions they may cause.


Table 41-2   -- Chemotherapeutic Agents and Common Cutaneous Side Effects

Alkylating agents

Alopecia

 

Neutrophilic eccrine hidradenitis

 

Pigmentation reactions—depigmentation and hyperpigmentation

 

Angioedema

 

Extravasation necrosis

 

Dysethesia and erythrodysesthesia (acral erythema)

 

Radiation recall

 

Reactivation erythema

Antimetabolites

Hyperpigmentation

 

Dysethesia and erythrodysesthesia (acral erythema)

 

Radiation recall

 

Alopecia

 

Extravasation necrosis

 

Cutaneous flare

Plant alkaloids

Alopecia

 

Dysethesia and erythrodysesthesia (acral erythema)

 

Radiation recall

 

Cutaneous “flare” (must be differentiated from extravasation necrosis; excellent prognosis)

 

Hair and nail dystrophy

Antitumor antibiotics

Xerosis/scaling

 

Radiation recall dermatitis

 

Rash/urticaria

 

Reversible total alopecia

 

Hyperpigmentation of nail beds

 

Onycholysis

 

Acral erythema

 

Flagellate erythema (bleomycin)

 

Cutaneous ulceration

 

Pseudo-dermatomyositis (hydroxyurea)

Topoisomerase inhibitors

Reversible alopecia

 

Dermatitis

 

Facial edema

 

Acral edema

 

Paronychial inflammations

 

Perianal dermatitis

 

Anal fissures

Biologics

Acneiform rash

 

Vasculitis-like eruption

 

Paronychial inflammation

 

Exfoliation/desquamation

 

Xerosis

 

Capillary leak syndrome

 

Pruritus

 

Urticaria/angioedema

 

Alopecia

 

Skin fissures

 

Sweet's syndrome

 

 

NONSPECIFIC REACTIONS

Alopecia

Of the myriad of drug-related cutaneous toxicities encountered by the cancer patient, alopecia is the most common.[1] Hair loss is an unfortunate side effect, because hair appearance often dictates a patient's self- and body image. Patients, especially females, receiving cancer chemotherapy often find alopecia psychologically and emotionally devastating. In fact, the occasional patient who is unable to cope with alopecia and the associated psychic trauma often opts to forgo potentially curative treatments.

Etiology

Systemic administration of a variety of cancer chemotherapeutic drugs can produce alopecia. Drug-induced inhibition of hair follicle stem cells within the hair matrix causes a reduction in the number and size of epithelial cells contained within the hair shaft. This results in a partially constricted and weakened hair shaft that is susceptible to breakage from trauma as minor as simple combing. Complete cessation of hair formation can also occur. Antineoplastic agents vary in their effects on hair matrix epithelium, hence their ability to induce alopecia. The degree of hair loss secondary to cancer chemotherapy is related to dosage, regimen, and route of administration. Drugs with a strong propensity to induce alopecia include doxorubicin, daunorubicin, cyclophosphamide, and etoposide. [2] [3] [4] [5]

Some novel dosage formulations of standard chemotherapeutic agents may ameliorate the extent of alopecia; for example, liposomes coupled with doxorubicin and mitoxantrone have been shown to significantly decrease the extent of drug-induced alopecia. [6] [7]

Clinical Manifestations

Chemically damaged and mechanically manipulated hair is more susceptible to the effects of chemotherapy.[8] Anagen effluvium (loss of hair during the proliferative or growth phase of its cycle) may begin 1 to 2 weeks after a single dose of chemotherapy but will be most noticeable after 1 to 2 months of continuous drug administration. It can also occur as late as 2 to 3 weeks after cessation of chemotherapy.[8] Alopecia associated with anagen effluvium is most pronounced and widespread on the scalp, because this site normally contains 60% to 85% of its hairs in the proliferating anagen phase. Repeated drug doses given over the course of 1 to 2 months ultimately synchronize with each follicle's matrix cells in anagen phase; total inhibition of cell replication follows, and alopecia results. The eyebrows, eyelashes, beard, groin, and axillary hairs have fewer hair follicles in the anagen phase at any one time; consequently, repeated doses over many more months are required to achieve significant alopecia in these areas. The onset of telogen effluvium (loss of hair during the resting phase of its cycle) occurs approximately 3 to 6 months after the start of chemotherapy.

Pathology

The normal scalp hair growth cycle consists of an anagen (growth) phase, a catagen (involution) phase, and a telogen (resting) phase. About 60% to 85% of scalp hairs are always in the anagen phase, 1% are in the catagen phase, and the remainder are in the telogen phase. Body hairs are not synchronized in such phases. During the anagen phase, germinative cells within the matrix of scalp hair have a cell replication time approximating 24 hours. Thus, scalp hair, by virtue of its content of highly proliferative matrix cells, is particularly susceptible to growth inhibition by chemotherapeutic drugs that inhibit cellular proliferation. Inhibition (anagen effluvium) ranges from partial to total. Patients with fewer anagen hairs are less sensitive to anagen effluvium induced by chemotherapy. Less commonly, certain drugs, such as recombinant interferon-α2b (IFN-α2b), can induce the anagen hair into the dormant telogen phase, which is followed by a period of total hair epilation.[9] Telogen effluvium can also occur in response to the emotional stress of chemotherapy or to an anemia associated with chemotherapy, principally iron deficiency anemia.

Differential Diagnosis

Most often, patients receiving cancer chemotherapy experience anagen effluvium; only a few experience telogen effluvium. Anagen effluvium alopecia usually persists throughout the period during which drug is given. Normally, hair returns shortly after drug administration ceases. There is always a temporal relationship to drug administration. Telogen effluvium results principally from psychic or bodily stress, high fever, nonmatrix toxic medication, or poor nutrition. Telogen effluvium is first noticeable about 3 to 6 months after insult and is temporary. Hair growth generally resumes, even as chemotherapy is continued.

Treatment and Outcome

It is important for the clinician to fully appreciate the negative emotional devastation that chemotherapy patients, particularly female, experience with rapid loss of hair. Strategies to ameliorate this experience include preparing patients mentally for such an event and constant reassurance that this effect is only temporary. Patients should receive early information on scalp hair care and on the availability and acceptable of wigs and other scalp covering.[10] In cooperation with the American Cancer Society, the Cosmetic Toiletries and Fragrances Association and groups of local beauticians have developed a highly successful image-building program called “Look Good, Feel Good.” This program is available free of charge to cancer patients with alopecia and other cosmetic defects.

Prognosis

Chemotherapy-associated alopecia is usually temporary. Regrowth can be apparent 3 to 10 months after withdrawal of the offending medication and may occur during prolonged cycles of therapy. Permanent alopecia has been reported infrequently with high-dose busulfan, bone marrow transplantation, and high-dose chemotherapy using cyclophosphamide, thiotepa, and carboplatin. [11] [12] Most patients experience some changes in the character of their regrown hair. These changes, which include alterations in color, texture, and type of hair shaft, are often transient.[13]

Prevention

Several different maneuvers have been used in an attempt to protect patients from chemotherapy-induced alopecia. These include physical modalities that may temporarily decrease scalp blood flow and drug contact time with the hair follicle—that is, use of scalp-cooling devices, such as the MSC cold cap system (Medical Specialties of California, London, UK), cooling fluid ring turbans, and cold air hoods that deliver cooling temperatures below 22°C. Each works to decrease the metabolic rate of matrix stem cells and blood flow to the follicle matrix.[14] Results using hypothermic devices has been encouraging.[15] Efficacy is increased during use of a chemotherapeutic agent that has a short half-life (e.g., adriamycin) and is given in low dose. Also, patients treated with rapidly administered combinations seem to benefit from scalp hypothermia.[13] Tumor metastases to the scalp have been reported after use of this technique. Other side effects include headaches, dizziness, nausea, vomiting, aversion to ice, cold feeling, and heavy feeling on the head.[16] It has been suggested that hypothermia is contraindicated in patients with leukemia, lymphoma, or highly metastatic neoplasms and for patients who have a tendency to develop migraine headaches. Folic acid can prevent alopecia when given with methotrexate.[8]

Imuvert has been shown to protect against alopecia induced by ara-C (cytarabine) and doxorubicin but not by cyclophosphamide. This protective effect is presumed to be mediated by interleukin-1 (IL-1). AS101, a new immune modulator, has also been stated to prevent chemotherapy-induced alopecia.[8]

Electrotrichogenesis, or the use of specific pulsed electrostatic fields, has shown promising results in preventing chemotherapy-induced hair loss. A pilot study of 13 patients undergoing treatment with cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) showed good hair retention without attributable side effects.[17] M50054, 2,2.-methylenebis (1,3-cyclohexanedione), a novel inhibitor of apoptosis, might be an effective agent in the future for preventing or reducing chemotherapy-induced alopecia.[18]

Cellulitis, Phlebitis, Extravasation Necrosis, and Various Flare Reactions

It has been estimated that local skin toxicity, other than alopecia, accounts for 2% to 5% of all adverse reactions from antineoplastic drugs. The extravasation of vesicant cancer chemotherapeutic agents remains one of the single most distressing causes of this complication. Local tissue injury occurs as intravenously administered agents irritate the lining of access veins during drug administration (phlebitis), or when a cytotoxic drug escapes the confines of the cutaneous vasculature and spreads throughout the surrounding tissues. A local inflammatory reaction (chemical cellulitis), or local tissue necrosis (extravasation necrosis) then occurs. Cellulitis and necrosis can involve skin alone or can extend to subcutaneous tissue, muscle, fascia, and tendons. Extravasation frequently occurs during use of subcutaneous indwelling vascular access devices.

Etiology

Clarification of the mechanism of local tissue injury after insult by chemotherapeutic agents awaits further investigation. It has been postulated that agents that produce highly alkaline, or acidic, hypertonic solutions are probable causes. Drugs that bind to DNA are considered the most frequent causes. Necrotic tissue reactions can continue for weeks and months after withdrawal of the inciting agent. There is support for the concept of tissue binding as a probable cause of local necrotic reactions. Other possible contributors include local chemical irritant reactions and maturation arrest induced in proliferating cells.

The list of agents causing severe local tissue toxicity include the vinca alkaloids, vincristine and vinblastine; the alkylating agents, mechlorethamine and mitomycin C; the anthracyclines, doxorubicin and daunorubicin; and the antibiotic dactinomycin. [19] [20] [21] [22] [23] Other drugs less likely to cause severe local toxicity include 5-FU, etoposide, bleomycin, cisplatin, mitoxantrone, paclitaxel, streptozocin, oxaliplatin, docetaxel, and doxil. [24] [25] [26] [27] [28] [29] [30] [31]

Delayed skin ulcers have been reported to appear within a prior mitomycin C infusion site after a second treatment is given into a site on the opposite extremity.

Doxorubicin local tissue reactivity includes, in addition to necrosis and radiation “recall effect,” a “venous flare” reaction. [32] [33] The “venous flare” that occurs is characterized by a linear eruption in the skin overlying access veins of the infusion site. Erythema, edema, induration, pruritus, and tenderness overlie the area ( Fig. 41-1 ). Superficial blisters and vesicles can appear. This reaction subsides without residual tissue damage within 48 hours after discontinuation of the infusion. It has been estimated that venous flares occur in up to 3% of all adriamycin infusions.

 
 

Figure 41-1  Venous flare reaction overlying access vein of the forearm.

 

 

Clinical Manifestations

During infusions that lead to necrosis, patients complain of acute burning pain and swelling. Within 7 days after the infusion, patients complain of pain, edema, erythema, and induration at the site. Severely involved untreated sites develop clusters of vesicles and large blisters, followed by ulceration or the development of a large plaque with a necrotic center, or both ( Fig. 41-2 ). Underneath the plaque, or ulcer, extensive areas of necrosis may be found. A hard black eschar ultimately forms. Peripheral to the eschar, erythema and swelling persist for weeks. Simultaneously with involvement of subcuticular tissue, there is joint stiffness, limitation of motion, neuropathy, and causalgia in the affected parts.

 
 

Figure 41-2  Extravasation injury, late-stage lesion with a central eschar, beneath which lies an extensive area of subcutaneous necrosis.

 

 

Pathology

Bhawan and colleagues among others reported early and late histologic changes in the skin of patients with doxorubicin extravasation.[34] In an early lesion, before eschar formation, marked epidermal hyperplasia is observed. Individual necrotic keratinocytes are abundant. All other cell types show similar reactive responses. In a late lesion, beneath the area of ulcer formation, panepidermal, dermal, and subcutaneous tissue necrosis is seen. Lateral to the ulcer, there is marked epidermal hyperplasia. Fibroblasts and endothelial cells show signs of extreme reactivity. Lobular panniculitis best describes lesions of the subcutaneous fatty layers. Curiously, signs of acute inflammation are not usually described in old or new lesions.

Differential Diagnosis

Local tissue extravasation must be differentiated from the doxorubicin “venous flare” reaction. Radiation recall phenomenon can occur with infusions of doxorubicin, mitomycin C, and 5-FU.This reaction tends to occur at remote sites of previous radiation dermatitis.

Treatment

Conservative, nonsurgical measures are very effective for treating small (500 mm2 or less), and medium-size (2000 mm2 or less) areas of extravasation. Phlebitis and cellulitis often cause mild injury, heal with minimum residual effects, and require minimum treatment. Because less than one-third of all local extravasations proceed to blister and ulcer formation, there is considerable disagreement about the correct approach to management of local tissue toxicity. [35] [36] [37] Termination of the infusion is mandatory and is almost always followed by complete healing without residual defect in areas of phlebitis and cellulitis. Elevation and intermittent cooling of the affected part can accelerate healing.

In more severe reactions the general use of a number of frequently recommended local antidotes is frowned upon. At most extravasation sites, antidotal treatments have often made necrosis and ulceration worse. There is general agreement that the infusion should be terminated immediately if the patient complains of pain, burning, or stinging at the infusion site or if local swelling is observed. If the original infusion needle or catheter is patent, aspiration of extravasated fluid may be attempted. If the line is not patent it should be removed immediately.

Elevation of the involved extremity is recommended for at least 48 hours. Local heat applications are recommended if the vesicant is one of the vinca alkaloids.[37] Cooling of the extremity may be beneficial after other vesicant injury, except that caused by the alkylating agents mechlorethamine and mitomycin C. [38] [39]

Although routine use of surgery is not indicated, timing and the ultimate use of surgical intervention are of utmost importance. Surgical consultation should be sought immediately on suspecting extravasation injury. Persistent pain, erythema, and swelling, even in the absence of ulceration and eschar formation, require surgical consultation and are indications for surgical intervention even in the absence of ulceration and eschar formation. Severe blistering, ulceration, and persistent pain make surgical intervention mandatory. Inordinate delay of surgery permits active drug to infiltrate and cause injury to tissues far beyond the original site of extravasation. In such cases, delay might ultimately cause the need for more extensive surgery ranging far beyond skin and subcutaneous tissues.

Outcome

Morbidity associated with extravasation injury is high, but mortality is nonexistent. The degree of discomfort experienced by some patients is severe enough to cause voluntary termination of treatment. Others become litigious, losing confidence in their therapist. The injury accompanying extravasation has no effect on disease status; thus there is no reason to stop further treatments with a given agent. Unless extravasation occurs again, retreatment of the patient with the same agent is not associated with recurrence of necrosis.

Prevention

In every patient considered for treatment with a known vesicant, prevention of local tissue injury is paramount. Prevention begins with selection of the infusion site. Sites to be avoided at all costs are the dorsal surfaces of the hands and the antecubital fossae, as well as extremities that have been sites of extensive ablative surgery. The preferred site of infusion is the proximal forearm that has not been surgically compromised, and where a large amount of subcutaneous tissue overlies vital structures. If tissue-poor areas such as the dorsal surface of the hand are used, a subcutaneous flexible indwelling catheter is preferred over the standard intravenous needle. When multiple infusions are anticipated over a prolonged period, placement of subcutaneous reservoirs with long indwelling lines should be considered. Nevertheless, even indwelling devices are not foolproof; an extravasation incidence of 6.4% has been reported using these devices.[40]

Drugs should always be administered through a free-flowing intravenous line. Any hint of obstruction within the line calls for immediate termination of the infusion and an attempt at correcting the problem. Every attempt should be made to administer a solution that is as dilute as possible over the shortest period of time, preventing injury from concentrated drug and eliminating lengthy exposure of tissues to a toxic agent.

Palmar-Plantar Dysesthesia and Erythrodysesthesia Syndrome (Acral Erythema)

The true incidence of this reaction is unknown. Yet, on the basis of personal experience, the number of cases reported in the literature, and a reported incidence of 39% in a group of patients treated for acute myeloid leukemia using the CHA regimen (lomustine, doxorubicin, cytosine arabinoside), one would suspect that erythrodysesthesia is fairly common and is among the most frequently encountered cutaneous reactions to cancer chemotherapeutic agents. [41] [42] [43]

Etiology

Early reports described this reaction in patients with hematologic malignancies. Subsequent reports described the reaction in patients receiving continuous infusions of 5-FU in solid tumors. Hence, 5-FU became widely recognized as the offending agent in nearly all cases of palmar-plantar erythrodysesthesia. A considerable variety of chemotherapeutic agents and treatment regimens have since been associated—for example, capecitabine, cytosine arabinoside, doxorubicin, methotrexate, 6-mercaptopurine, hydroxyurea, etoposide, 5-fluoro-2-deoxyuridine, and various combinations of agents. There appear to be no age, sex, or racial predilections for susceptibility to this phenomenon. There is no known mechanism for the reaction pattern other than that it seems to be dependent on drug dose.

Clinical Manifestations

Weeks to months after beginning high-dose intravenous chemotherapy, dysesthesia and paresthesia, expressed as a tingling sensation in the hands and feet, herald the onset of the syndrome. Increasing discomfort (consisting of burning sensations, pain, and tenderness while holding objects and while walking) signals progression of disease. Pain with swelling and erythema develop within 2 to 4 days of onset. Reddening begins over thenar and hypothenar eminences and spreads to involve the entire palm and sole ( Fig. 41-3A and B ). Blanching and erythema also occur on the interarticular spaces, and erythema appears in the periungual areas. Swelling and severe pain occur even at rest. Eventually, many of the blanching areas become bullous. This typical pattern is commonly seen with cytarabine therapy. Desquamation followed by healing of the palms and soles occurs within several weeks ( Fig. 41-4 ). In a few patients, erythematous scaling dermatoses develop on other body areas, together with nail disturbances, including onycholysis. Recall-induced palmar-plantar erythrodysesthesia syndrome has been described with a variety of chemotherapy regimens.[44]

 
 

Figure 41-3  A and B, Palmar-plantar dysesthesia and erythrodysesthesia. Early manifestation with prominent erythema and edema.

 

 

 
 

Figure 41-4  Late manifestation of palmar-plantar dysesthesia showing palmar desquamation after clofarabine use.

 

 

Pathology

Pathologic findings in a small number of patients have been described as nonspecific, showing mild focal spongiosis of the lower epidermis, mild to moderate epidermal atypia, mononuclear cell infiltration of the superficial dermis, and mild vasculitis of small vessels. Mild focal vacuolar degeneration of the basal cell layer has also been described.[43] Immunofluorescent studies are negative.

Differential Diagnosis

ACRAL ERYTHEMA ASSOCIATED WITH ACUTE GRAFT-VERSUS-HOST DISEASE.

Dermatitis of the palms and soles may occur as the earliest and only sign of acute graft-versus-host disease (GVHD). Dermatoses of GVHD usually occur within a period varying from 4 to 47 days after allogeneic bone marrow transplantation, but the onset of palmar-plantar lesions may be delayed by as long as 100 days. Unlike the spotty erythema of erythrodysesthesia that begins on thenar and hypothenar areas, acute GVHD palmar-plantar erythema presents with reddening of the dorsal aspects of the fingers and within periungual skin. Diffuse erythema of the hands and feet soon follows. Pruritus and tenderness of the palms and soles characterize acute GVHD, as opposed to severe pain and swelling associated with the palmar-plantar dysesthesia syndrome. Other findings associated with acute GVHD and acral erythema include nausea, vomiting, intractable diarrhea, and a severe rise in serum bilirubin levels. Both diseases can occur concurrently.[45]

ACRAL ERYTHEMA OCCURRING IN SEVERE LIVER DISEASE.

Acral erythema with severe liver disease is a chronic abnormality and is not generally accompanied by pain, blistering, or desquamation of the skin. Liver abnormalities are profound, with elevated serum enzymes and serum bilirubin.

Treatment

Treatment has been quite variable. In some patients complete cessation of chemotherapy is mandatory, followed by simple but intensive topical care consisting of frequent wet dressings and topical applications of midrange-potency corticosteroids. Often this regimen is sufficient to clear the eruption. Pain, swelling, and blister formation clear within 1 week without residual effects. Many patients heal completely without therapeutic intervention.

In some patients a moderate reduction in chemotherapy dosage and intensive topical care allows continuation of infusion therapy. A return to the original chemotherapy dosage is usually associated with recurrence of skin disease.

In other patients cutaneous manifestations have been ignored, and treatment with the offending agent has been continued at presyndrome dose levels. Only symptomatic treatment measures were required. Successful treatment of a group of patients using daily oral dosages of pyridoxine during infusions has been noted. Its use has permitted continued treatment with high-dose infusions, without recurrence or worsening of the palmar-plantar dysesthesia syndrome, or adverse effects on disease response to chemotherapy.[46] The use of pyridoxine for prevention of dysesthesia is empiric. Topical 99% dimethyl sulfoxide has shown promising results for treatment of liposomal doxorubicin-induced palmar-plantar erthrodysesthesia.[47]

Outcome

Severe acral pain and blister formation can cause considerable morbidity and poor patient compliance. No matter how severe the process may appear, it has no effect on the patient's disease status. Most chemotherapists agree that acral dysesthesia is not life-threatening, yet it can cause sufficient discomfort to require withdrawal of drug or alteration in drug dosage.

Hyperpigmentation

A variety of patterns of hyperpigmentation have been described in association with cytotoxic agents. Cutaneous hyperpigmentation can be generalized or can occur in specific localized patterns. Mucous membranes, hair, teeth, and nails can be affected by changes in pigmentation produced by cancer chemotherapy. [48] [49] [50]

Etiology

Generalized hyperpigmentation has been described in association with busulfan, cyclophosphamide, bleomycin, 5-FU, mechlorethamine, hydroxyurea, daunorubicin, dactinomycin, doxorubicin, and procarbazine. Localized patterns of skin hyperpigmentation occur after administration of cyclophosphamide, thiotepa, bleomycin, doxorubicin, daunorubicin, 5-FU, vinca alkaloids, plicamycin, and paclitaxel. Mucosal pigmentation is seen after doxorubicin, 5-FU, cisplatin, and busulfan therapy. Nail pigmentation is produced by cyclophosphamide, bleomycin, doxorubicin, daunorubicin, 5-FU, and hydroxyurea. Alteration in hair pigmentation has been caused by methotrexate. Cyclophosphamide may also produce pigmentation of the teeth.

Increased pigmentation from cancer chemotherapy is due to increased deposition of melanin in the affected tissue; a similar mechanism is shown to occur when hyperpigmentation is produced by antimalarials, tetracyclines, or heavy metal therapy, and is not caused by an accumulation of drug or its byproducts. Melanin, a pigment product or polymer, is manufactured within the basal layer of the epidermis of skin, nails, and hair follicles by melanocytes. Melanocytes package the pigment into containers called melanosomes and distribute them to neighboring epithelial cells through tubular cytoplasmic extensions called dendritic processes. Alterations in baseline pigmentation can occur when there is an increase in melanin production, an increase in the size of melanosomes, or a change in the distribution of melanosomes within the epithelial cells of skin, nails, and hair. How chemotherapeutic agents act to produce increased pigmentation is unknown. They may act to increase pigmentation by a direct stimulatory or toxic effect on melanocytes and/or by slowing the turnover and transit rates of epithelial cells, thus allowing more time for the transfer of melanin to occur. Adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH) are central nervous system–produced polypeptides that stimulate overall pigmentation in humans. ACTH and MSH are known to produce generalized hyperpigmentation in Addison's disease after bilateral adrenalectomy and after parenteral administration. The role of these hormones in the normal regulation of human pigmentation is poorly understood. ACTH and MSH levels have been studied in patients with pigmentary abnormalities while receiving cytotoxic agents; no elevation of these hormones has been detected. [51] [52]

Clinical Manifestations: Alkylating Agents

BUSULFAN.

Busulfan can produce generalized brown hyperpigmentation that is accentuated on the face, trunk, and forearms. Hyperpigmentation may be accompanied by symptoms of fatigue, nausea, anorexia, and weight loss, resulting in a condition much like Addison's disease. In such patients, however, hyperpigmentation of mucous membranes and palmar creases is rarely observed, and there is no evidence of increased ACTH or MSH activity. Busulfan hyperpigmentation occurs in 5% to 15% of treated individuals. It resolves when the drug is discontinued.

CARMUSTINE.

Carmustine has produced erythema followed by postinflammatory hyperpigmentation when it is spilled on the skin inadvertently, but parenteral use is not associated with pigmentary changes.

CYCLOPHOSPHAMIDE.

Cyclophosphamide can cause generalized skin pigmentation (which could be photoaccentuated) in addition to localized pigmentation of the palms, soles, and nails. Nail pigmentation can be diffuse or can present as horizontal or longitudinal dark bands. On cessation of therapy, this pigmentation usually resolves as the nail grows. In one large series of patients treated with cyclophosphamide, the incidence of skin and nail pigmentation was less than 50%. There is a single report of a child in whom a persistent brown line developed on the teeth as a result of cyclophosphamide therapy.

MECHLORETHAMINE.

Used topically in the treatment of mycosis fungoides, mechlorethamine produces diffuse hyperpigmentation. This problem can occur with or without clinical evidence of allergic or irritant contact dermatitis.

THIOTEPA.

Given intravenously in high doses, thiotepa may cause discrete areas of hyperpigmentation corresponding to sites occluded by adhesive patches or tape. This effect might result from an enhanced local toxic effect of the drug, which is excreted in sweat.

Clinical Manifestations: Antibiotics

ACTINOMYCIN.

Persistent serpentine surpravenous hyperpigmentation has been associated with actinomycin and vincristine chemotherapy.

BLEOMYCIN.

Bleomycin causes several patterns of hyperpigmentation. These include a generalized darkening of the skin that includes the palmar creases and cuticles, and patchy pigmentation at pressure points that might be delayed in appearance over the elbows, shoulders, and buttocks. The most distinctive pattern seen in 30% or more of patients consists of linear or “flagellate” streaks on the trunk that appear to correspond to areas of pruritus and trauma ( Fig. 41-5 ). Attempts to reproduce these lesions experimentally have met with variable success. Flagellate hyperpigmentation has its onset after 3 weeks of therapy and persists up to 5 months. Horizontal brown nail banding has also been observed.

 
 

Figure 41-5  Bleomycin pigmentation. This is the most distinctive pattern of pigmentation following the administration of bleomycin. Erythematous, linear lesions often precede the appearance of increased pigmentation.

 

 

DACTINOMYCIN.

Intertriginous, trauma-induced, and diffuse hyperpigmentation have been associated with dactinomycin therapy.

DAUNORUBICIN.

Chemically related to doxorubicin, daunorubicin has also been reported to cause skin and nail pigmentation, but with less frequency. Transverse pigmented nail bands and polycyclic pigmentation of the scalp have been reported.

DOXORUBICIN.

Doxorubicin is associated with localized pigmentation of the nails, palms and soles, dorsa of the hands, face, and interphalangeal and palmar creases. Diffuse pigmentation also can occur. Intraoral pigmentation occurs on the buccal mucosa and tongue. Nail pigmentation can present as horizontal or longitudinal bands or in a diffuse manner. These changes are more common among black patients. MSH levels are not elevated in patients with doxorubicin-induced pigmentation.

Clinical Manifestations: Mitotic Inhibitors

ETOPOSIDE.

Hyperpigmentation occurs in occluded areas.

IFOSFAMIDE.

Hyperpigmentation on the hands, feet, and occluded areas has been reported.

MITHRAMYCIN.

Mithramycin has been associated with postinflammatory hyperpigmentation following intense flushing and facial edema.

PACLITAXEL.

Causes localized hyperpigmentation.

PROCARBAZINE.

Localized hyperpigmentation has been reported.

Clinical Manifestations: Antimetabolites

5-FLUOROURACIL.

5-FU causes uniform pigmentation in sun-exposed areas in 2% to 5% of patients. Localized hyperpigmentation can occur at previously irradiated sites. Many localized patterns of pigmentation in nonirradiated areas have also been described. Serpentine supravenous hyperpigmentation occurs over veins used for repeated 5-FU infusions even in the absence of phlebitis or thrombosis. Serpentine pigmented streaks and reticulate pigmentation on the back and buttocks have also been reported. Hyperpigmentation can present in stria distensae. Banded pigmentation over small joints of the hands, diffuse pigmentation of the palms, and macular pigmentation of the palms and soles have been described. Nail pigmentation can occur as transverse banding, and pigmentation of the oral mucosa can result after long-term therapy.

METHOTREXATE.

Methotrexate has been reported to cause horizontal dark banding of the hair after intermittent therapy, similar to the “flag sign” of kwashiorkor.

Clinical Manifestations: Miscellaneous Drugs

CISPLATIN.

Cisplatin has been reported to produce a gingival band of pigmentation similar to a “lead line.” Hyperpigmentation at sites of pressure is common and is seen in as many as 70% of patients.

HYDROXYUREA.

Hydroxyurea has caused generalized hyperpigmentation and scaling in patients receiving long-term maintenance therapy. Pigmentation is accompanied by partial alopecia, cutaneous and subcutaneous atrophy, and erythema of the face and hands. Multiple longitudinal pigmented nail bands have also been observed.

Pathology

Skin biopsy specimens have demonstrated a variety of alterations in both the amount of melanin present and its distribution within the epidermis. Melanin can also be seen in dermal macrophages. On occasion, melanocytes might be increased in number, are larger than normal, and might appear to have more dendritic processes.[53]

Differential Diagnosis

Diffuse generalized hyperpigmentation can be seen in Addison's disease or primary adrenal insufficiency, which could be caused by metastatic carcinomas or Hodgkin's lymphoma. Addison's disease is also characterized by constitutional symptoms of fatigue, anorexia, and malaise, which are noted commonly among patients receiving cancer chemotherapy. Pigmentation in Addison's disease usually involves the oral mucosa and is accentuated in skin folds and creases, on the areolae and genitalia, and in sun-exposed areas. ACTH levels are elevated, and there is an abnormal response to ACTH stimulation. These laboratory findings are not present in patients with hyperpigmentation due to cytotoxic drugs.

Patients with hemochromatosis, an iron storage disease, show diffuse bronze pigmentation. The acquired form can present in patients who have received multiple blood transfusions. Hepatomegaly is usually present. Hyperpigmentation is due primarily to melanin, but hemosiderin deposition can be present in the skin also. Serum iron levels are elevated, and saturation of transferrin is noted in patients with hemochromatosis. Generalized hyperpigmentation and melanuria can occur in patients with advanced metastatic melanoma.

Melasma is an acquired macular brown pigmentation of the face that becomes pronounced with sun exposure. It can be seen during pregnancy and in patients on oral contraceptive or phenytoin therapy. Multiple pigmented longitudinal nail bands can occur as a normal finding among dark-skinned individuals and can be seen in metastatic melanoma. These are caused by benign melanocytic hyperplasia, lentigos, or junctional nevi within the nail matrix. Diffuse brown nail pigmentation can be caused by drugs other than cytotoxic agents, such as antimalarials, phenothiazines, tetracyclines, psoralens, and gold salts.

Treatment and Outcome

Hyperpigmentation secondary to cytotoxic agents is primarily a cosmetic problem and does not affect the continuation of treatment. Some patients might suffer psychologic distress but should be reassured that cutaneous hyperpigmentation, though persisting for several months, usually resolves after cessation of treatment. Nail pigmentation also resolves as the nails grow after treatment is discontinued.

Prevention

Use of sunscreens and avoidance of excessive sun exposure might prevent accentuation of pigmentary changes.

Nail Disorders

In addition to pigmentary nail abnormalities, cytotoxic drugs may disturb normal nail growth to produce a variety of nail changes, including Beau's lines, transverse white bands, onycholysis, and brittle nails.

Etiology and Pathogenesis

Cytotoxic agents can cause a direct toxic effect on the mitotically active cells of the nail matrix, which, as noted in the discussion on alopecias, can lead to cessation of growth with incomplete formation of the nail plate and the formation of Beau's lines. Disruption of nail keratinocyte differentiation can produce an abnormal nail plate. Measurements of the distance between Beau's lines and transverse white bands have shown a temporal relationship between nail abnormalities and the sequence of drug administration.[54]

Signs and Symptoms

Beau's lines are transverse depressions of the nail plate produced by the temporary cessation of nail growth. Typically, all nails are affected, but Beau's lines are most readily visible on the thumbs. They are commonly observed after short, intense chemotherapy regimens.[54]

Multiple transverse white bands of all 10 fingernails can result from combination chemotherapy featuring a variety of agents that include cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin, methotrexate, procarbazine, carmustine, semustine, and cisplatin.[55]

Onycholysis, or separation of the nail plate from the nail bed, has been reported among patients receiving 5-FU and bleomycin.[56] Doxorubicin may cause onycholysis, subungual blistering, blistering of the soles, and subsequent callus formation.[57] Brittle nails have been reported secondary to the administration of 5-FU and hydroxyurea.

Differential Diagnosis

Beau's lines can be seen after many severe febrile illnesses, after myocardial infarction, and with Raynaud's syndrome, zinc deficiency, or chronic dermatitis of the nail folds. Transverse white bands can sometimes be seen after an acute illness or after ingestion of arsenic, thallium, or fluoride. Onycholysis is common in psoriasis and fungal infections of the nail and secondary to trauma.

RADIATION-ASSOCIATED REACTIONS

Two types of reactions have been associated with the use of chemotherapeutic drugs and ionizing radiation: radiation enhancement and radiation recall. The resulting reactions correlate with the specific drug given and with the sequence of administration.

Radiation Recall

Radiation recall is an acute inflammatory cutaneous or organ reaction that develops within a previously irradiated site and after administration of a chemotherapeutic agent.[58] Involved organs may include skin and mucous membranes, lung, esophagus, gastrointestinal tract, central nervous system, bladder, and heart.

Etiology

Multiple drugs have been reported to cause radiation recall. The most common drugs known to cause this reaction are the cytotoxic antibiotics (dactinomycin, doxorubicin, daunorubicin, and bleomycin), the taxanes (paclitaxel, docetaxel), and methotrexate.[59]

Clinical Manifestations

Radiation recall may develop without clinically apparent antecedent radiation damage to the skin. Clinical manifestations usually develop within days after chemotherapy is given; however, the time interval between radiotherapy and the resultant radiation recall reaction can vary from several days to years. Mild reactions appear as erythema and edema followed by dry desquamation, similar to first-degree burns ( Fig. 41-6 ). More severe reactions are associated with moist desquamation, painful blistering, weeping, and in the most severe cases, full skin necrosis and painful ulcerations. The severity of the cutaneous reaction seems to correlate with the time interval between radiation and chemotherapy, with the shortest time intervals resulting in more severe reactions.

 
 

Figure 41-6  Radiation recall. This patient had small-cell cancer of the lung treated with radiation. Cyclophosphamide treatment some months later elicited erythema and desquamation within the portal of radiation. This lesion is now in the healing phase.

 

 

Pathology

The pathogenesis of radiation recall is controversial. The severity of the radiation recall reaction is also related to the tissue at risk, type and dosage of drug, the radiation dose utilized, and the sequential relationship between the administration of radiation and the administration of the chemotherapeutic agent. [60] [61]

Differential Diagnosis

Radiation recall reaction could be difficult to differentiate from cytostatic drug recall of acute inflammation caused by ultraviolet light or other cutaneous irritants and infections. Areas that have experienced an acute or remote sunburn reaction or have been sites of previous irritation or infection can also become further inflamed during the administration of a chemotherapeutic agent. The resulting skin reaction does not differ from that noted as radiation recall.[62]

Treatment and Outcome

Mild cases of radiation recall, which are characterized by erythema, edema, and dry desquamation, are self-limiting. Cool compresses and lubricating creams or ointments provide symptomatic relief. In the more severe cases in which exudates and/or blisters predominate, wet to dry compresses should be used to promote drying. Upon cessation of exudates formation, moist wound healing strategies should be implemented. Infected sites should be cultured and treated.

Radiation-induced necrotic ulcers are slow to heal. They are poor candidates for grafting because neovascularization and fibroblastic repair is limited. Strategies that attempt to both limit the amount of exudates and provide for moist wound healing should be implemented. Topical corticosteroids have little effect in treatment of radiation recall injuries.[61]

Radiation Enhancement

Certain chemotherapeutic drugs, termed radiation sensitizers, potentiate or enhance the effect of ionizing radiation. The occurrence of radiation enhancement depends on drug delivery being concurrent with or following within 3 weeks of radiation therapy. Although radiation enhancement might be planned to increase tumor destruction, this technique often causes significant injury and morbidity in adjacent noncancerous tissues.

Etiology

Radiation sensitizers include gemcitabine, IFN-α2a, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, 5-FU, bleomycin, and hydroxyurea.

These drugs interfere with the repair processes that allow sublethally damaged cells to recover from radiation injury. The degree of reaction depends on the type of drug and dosage, the radiation dosage, and the time interval between the delivery of radiation and drug.

Clinical Manifestations

The clinical manifestations of radiation enhancement fall into one of three patterns:

  

1.   

A mild reaction consisting of erythema, edema, and dry desquamation

  

2.   

A moderate reaction with moist desquamation, vesiculation, blister formation, and erosion

  

3.   

Severe necrotic ulcerative reactions that could result in residual skin hypopigmentation.

The affected sites are not limited to the radiation port but also involve contiguous skin.

Differential Diagnosis

Acute radiation-induced dermatitis may show clinical findings similar to those of radiation enhancement. However, they differ in time of occurrence following irradiation. Radiation dermatitis tends to occur within 1 to 3 weeks after radiation. Recall reactions occur weeks to months after irradiation.

Treatment and Outcome

Prognosis and treatment are dependent on the severity of the reaction and are similar to those described in the section on radiation recall reactions.

Reactivation Dermatitis

Cytostatic drugs frequently reactivate acute inflammation and exacerbate pre-existing eczema and other cutaneous diseases [63] [64] (Figs. 41-7 and 41-8 [7] [8]). IFN-α often exacerbates psoriasis and psoriatic arthritis.[65]

 
 

Figure 41-7  Reactivation dermatitis. This elderly diabetic female had a previous history of a Candida infection of the groin several years before. Methotrexate administration on each of several occasions caused the development of a weeping erosive dermatitis.

 

 

 
 

Figure 41-8  Inflamed actinic keratoses secondary to the administration of systemic 5-FU.This patient had extensively photodamaged skin showing “activation” of previously unrecognized actinic keratoses. Red scaling papules and cutaneous ulcerations predominate.

 

 

It is paradoxical that immunosuppressive agents can enhance cutaneous hypersensitivity reactions. Methotrexate blocks the induction of allergic contact dermatitis during the period of its administration, yet it can reactivate a positive patch test to 10% benzalkonium chloride solution.[63] Cyclophosphamide-treated guinea pigs can experience an enhanced allergic contact dermatitis when challenged with dinitrochlorobenzene.[66]

Although both topical and systemic administration of 5-FU can result in a seborrheic dermatitis-like eruption, this reaction does not appear to be reactivation but instead a de novo cutaneous adverse effect.[67]

Neutrophilic Eccrine Hidradenitis

Neutrophilic eccrine hidradenitis is an acute dermatosis associated with the administration of multiple chemotherapeutic agents including bleomycin, chlorambucil, cytarabine, daunorubicin, doxorubicin, mitoxantrone, vincristine, and topotecan.[68] Once considered rare and confined to adults receiving cytarabine for acute myeloid leukemia, it has been suggested more recently that the entity is more common than previously admitted. Not only has it been observed in children undergoing systemic chemotherapy, but neutrophilic eccrine hidradenitis has been reported in association with bacterial infections, acquired immunodeficiency syndrome, and a variety of medications. [69] [70] It has been observed to occur in children and adults with several different malignancies and receiving a wide spectrum of systemic chemotherapeutic drugs. The clinical appearance is quite variable, yet the histopathologic picture remains characteristic.

Etiology

The primary histopathologic lesion in this disease is localized necrosis of the eccrine glands in the skin. Associated necrosis of apocrine glands has been reported. The mechanism whereby necrosis is induced is unclear.[71] The histologic picture, which is quite characteristic, tends to rule out hypersensitivity vasculitis as a cause. Necrosis caused by the accumulation of high concentrations of cytotoxic agents within the sweat glands cannot be excluded.

Clinical Manifestations

Affected patients present with a wide variety of cutaneous lesions. Tender erythematous to purpuric macules, papules, nodules, and plaques, some with dark central areas, will suddenly appear on any body area during active administration of a cytotoxic agent. Lesions might appear within 2 to 3 days of starting chemotherapy or may go unnoticed until weeks after chemotherapy has started. Some unusual presentations include periorbital edema with erythema and injection site reactions.[72] Usual manifestations include hyperpigmented plaques and painful edema of the ears. Spiking fevers often accompany the onset of cutaneous lesions.

In many patients, skin lesions begin to resolve within 7 to 21 days after onset despite continuous chemotherapy administration. Likewise, new lesions can appear days and weeks after resolution of an original outcropping or might recur with the reinstitution of a course of chemotherapy. New papules, plaques, and nodules also might develop within sites previously involved by initial lesions.

Pathology

Histopathologic changes within affected skin sites are quite characteristic for this disease. There is pronounced neutrophilic infiltration of the dermis about and focally within the eccrine glands, resulting in focal epithelial necrosis and basilar vacuolization of eccrine epithelial cells. The neutrophilic infiltrate is heaviest in those glands demonstrating vacuolar changes and less intense around those glands showing intense necrosis. Neutrophilic infiltration of the coiled duct and straight duct may or may not be observed. Some secretory coil epithelial cells show marked nuclear pyknosis and cytoplasmic eosinophilia. Mucinous degeneration of the eccrine gland adipose tissue cuff, along with an infiltrate of lymphocytes, eosinophils, and neutrophils, may be present, as well as focal areas of hemorrhage within the dermis, mild to moderate spongiosis, and occasional vacuolization of the epidermis. In patients with active leukemia, abnormal or immature leukemia cells do not make up part of the tissue infiltrate.

Differential Diagnosis

Because neutrophilic eccrine hidradenitis is a fairly benign, self-limiting disease, it is imperative that it be differentiated clinically from other, more serious diseases that it might mimic. The variety of cutaneous lesions described in patients with neutrophilic eccrine hidradenitis could easily cause confusion with a fairly large number of clinical entities. Among these are leukemia cutis, cutaneous tumor metastases, erythema multiforme, vasculitis, drug hypersensitivity, sepsis (bacterial and fungal), Sweet's syndrome, and pyoderma gangrenosum. The localized nature of lesions associated with neutrophilic eccrine hidradenitis, and the temporal relationship of cutaneous lesions to the administration of chemotherapy, should aid clinically in differentiating neutrophilic eccrine hidradenitis from most diseases. Because the abnormal histopathologic picture presented by this disease is quite unique, histologic sampling of tissue is of importance.

The histologic differential diagnosis would include several entities involving necrosis of the eccrine gland, including bacterial sepsis with eccrine hidradenitis or other neutrophilic dermatoses; however, the well-trained pathologist, aided by the astute clinician, should combine to make a definitive diagnosis possible.

Treatment and Outcome

Neutrophilic eccrine hidradenitis is a benign, self-limiting disease that generally requires no treatment. The course or the disease does not appear to be influenced by chemotherapy protocols that often include high dosages of systemic corticosteroids. Within 7 to 10 days of origin, most lesions tend to resolve. Recurrent lesions appear to be less severe than preceding lesions and have been suppressed with concurrent dapsone administration.[73] In all patients described to date, healing occurs without residual scarring.

Prognosis

The prognosis for total recovery without sequelae is excellent.

Syringosquamous Metaplasia

Although it can present as a histopathologic finding in association with various other cutaneous conditions, syringosquamous metaplasia has become increasingly associated with the administration of a variety of chemotherapeutic agents and cancers.[74] It has been described in association with bleomycin, cytarabine, daunorubicin, doxorubicin, mitoxantrone, suramin, and docetaxel.[75]

Etiology

The exact etiology of syringosquamous metaplasia is unknown. It is presumed to be a reactive or inflammatory response of the eccrine duct epithelium to the offending agent.

Clinical Manifestations

During or soon after the administration of chemotherapy, there is the onset of nondescript erythematous papules, plaques, or vesicles. These may be generalized or localized and have been reported to occur only in the intertriginous areas. [76] [77]

Pathology

The characteristic histopathology shows eosinophilic squamous metaplasia of the eccrine ducts within the dermis. Focal necrosis of the ductal epithelium has also been noted. The prominent neutrophilic infiltrate of neutrophilic eccrine hidradenitis is not present.

These pathologic changes are not specific and have been described in other disorders unrelated to chemotherapy.[77]

Differential Diagnosis

The differential diagnosis is extensive and includes neutrophilic eccrine hidradenitis; bacterial, viral, or fungal infections; erythema multiforme, metastatic disease; and drug hypersensitivity. Histopathology is necessary to differentiate among these various entities.

Treatment and Outcome

The eruption is benign and resolves spontaneously after cytotoxic treatment is discontinued.

REACTIONS TO BIOLOGIC RESPONSE MODIFIERS

The recent introduction of a group of agents referred to as biologic response modifiers in the treatment of cancer has led to the occurrence of a host of cutaneous reactions.

These powerful physiologic agents used in the setting of underlying malignancy, immunosuppression, other medications, and individual genetically determined host factors have precipitated a variety of specific and nonspecific cutaneous responses. These reactions are summarized in Table 41-2 .

Cutaneous Reactions to Interleukin-2

Recombinant human IL-2, or T-cell growth factor, is a glycoprotein that exerts a wide variety of biologic effects on the immune system. It has found use in the treatment of advanced malignancies, including malignant melanoma, cutaneous T-cell lymphoma, renal cell carcinoma, advanced colorectal carcinoma, and advanced lymphoma. [78] [79] [80] [81] [82] [83] IL-2 has been used after autologous bone marrow transplantation to prevent or reduce the high relapse rate of advanced hematologic malignancies.[84] In the clinical setting, IL-2 is often used in combination with other biologic response modifiers, including lymphokine-activated killer (LAK) cells and IFN-α.[84] IL-2 has also been used in complex with diphtheria toxin as a fusion protein (denileukin diftitox) for the treatment of malignancies characterized by a predominance of activated T and B cells and/or macrophages that express the IL-2 receptor.

IL-2 alone and in combination with LAK and IFN-α has produced a wide variety of toxicities, including one characteristic cutaneous eruption. It is estimated that 50% to 100% of patients treated with IL-2 alone or in combination with other biologic response modifiers will experience some form of cutaneous eruption.[85]

Etiology

Within 48 to 72 hours after the start of an infusion of IL-2 alone or in combination with another cytokine, patients develop a skin eruption of varying severity. The precise etiology is unclear, except it seems that cutaneous reactions occur more often when high doses of IL-2 (100,000 μg/kg) rather than low doses (30,000 μg/kg) are used.[85] There is no difference in rate of occurrence, whether bolus or continuous infusions are administered.

Thus far, no racial or sexual predominance has been observed. More than one-quarter of all patients treated with IL-2 develop a capillary leak syndrome, which, except for extensive edema, does not as yet seem to be entirely related to the development of cutaneous lesions. Nearly all patients receiving IL-2 therapy develop fever and chills. These symptoms tend to occur almost immediately with the initiation of treatment. Gaspari and colleagues[85] have studied IL-2 cutaneous reactions extensively and have concluded that there is immunohistochemical and histologic evidence to support the presence of a cell-mediated immune response during IL-2 therapy. Other studies have implicated a possible role for nitric oxide, Fas ligand and perforin, and complement and other inflammatory mediators in affecting vascular permeability, resulting in a capillary leak syndrome. [86] [87] [88] It is likely that vascular leak syndrome occurs as a result of multiple mechanisms: cell-mediated damage, cytokine-mediated damage, inflammatory mediators, and modification of endothelial cell integrity and the extracellular matrix.[89]

Clinical Manifestations

Chills and fever along with transient cutaneous flushing occur during the first 24 to 48 hours of IL-2 administration. After 48 to 72 hours, persistent erythema associated with itching and a burning sensation develop, first on the malar aspects of the face and then on the neck and chest. In other patients, total body erythema (erythroderma) develops along with erythema and edema of the palms and soles ( Fig. 41-9 ). If the use of IL-2 is combined with LAK cell infusions, it appears that the onset of the eruption might begin within 24 hours. Resolution of disease can occur within 2 to 3 days, when drug administration is stopped. Resolution is associated with continuing pruritus and desquamation of involved skin. There are other reports of erythema progressing to life-threatening bullous eruptions and toxic epidermal necrolysis-like lesions. Some investigators report that the histopathologic findings in these cases separate these patients from those suffering the most frequently observed IL-2 reactions. Erosions of the buccal mucosa, icterus, glossitis, and cutaneous erosions have also been described. A persistent but not progressive vitiligo-like depigmentation has been described after IL-2 and IFN-λ, plus carmustine, cisplatin, and dacarbazine treatment of malignant melanoma.[90]

 
 

Figure 41-9  IL-2 cutaneous reaction. This patient's disease is characterized by intense facial redness, red swollen hands and feet, and a generalized macular eruption.

 

 

Pathology

Histopathologic findings thus far are nonspecific. Within the epidermis, foci of spongiosis, focal vacuolar basal cell degeneration, rare necrotic keratinocytes, and exocytosis of mononuclear cells are seen. In the dermis, mild papillary edema, mild to moderate perivascular mononuclear cell infiltrates, and occasional engorgement of blood vessels occur. These are nonspecific findings. Immunohistochemistry shows activated T cells within the epidermis and dermis with approximately equal numbers of major histocompatibility complex class I and II reactive cells.

Differential Diagnosis

Viral and bacterial exanthems, drug or phototoxic reactions, toxic shock syndrome, staphylococcal scalded skin syndrome, toxic epidermal necrolysis, and acute graft-versus-host reactions must be considered and ruled out with appropriate tests.

Treatment and Outcome

Cessation of treatment is followed 48 to 72 hours later with complete clearing of the skin and little or no residual effect except transitory hyperpigmentation.

Antihistamines given during drug administration and the application of emollients have shown some benefit in the relief of pruritus. The use of systemic glucocorticoids that could offer some immediate relief of symptoms is not indicated; glucocorticoids decrease IL-2 toxicity but might also reduce IL-2 efficacy. [91] [92]

Cutaneous Reactions to Proteasome Inhibitors

Proteasomes exist as large multiprotein particles within the cytosol and cell nucleus and are responsible for regulation of protein expression and degradation of damaged or obsolete proteins within the cell. Proteasome inhibitors have been recently introduced as anticancer agents. [93] [94] [95] The ubiquitin-proteasome pathway is the major proteolytic system in eukaryotic cells. Some of the proteins regulated by this pathway are mediators of cell-cycle progression and apoptosis. These pathways are needed for the survival of all cells including cancer cells. Proteasomes allow the cell to progress through the cell cycle by such mechanisms as degrading cell-cycle regulatory proteins or regulating transcriptional factors such as nuclear factor-κB (NF-kB).[93]

It has been suggested that malignant cells are more susceptible to proteasome blockade than noncancerous cells.[94] Proteasome inhibitors fall into five classes: peptide aldehydes, peptide vinyl sulfones, peptide boronates, peptide epoxiketones, and beta-lactones. All except peptide boronates have been found unsuitable for clinical development.[93] Cutaneous toxicity has been variously described in from 20% to 30% of patients treated. Severity grade varies from 1 to 3.

Etiology

The proteasome inhibitor bortezomib, a peptide boronate, was approved for treatment of refractory multiple myeloma. Investigations are currently underway for treatment of non-Hodgkins lymphoma and a variety of solid tumors. It has been suggested that bortezomib's cutaneous toxicity occurs as an inflammatory response associated with delayed hypersensitivity, cell-mediated immune responses, vascular damage, or direct toxic reactions.[96] Enhancement of the release of proinflammatory cytokines may also be involved.[97]

Clinical Manifestations

In most patients described thus far cutaneous adverse reactions vary in severity and occurrence. An undefined “exanthem” consistent with a hypersensitivity reaction seems to be most common. It resolves spontaneously without treatment but recurs with additional treatment cycles.

At least 20% of patients develop lower extremity edema. An unspecified rash, pruritus, urticaria, sweating, dry skin, and eczema appear commonly, whereas alopecia seems to be rare.[98] Red nodules or plaques on the trunk, and a generalized exanthem associated with ulceration and fevers may appear during the second to fourth treatment cycles; however, they can be seen in the first cycle.[98] Drug-induced Sweet's syndrome [98] [99] and erythematous maculopapular eruptions that on biopsy display “leukocytoclastic vasculitis” have been seen in many patients. [97] [100] [101] It has been suggested that the development of vasculitis may be a possible surrogate marker of disease response.[101] A folliculitis-like eruption has also been described,[102] as has reactivation of latent varicella zoster virus.[103]Finally, a solitary paranasal plaque and eschar have been described.[104]

Pathology

Histology differs depending on the type of skin eruption. In patients with nodules, plaques, and exanthem, histology ranged from perivascular dermatitis to interstitial and interface dermatitis.[96] In those with leukocytoclastic vasculitis, perivascular neutrophilic infiltrates with fibrinoid necrosis is seen. In Sweet's syndrome there are diffuse neutrophilic infiltrates in the reticular dermis with papillary dermal edema. Leukocytoclastic nuclear debris is often seen interstitially, but true vasculitic changes are absent. In the folliculitis-like lesions, perivascular lymphoid infiltrates were seen.[102] In a solitary alar lesion, a superficial perivascular and interface dermatitis compatible with drug eruption was seen.[104]

Differential Diagnosis

Infectious exanthems and other eruptions due to medicines other than bortezomib must be considered. Sweet's syndrome must be distinguished from other reactions such as neutrophilic eccrine hidradenitis, pyoderma gangrenosum (bullous), erythema multiforme, vasculitis, and other infectious or neoplastic causes. Vasculitis must be distinguished from capillaritis, vasculopathy, and other inflammatory dermatoses such as Sweet's syndrome, urticaria, and erythema multiforme. Additionally, Sweet's syndrome and leukocytoclastic vasculitis can be due to several etiologies, and there do not seem to be any unique features suggesting bortezomib as the etiology.

Treatment and Outcome

In some cases lesions resolve without specific treatment, or with the use of oral corticosteroids and/or antihistamines. [96] [97] [98] [100] [102] Oral corticosteroids have been used prophylactically to prevent recurrence of lesions [96] [97] [98] [102] or reduce the number and extent of lesions.[96] Antihistamines alone were not sufficient to prevent occurrence.

Histone Deacetylase Inhibitors

Histone deacetylase inhibitors (HDACs) have recently emerged as potential agents for use in cancer therapy.[105] Acetylation of histone proteins can affect gene activation. Histone deacetylases remove acetyl groups from histones leading to repression of gene transcription. Dysregulation of acetylation has been implicated in cancer development when genes involved in cell-cycle control or apoptosis are affected. HDACs are thought to work by allowing gene reactivation of tumor suppressor or apoptotic pathway genes leading to cell-cycle arrest or cell death.

Five classes of HDACs have been described. A few medications have been tested in phase I and II trials including depsipeptide, suberoylanilide hydroxamic acid, and MS 275.[105] Thus far, skin toxicity appears to be minimal. In two phase I trials for depsipeptide [106] [107] it was noted that skin toxicities seem to be distinct from conventional agents. No alopecia or mucositis was noted. No sign of skin toxicity or bleeding was noted. Similarly, in a recent phase I study by Kelly and associates no cutaneous reactions were described for suberoylanilide hydroxamic acid.[108] Finally, another HDAC, MS-275, was evaluated in a phase I trial by Ryan and coworkers.[109] Cutaneous reactions were rare, with edema noted in four patients, and sweating and nail changes noted in one patient each. An allergic reaction was noted in one patient, but this was not further described. Further use of these medicines will better elucidate the adverse cutaneous effect profile.

Toll-like Receptor Agonists

Toll-like receptor agonists have emerged as other potential cancer medications.[110] There are 10 Toll-like receptors (TLRs) in humans that are expressed on cells of the innate immune system. Most signaling through these pathways results in the production of proinflammatory cytokines. Agonists have been found to drive adaptive immunity toward a Th1 response, which then targets tumor cells. In chronic lymphocytic leukemia, these agonists may enhance the activity of T cells and natural killer cells, and inhibit angiogenesis. TLR-7 and TLR-9 agonists in particular may lead to production of cytokines that render tumor cells more susceptible to killing. In this way they may be useful as adjuvant medications.

TLR-7 agonists, imidazoquinolines, are currently being studied (including S28690). There is minimal information available on cutaneous adverse effects of these medications. Imiquimod (Aldara) is also an imidazoquinoline that has been used topically for treatment of verruca and skin cancers. Topical use of this medication has been associated with systemic and cutaneous side effects. In recent trials itching, pain, and tenderness at the site of the application were the most common cutaneous complaints.[111] Other local reactions included scabbing, erosion, ulceration, erythema, and vesiculation.

Cutaneous Reactions to Epidermal Growth Factor Receptor Inhibitors

The EGFR (or ErbBl) is a 170-kd transmembrane protein that includes an extracellular ligand-binding domain and an intracellular protein tyrosine kinase.[112] Stimulation of this often overexpressed receptor in aberrant cell lines propagates pathways of cellular proliferation (including tumor growth, progression, and metastasis of human cancer); thus, EGFR therapeutic blockade has proven beneficial in treating a variety of solid tumors.[113] Two classes of EGFR inhibitors are currently in use: monoclonal antibodies that target the extracellular domain to inhibit ligand binding and induce receptor downregulation, and receptor tyrosine kinase inhibitors that competitively block receptor phosphorylation.[112] Dermatologic reactions are the most commonly reported toxicities with both classes. The most characteristic is an acneiform eruption reaction, which is seen in 50% to 90% of treated patients.[114]

Etiology

Within the first 2 weeks of treatment, a characteristic rash appears as an acne-like folliculitis, typically starting on the face, upper chest, back, and scalp but potentially extending to the extremities ( Fig. 41-10 ). The descriptive term “acneiform” is commonly encountered in the literature, but it is important to emphasize that the pathophysiology of the primary lesion, a pustule, seems to be distinct from that of acne vulgaris.[115] The precise etiology is unclear. It has been postulated that inhibition of the EGFR pathway results in disruptions of normal development and maintenance of the hair follicle. Follicular rupture and an inflammatory reaction result.

 
 

Figure 41-10  EGFR typical eruption. A, Right breast with numerous pink acneiform papules and macules. B, Forehead with characteristic acneiform eruption of several pink papules and pustules some with crust. C, Bilateral forearms and dorsal hands with small pink papules and macules.

 

 

Clinical Manifestations

There seems to be a drug-dosage relationship to the severity of the skin reaction. Severity is often rated 2 to 3. Most commonly the face is affected, including forehead, nose, nasolabial folds, cheeks, and chin.[115] There may be caudal progression of disease, but mucosa and acral surfaces are spared. Pustular lesions are primary, although erythema and cystic nodules have also been described.[115] The rash typically appears 1 to 3 weeks after onset of treatment, appearing maximal between weeks 3 and 5. It commonly resolves once treatment is stopped but may persist for more than 12 weeks after cessation. Resumption of treatment may cause reappearance or worsening of the rash. Other than hyperpigmentation there are few residual effects.[116] Limited data suggest that patients with a skin rash of any grade may have a superior survival as compared with patients with no skin rash, and furthermore, there may be a trend toward improved survival with increasing grade of rash.[117] There is some evidence to suggest that the rash parallels saturation of receptor clearance and may be used as a measure of optimum biologic dose in those patients so affected.

Histopathology

Two primary reaction patterns have been identified: suppurative folliculitis with epithelial rupture and superficial perifollicular dermal inflammation with hyperkeratotic and ectatic infundibula. [114] [115]The stratum corneum demonstrates compact orthokeratosis with focal parakeratosis and prominent follicular plugs. Also occasionally reported are basilar vacuolar degeneration, lichenoid patterns, and intradermal acantholysis.[115]

Treatment and Outcome

Depending on severity, which ranges from grade 1 to 4,[117] cutaneous toxicity, management may include drying agents, topical antibiotics and antiseptics, systemic antibiotics, topical retinoids, topical or systemic corticosteroids, or topical immunomodulatory agents. Secondary complications including Staphylococcus aureus infections and severe pruritus may occur and will require appropriate interventions.[116] Several published studies have even suggested that the severity of the skin eruption may parallel patient survival.[117]

Other Dermatologic Side Effects of Anti-EGFR Therapy

Additional and less common cutaneous effects reported include nail bed infections and paronychial inflammation with associated swelling of the lateral nail folds of the toes and fingers, onycholysis of nails, with the great toes and thumbs as the most commonly affected digits [114] [115]; generalized exfoliation and desquamation; xerosis; pruritus; urticaria and angioedema (primarily with trastusumab); alopecia; skin fissures; and mild to moderate stomatitis and mucositis.[115] Treatment is primarily symptomatic.

REFERENCES

  1. Love RR, Leventhal H, Easterling DV, Nerenz DR: Side effects and emotional distress during chemotherapy.  Cancer1989; 63:604-612.
  2. Wiernik TH, Schmipff SC, Schiffer CA, et al: Randomized clinical comparison of daunorubicin (NSC-82151) along with a combination of daunorubicin, cytosine arabinoside (NSC-63878), 6-thioguanine (NSC-752) and pyrimethamine (NSC-3061) for the treatment of acute nonlymphocytic leukemia.  Cancer Treat Rep1976; 60:41-53.
  3. Benjamin RS: A practical approach to adriamycin (NSC-123127) toxicology.  Cancer Chemother Rep1975; 6:191.
  4. Jessen RT, Straight M, Smith EB: Cutaneous and other complications of cyclophosphamide: a brief review.  Rocky Mountain Med J1978; 75:204-206.
  5. Estape J, Palombo H, Sanchez-Lloret J, et al: Chronic oral etoposide in non-small cell lung carcinoma!.  Eur J Cancer1992; 28A:835-837.
  6. Owen RR, Sells RA, Gilmore IT, et al: A phase I clinical evaluation of liposome-entrapped doxorubicin (Lip-Dox) in patients with primary and metastatic hepatic malignancy.  Anticancer Drugs1992; 3:101-107.
  7. Pestalozzi B, Schwendener R, Sauter C: Phase I/II study of liposome-complexed mitoxantrone in patients with advanced breast cancer.  Ann Oncol1992; 3:445-449.
  8. Batchelor D: Hair and cancer chemotherapy: consequences and nursing care—a literature study.  Eur J Cancer Care2001; 10:147-163.
  9. Brodin MB: Drug related alopecia.  Dermatol Clin1987; 5:571-579.
  10. Joss RA, Kiser J, Weston S, Brunner KW: Fighting alopecia in cancer chemotherapy.  Recent Results Cancer Res1988; 106:117-126.
  11. Koppel RA, Boh EE: Cutaneous reactions to chemotherapeutic agents.  Am J Med Sci2001; 321:327-335.
  12. de Jonge ME, Mathot RA, Dalesio O, et al: Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy.  Bone Marrow Transplant2002; 30:593-597.
  13. Robinson A, Jones W: Change in scalp hair after cancer chemotherapy.  Eur J Cancer Clin Oncol1989; 25:155-156.
  14. Christodoulou C, Klouvas G, Efstathiou E, et al: Effectiveness of the MSC cold cap system in the prevention of chemotherapy-induced alopecia.  Oncology2002; 62:97-102.
  15. Villani C, Inghirami , Pietrangeli D, et al: Prevention by hypothermic cap of antiblastic-induced alopecia.  Eur J Gynaecol Oncol1986; 7:15-17.
  16. Dean JC, Griffith KS, Cetas TC: Scalp hypothermia: a comparison of ice packs and Kold Kap in the prevention of doxorubicin-induced alopecia.  J Clin Oncol1983; 1:33-37.
  17. Benjamin B, Ziginskas D, Harman J, Meakin T: Pulsed electrostatic fields (ETG) to reduce hair loss in women undergoing chemotherapy for breast carcinoma: a pilot study.  Psychooncology2002; 11:244-248.
  18. Tsuda T, Ohmori Y, Muramatsu H, et al: Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia.  Eur J Pharmacol2001; 433:37-45.
  19. Dorr RT, Alberts DS: Vinca alkaloid skin toxicity: antidote and drug disposition studies in the mouse.  J Natl Cancer Inst1985; 74:113.
  20. Goodman LD, Wintrobe MM, Dameshek W, et al: Nitrogen mustard therapy.  JAMA1946; 132:126.
  21. Argenta LC, Manders EK: Mitomycin C extravasation injuries.  Cancer1983; 51:1080-1082.
  22. Villani C, Pace S, Tomao S, et al: Skin necrosis due to antiblastics (procedures of prevention and therapy).  Eur J Gynaecol Oncol1986; 7:58-61.
  23. Frei E: The clinical use of actinomycin.  Cancer Chemother Rep1974; 58:49-54.
  24. Dorr RT, Alberts DS: Skin ulceration potential without therapeutic anticancer activity for epipodophyllotoxin commercial diluents.  Invest New Drugs1983; 1:151-159.
  25. Preuss P, Partoff S: Cytostatic extravasations.  Ann Plast Surg1987; 19:323-329.
  26. Martin Algarra S, Dy C, Bilbao I: Cutaneous necrosis after intraarterial treatment with cisplatin.  Cancer Treat Rep1986; 70:687-688.
  27. Peters TM, Brijnen JA, Huinink WWB: Mitoxantrone extravasation injury.  Cancer Treat Rep1987; 71:992-993.
  28. Herrington JD, Figueroa JA: Severe necrosis due to paclitaxel extravasation.  Pharmacotherapy1997; 17:163-165.
  29. Baur M, Kienzer HR, Rath T, Dittrich C: Extravasation of oxaliplatin (eloxatin [R])–clinical course.  Onkologie2000; 23:468-471.
  30. Berghammer P, Pohnl R, Baur M, Dittrich C: Docetaxel extravasation.  Support Care Cancer2001; 9:131-134.
  31. Lokich J: Doxil extravasation injury: a case report.  Ann Oncol1999; 10:735-736.
  32. Donaldson SS, Glick JM, Wilbur JR: Adriamycin activating a recall phenomenon after radiation therapy.  Ann Intern Med1974; 81:407-408.
  33. Vogelzang NJ: “Adriamycin flare”: a skin reaction resembling extravasation.  Cancer Treat Rep1979; 63:2067-2069.
  34. Bhawan J, Petry J, Rybak ME: Histologic changes induced in skin by extravasation of doxorubicin (Adriamycin).  J Cutan Pathol1989; 16:158-163.
  35. Tsavaris NB, Karagiaouris P, Tzannou I, et al: Conservative approach to the treatment of chemotherapy induced extravasation.  Dermatol Surg Oncol1990; 16:519-522.
  36. Rudolph R, Larson DL: Etiology and treatment of chemotherapeutic agent extravasation injuries: a review.  J Clin Ocol1987; 5:1116-1126.
  37. Dorr RT: Antidotes to vesicant chemotherapy extravasations.  Blood Rev1990; 4:41-60.
  38. Dorr RI, Soble M, Alberts DS: Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse.  Cancer Chemother Pharmacol1988; 22:299-302.
  39. Dorr RT, Soble M, Liddil JD, Keller JH: Mitomycin C skin toxicity studies in mice. Reduced ulceration and altered pharmacokinetics with topical dimethyl sulfoxide.  J Clin Oncol1986; 4:1399-1404.
  40. Brothers TE, Niederhyber JE, Roberts JA, Ensminger WD: Experience with subcutaneous infusion ports in three hundred patients.  Surg Gynecol Obstet1988; 166:295-305.
  41. Zuehlke RL: Erythematous eruption of the palms and soles associated with mitotane therapy.  Dermatologica1974; 148:90-92.
  42. Lokich JJ, Moore C: Chemotherapy-associated palmar plantar erythrodysesthesia syndrome.  Ann Intern Med1984; 101:798-799.
  43. Oksenhentler E, Landais P, Cordonnier C, et al: Erythema and systemic toxicity related to CHA induction therapy in acute myeloid leukemia.  Eur J Cancer Clin Oncol1989; 25:1181-1185.
  44. Hui YF, Giles FJ, Cortes JE: Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome-recall following different chemotherapy agents.  Invest New Drugs2002; 20:49-53.
  45. Horwitz LJ, Dreizen S: Acral erythema induced by chemotherapy and graft-versus-host disease in adults with hematological malignancies.  Cutis1990; 46:397-404.
  46. Vukelja SJ, Lombardo FA, James WD, Weiss RB: Pyridocine for the plamar-plantar erythrodysesthesia syndrome.  Ann Intern Med1989; 111:688-689.
  47. Lopez AM, Wallace L, Dorr RT, et al: Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia.  Cancer Chemother Pharmacol1999; 44:303-306.
  48. Kyle RA, Schwartz RS, Oliner HL, et al: A syndrome resembling adrenal cortical insufficiency associated with long term busulfan (Myleran) therapy.  Blood1961; 18:497-510.
  49. Adrian RM, Hood AF, Skarin AT: Mucocutaneous reactions to antineoplastic agents.  CA Cancer J Clin1980; 30:143-157.
  50. Bronner AK, Hood AF: Cutaneous complications of chemotherapeutic agents.  J Am Acad Dermatol1983; 9:645-663.
  51. Kew MC, Mzamane D, Smith AG, et al: Melanocyte-stimulating hormone levels in doxorubicin-induced hyperpigmentation.  Lancet1977; 1:811.
  52. Harrold BP: Syndrome resembling Addison's disease following prolonged treatment with busulfan.  BMJ1966; 1:463-464.
  53. Fitzpatrick JE, Hood AF: Histopathologic reactions to chemotherapeutic agents.  Adv Dermatol1988; 3:161-163.
  54. Singh M, Kaur S: Chemotherapy-induced multiple Beau's lines.  Int J Dermatol1986; 25:590-591.
  55. Shetty MR: White lines in the fingernails induced by combination chemotherapy.  BMJ1988; 297:1635.
  56. Katz ME, Hansen TW: Nail plate–nail bed separation: an unusual side effect of systemic fluorouracil administration.  Arch Dermatol1979; 115:860-861.
  57. Manalo FB, Marks A, Davis Jr HL: Doxorubicin toxicity: onycholysis, plantar callus formation, and peidermolysis.  JAMA1975; 233:56-57.
  58. Jeter MD, Janne PA, Brooks S, et al: Gemcitabine-induced radiation recall.  Int J Radiat Oncol Biol Phys2002; 53:394-400.
  59. Yeo W, Johnson PJ: Radiation-recall skin disorders associated with the use of antineoplastic drugs.  Am J Clin Dermatol2000; 1:113-116.
  60. Seymour CB, Mothersill C, Alper T: High yields of lethal mutations somatic mammalian cells that survive ionizing radiation.  Int J Radiat Biol1986; 50:167-179.
  61. Yarbro JW: Dermotoxicity.   In: Perry MC, ed. Toxicity of Chemotherapy,  Orlando: Grune & Stratton; 1984.
  62. Del Guidice SM, Gerstley JK: Sunlight-induced radiation recall.  Int J Dermatol1998; 27:415-416.
  63. Moller H: Cytostatic drugs and inflammation.  Lancet1970; 2:427.
  64. Dunagin WG: Clinical toxicity of chemotherapeutic agents: dermatologic toxicity.  Semin Oncol1982; 9:14-22.
  65. Pauluzzi P, Kokelj F, Perkan V, et al: Psoriasis exacerbation induced by interferon-alpha. Report of two cases.  Acta Derm Venereol1993; 73:395.
  66. Maguire Jr HC, Ettore VL: Enhancement of dinitrochlorobenzene (DNCB) contact sensitization by cyclophosphamide in the guinea pig.  J Invest Dermatol1967; 48:39-43.
  67. Dudley K, Micetich K, Massa MC: Erythema with features of seborrheic dermatitis and lupus erythematosus associated with systemic 5-fluorouracil.  Cutis1987; 39:64-65.
  68. Harrist TJ, Fine JD, Berman R, et al: Neutrophilic eccrine hidradenitis.  Arch Dermatol1982; 118:263-266.
  69. Combemale P, Faisant M, Azoulay-Petit C, et al: Neutrophilic eccrine hidradenitis secondary to infection with Serratia marcescens..  Br J Dermatol2000; 142:784-788.
  70. Krischer J, Rutschmann O, Roten SV, et al: Neutrophil eccrine hidradenitis in a patient with AIDS.  J Dermatol1998; 25:199-200.
  71. Brehler R, Reimann S, Bonsmann G, Metze D: Neutrophilic hidradenitis induced by chemotherapy involves eccrine and apocrine glands.  Am J Dermatopathol1997; 19:73-78.
  72. Osttere LS, Wells J, Stevens HP, et al: Neutrophilic eccrine hidradenitis with an unusual presentation.  Br J Dermatol1993; 128:696-698.
  73. Shear NH, Knowles SR, Shapiro L, et al: Dapsone in prevention of recurrent neutrophilic eccrine hidradenitis.  J Am Acad Dermatol1996; 35:819-822.
  74. Bhawan J, Malhotra R: Syringosquamous metaplasia: a distinctive eruption in patients receiving chemotherapy.  Am J Dermatopathol1990; 12:1-6.
  75. Koppel RA, Boh EE: Cutaneous reactions to chemotherapeutic agents.  Am J Med Sci2001; 321:327-335.
  76. Wong P, Bangert JL, Levin N: A papulovesicular eruption in a man receiving chemotherapy for metastatic melanoma.  Arch Dermatol1993; 129:232-233.
  77. Valks R, Fraga J, Porras-Luque J, et al: Chemotherapy-induced eccrine squamous syringometaplasia: a distinctive eruption in patients receiving hematopoietic progenitor cells.  Arch Dermatol1997; 133:873-878.
  78. Hamada I, Kato M, Okada K: Multi-cytokine therapy for advanced renal cell carcinoma: determination of the minimal effective dose.  Anticancer Res2002; 22:2429-2436.
  79. Apisarnthanarax N, Talpur R, Duvic M: Treatment of cutaneous T cell lymphoma: current status and future directions.  Am J Clin Dermatol2002; 3:193-215.
  80. Skubitz KM, Anderson PM: Inhalational interleukin-2 liposomes for pulmonary metastases: a phase I clinical trial.  Anticancer Drugs2000; 11:555-563.
  81. Farag SS, George SL, Lee EJ, et al: Postremission therapy with low-dose interleukin 2 with or without intermediate pulse dose interleukin 2 therapy is well tolerated in elderly patients with acute myeloid leukemia: Cancer and Leukemia Group B study 9420.  Clin Cancer Res2002; 8:2812-2819.
  82. Sobol RE, Shawler DL, Carson C, et al: Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumor cells and genetically engineered fibroblasts: a phase I study.  Clin Cancer Res1999; 5:2359-2365.
  83. Apisarnthanarax N, Talpur R, Duvic M: Treatment of cutaneous T cell lymphoma: current status and future directions.  Am J Clin Dermatol2002; 3:193-215.
  84. Ozsahin H, Fluss J, McLin V, et al: Rituximab with interleukin-2 after autologous bone marrow transplantation for acute lymphocytic leukemia in second remission.  Med Pediatr Oncol2002; 38:300-301.
  85. Gaspari AA, Lotze MT, Rosenberg SA, et al: Dermatologic changes associated with interleukin-2 administration.  JAMA1987; 258:1624-1629.
  86. Locker GJ, Kofler J, Stoiser B, et al: Relation of pro- and anti-inflammatory cytokines and the production of nitric oxide in patients receiving high-dose immunotherapy with interleukin-2.  Eur Cytokine Netw2000; 11:391-396.
  87. Rafi AQ, Zeytun A, Bradley MJ, et al: Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome.  J Immunol1998; 161:3077-3086.
  88. Baluna R, Rizo J, Gordon BE, et al: Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome.  Proc Natl Acad Sci USA1999; 96:3957-3962.
  89. Baluna R, Vitetta ES: Vascular leak syndrome: a side effect of immunotherapy.  Immunopharmacology1997; 37:117-132.
  90. Rosenberg S, White D: Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy.  J Immunother Tumor Immunol1996; 19:81-84.
  91. Vetto JT, Papa MZ, Lotze MT, et al: Reduction of toxicity of IL-2 and lymphokine activated killer cells in humans by the administration of corticosteroid.  J Clin Oncol1987; 5:496-503.
  92. Buzaid AC, Atkins M: Practical guidelines for the management of biochemotherapy-related toxicity in melanoma.  Clin Canc Res2001; 7:2611-2619.
  93. Adams J: The development of proteasome inhibitors as anticancer drugs.  Cancer Cell2004; 5:417-421.
  94. Adams J: The proteasome: a suitable antineoplastic target.  Nat Rev Cancer2004; 4:349-360.
  95. Kisselev AF, Goldberg AL: Proteasome inhibitors: from research tools to drug candidates.  Chem Biol.2001; 8:739-758.
  96. Ozcan MA, Alacacioglu I, Piskin O, et al: Bortezomib-induced skin lesion.  Acta Haematol2006; 116:226-227.
  97. Min CK, Lee S, Kim YJ, et al: Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient; association with proinflammatory cytokines.  Eur J Haematol2006; 76:265-268.
  98. Van Regenmortel N, Van de Voorde K, De Raeve H, et al: Bortezomib-induced Sweet's syndrome.  Haematologica2005; 90(12 Suppl):ECR43.
  99. Knoops L, Jacquemain A, Tennstedt D, et al: Bortezomib-induced Sweet syndrome.  Br J Haematol2005; 131:142.
  100. Agterof MJ, Biesma DH: Images in clinical medicine. Bortezomib-induced skin lesions.  N Engl J Med2005; 352:2534.
  101. Gerecitano J, Goy A, Wright J, et al: Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: a possible surrogate marker of response?.  Br J Haematol2006; 134:391-398.
  102. Pour L, Hajek R, Zdenek A, et al: Skin lesions induced by bortezomib.  Haematologica2005; 90(12 Suppl):ECR44.
  103. Kroger N, Zabelina T, Ayuk F, et al: Bortezomib after dose-reduced allogeneic stem cell transplantation for multiple myeloma to enhance or maintain remission status.  Exp Hematol2006; 34:770-775.
  104. Wu KL, Heule F, Lam K, Sonneveld P: Pleomorphic presentation of cutaneous lesions associated with the proteasome inhibitor bortezomib in patients with multiple myeloma.  J Am Acad Dermatol.2006; 55:897-900.
  105. Fouladi M: Histone deacetylase inhibitors in cancer therapy.  Cancer Invest2006; 24:521-527.
  106. Sandor V, Bakke S, Robey RW, et al: Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.  Clin Cancer Res2002; 8:718-728.
  107. Marshall JL, Rizvi N, Kauh J, et al: A phase I trial of depsipeptide (FR901228) in patients with advanced cancer.  J Exp Ther Oncol2002; 2:325-332.
  108. Kelly WK, O'Connor OA, Krug LM, et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer.  J Clin Oncol2005; 23:3923-3931.
  109. Ryan QC, Headlee D, Acharya M, et al: Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma.  J Clin Oncol2005; 23:3912-3922.
  110. Spaner DE, Masellis A: Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia.  Leukemia, advance online publication, 26 Oct2006;1-8.
  111. Geisse JK, Rich P, Pandya A, et al: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study.  J Am Acad Dermatol2002; 47:390-398.
  112. Saltz LB, Meropol NJ, Loehrer Sr PJ, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.  J Clin Oncol2004; 22:1201-1208.
  113. Ross JS, Schenkein DP, Pietrusko R, et al: Targeted therapies for cancer 2004.  Am J Clin Pathol2004; 122:598-609.
  114. Fox LP: Pathology and management of dermatologic toxicities associated with anti-EGFR therapy.  Oncology2006; 20(Suppl 2):26-34.
  115. Agero AL, Dusza SW, Benvenuto-Andrade C, et al: Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.  J Am Acad Dermatol2006; 55:657-670.
  116. Brunton LL, Lazo JS, Parker KL: Goodman & Gilman's The Pharmacological Basis of Therapeutics,  11th ed.. New York, McGraw-Hill, 2006.
  117. Perez-Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer.  J Clin Oncol2004; 22:3238-3247.