Recognizing Nail and Skin Changes Associated With Chemotherapy

MAY 18, 2007
Constantin A. Dasanu, MD, PhD, Doru T. Alexandrescu, MD, and Peter H. Wiernik, MD, Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY
Constantin A. Dasanu, MD, PhD
Hematology-Oncology Fellow

Doru T. Alexandrescu, MD
Faculty, Department of Oncology

Peter H. Wiernik, MD

Professor of Medicine

Our Lady of Mercy Cancer Center New York Medical College Bronx, NY

Many chemotherapeutic agents can cause a variety of nail and skin changes. These changes are usually not accompanied by pain and are reversible after the offending drug is discontinued. Transverse melanonychia, Muehrcke?s lines, and Beau?s lines are some of the common manifestations of these changes. Physician awareness of chemotherapy-induced nail injuries is important to provide reassurance to the patient and avoid unnecessary diagnostic workup.

Nail changes may signal exposure to heavy metals, radiation, or result from a variety of systemic diseases; be a side effect of certain drugs; or be caused by an unusual environmental exposure or malnutrition. In addition, several types of age-associated nail disorders in the geriatric population that are not related to drugs have been described.1

Drug-induced nail abnormalities result from toxicity to the matrix, nail bed, periungual tissues, or digit blood vessels. The changes can involve some or all the nails, are asymptomatic, and are reversible after the offending agent is discontinued.2 Although often perceived as cosmetically disturbing, only rarely do these nail abnormalities cause significant pain or impair manual activities.

Dermatologic changes encountered during use of chemotherapeutic agents include nail dystrophies, different patterns of nail discoloration (known as chromonychia), alopecia, and skin hyperpigmentation. Interaction of chemotherapeutic agents with radiotherapy or ultraviolet light can aggravate or cause dermatologic problems, such as the severe skin rash that is known as ?radiation recall.?3

PRACTICE POINTS
? Dermatologic changes occurring with chemotherapeutic agents include nail dystrophies, chromonychia, alopecia, and skin hyperpigmentation.

? These nail abnormalities result from toxicity to the matrix, nail bed, periungual tissues, or digit blood vessels.

? These changes disappear with discontinuation of the offending drug.

? Physicians should reassure the patient about the nature of these changes and avoid unnecessary diagnostic workup.

The most frequent form of chromonychia is melanonychia, a dark pigmentation of the nails that can be diffuse or in transverse or longitudinal bands.4 It may coexist with diffuse pigmentation of the skin and mucosa. Although some evidence suggests that subungual melanin deposits may be a cause, the mechanism of the hyperpigmentation remains obscure. These changes are observed more frequently in dark-skinned than in light-skinned patients.

Transverse white bands on the nail, also known as leukonychia striata or Muehrcke?s lines, can be inherited or caused by a variety of diseases and medications, including some cancer chemotherapeutic agents.5,6 Leuk?onych?ia striata, which are not as common as melanonychia in patients receiving chemotherapy, are thought to represent a side effect of the cancer drug rather than a manifestation of the underlying malignancy.7

Transverse grooves of the nails, or Beau?s lines, have been observed in some patients with malignant lymphoma who receive chemotherapy.8 These abnormalities are likely the result of suppressed growth of the nail matrix caused by the antimitotic drugs.

Illustrative Case
A 53-year-old man from Guyana presented with the chief complaint of an unusual discoloration of his fingernails that had been present for the past 6 weeks. His wife had also noticed darkening of the skin over his palms and forearms.

His medical history was significant for stage 3 multiple myeloma immunoglobulin G type kappa, which had been diagnosed 8 months earlier. He received 5 monthly chemotherapy cycles with vincristine sulfate (Vincasar), nonliposomal doxorubicin (Adriamycin), and dexamethasone (Decadron), to which he had a partial response. He had received radiotherapy to his lumbar spine for a painful compression fracture at vertebra L3. He also had painful dysesthesias in his legs.

The patient was taking daily doses of gabapentin (Gabarone, Neurontin), allopurinol (Zyloprim), finasteride (Proscar), and tamsulosin HCl (Flomax). Furthermore, he received weekly subcutaneous erythropoietin (Epogen, Procrit) injections and monthly intravenous zoledronic acid (Zometa) infusions.

Physical examination revealed transverse grooves in his fingernails (Figure 1), along with multiple white bands alternating with brown-black lines (Figure 2) that involved all his fingernails and toenails and were regularly spread across the breadth of the fingernail plates, which had smooth borders with a rounded distal edge.

The patient?s skin and mucous membranes appeared to be darkened, especially on his palmar creases (Figure 3) and lips, but without any icterus. He also had diffuse alopecia.

He was informed that the nail changes would likely disappear within approximately 3 to 6 months after stopping the triple chemotherapy regimen.

Medications Associated with Nail Changes
Numerous drugs may induce nail changes, including retinoids; tetracyclines; antimalarial agents; and cancer chemotherapeutic agents, such as anthracyclines, cyclophosphamide (Cytoxan, Neosar), and vincristine (Table).5,9 A review of 74 patients with cancer who received chemotherapy showed that 23% had transverse white bands of the nails, and 19% had nail hyperpigmentation.10

Nail dystrophic changes have been described in association with the mitotic inhibitors docetaxel (Taxotere) and paclitaxel (Onxol, Taxol), as well as with etoposide (Etopophos, Toposar, VePesid). Nail pigmentation, Beau?s lines, onycholysis, subungual suppuration, and even subungual hematoma have been linked to therapy with the taxanes paclitaxel and do?cetaxel.11 In one study of 58 patients treated with weekly paclitaxel for metastatic breast cancer, 16 patients (27.6%) developed nail toxicity; three fourths of these patients had at least grade 2 toxicity (ie, partial or total loss of nails or pain in the nailbeds). In 2 patients, chemotherapy had to be delayed to treat the painful nail condition, because it was severely limiting their daily functioning.12 In a second study of 57 patients with metastatic breast cancer who were treated with weekly docetaxel, 17 patients (30%) had grade 1 nail toxicity (ie, discoloration, ridging, pitting) and 8 (14%) had grade 2 toxicity.13

Among anthracyclines, melanonychia has been known to occur in patients taking doxorubicin, daunorubicin HCl (Cerubidine), or idarubicin HCl (Idamycin PFS).14 When not associated with dystrophic nail changes, chromonychia by itself constitutes only an unpleasant aesthetic side effect of these drug classes. The nail changes usually reverse a few months after the drug is withdrawn.8,15 In fact, all these patterns of nail changes disappear with discontinuation of therapy and subsequent nail regrowth.

Common Nail Changes
Beau?s lines and chromonychia
Our patient presented with 3 nail abnormalities?transverse melanonychia, Muehrcke?s lines, and Beau?s lines?in addition to hyperpigmentation of the skin. It is very likely that all these changes were caused by the doxorubicin or vincristine used to treat his myeloma. None of the other drugs he was taking is known to be associated with such manifestations. No clinical or laboratory data suggested carotenemia, primary adrenal failure, or jaundice in our patient. Although these diseases may cause a somewhat similar skin discoloration, they are not known to be associated with the described nail changes.

Mees? lines
The development of streaks on the nails of the hands and feet, also known as Mees? lines, is associated with exposure to thallium, arsenic, and radiation.16,17 Beau?s lines and diffuse skin hyperpigmentation have also been described with chronic arsenic poisoning,16 whereas alopecia and skin hyperesthesia are more common with chronic thallium poisoning.17 Our patient?s blood and urine assays were negative for these heavy metals.

Dystrophic nails
Paronychialike changes and onycholysis have been reported in patients treated with the anti-acne agent isotretinoin (Accutane, Claravis).18 Our patient denied using this drug.

Whitening of the nail beds
Whitened nail beds have been linked to severe malnutrition and very low levels of selenium.19 Neither of these conditions was relevant to our patient, since his serum albumin and cholesterol levels were normal.

Blue fingernails
A blue discoloration of the fingernails has been reported in 2 patients with pernicious anemia,20 but both had normal-colored nail regrowth after treatment discontinuation. Cobalamin deficiency was not high on the list of the differential diagnosis of our patient, and the appropriate testing was negative.

Amyloidosis-related nail dystrophy
Amyloidosis is known to occasionally accompany multiple myeloma, especially later in the course of the disease. Although rare, nail dystrophic changes are recognized features of systemic amyloidosis developing secondary to multiple myeloma.21 Case reports have described nail changes as the only skin manifestation of systemic amyloidosis in patients with myeloma.22

Our patient had peripheral neuropathy, but it was not idiopathic and therefore not likely to be related to systemic amyloidosis. Instead, the neuropathy was very likely a consequence of both vincristine use and spinal nerve impingement at vertebra L3. Of note, his painful leg dysesthesias responded well to gabapentin. Furthermore, true multiple myeloma?associated amy?loidosis is uncommon and, when present, is associated with lambda rather than kappa monoclonal light chains.

Conclusion
The nail abnormalities encountered in patients with various malignancies likely represent side effects of many antineoplastic agents. Important considerations in the differential diagnosis include heavy-metal poisoning, radiation exposure, isotretinoin and other drug use, malnutrition, other systemic illness, and advanced age. Physicians should reassure the patient about the nature of these changes and avoid unnecessary diagnostic workup.

Self-assessment test
1. Nail changes have been described with all the following conditions, except:
A. Heavy-metal poisoning
B. Malnutrition
C. Advanced age
D. Neuropathy

2. All these statements about drug-induced nail changes are true, except:
A. The changes usually reverse within a few months after stopping therapy
B. Melanonychia is more common in light-skinned than dark-skinned individuals
C. Leukonychia striata is less common than melanonychia in patients receiving chemotherapy
D. Melanonychia is the most common type of chromonychia

3. Which drug is least likely to cause Beau?s lines?
A. Methotrexate
B. Bleomycin
C. Paclitaxel
D. Vincristine

4. Which nail abnormality is most typical of arsenic toxicity?
A. Dystrophy
B. Blue discoloration
C. Beau?s lines
D. Mees? lines

5. Which of these conditions is most likely to be caused by isotretinoin therapy?
A. Whitened nail beds
B. Streaks
C. Onycholysis
D. Transverse melanonychia

(Answers at end of reference list)

References
1. Cohen PR, Scher RK. Geriatric nail disorders: diagnosis and treatment. J Am Acad Dermatol. 1992; 26:521-531.

2. Piraccini BM, Iorizzo M, Antonucci A, et al. Drug-induced nail abnormalities. Expert Opin Drug Saf. 2004;3 :57-65.

3. Trojan A, Borelli S. Adverse chemotherapy effects on skin and mucous membranes [in German]. Schweiz Rundsch Med Prax. 2002; 91: 1078-1087.

4. Unamuno P, Fernandez-Lopez E, Santos C. Leukonychia due to cytostatic agents. Clin Exp Dermatol. 1992; 17: 273-274.

5. Vassallo C, Brazzelli V, Ardigo M, et al. Nail changes in onco-hematologic patients. Haematologica. 2001; 86:334-336.

6. Chapman S, Cohen PR. Transverse leukonychia in patients receiving cancer chemotherapy. South Med J. 1997; 90:395-398.

7. Modesto dos Santos V, Sugai TA, Cezar BF, et al. Transverse leukonychia: a case report. West Afr J Med. 2005; 24:181-182.

8. Ben-Dayan D, Mittelman M, Floru S, et al. Transverse nail ridgings (Beau?s lines) induced by chemotherapy. Acta Haematol. 1994; 91:89-90.

9. Gul U, Kilic A. Muehrcke?s lines on nails after cyclophosphamide/ adriamycin/fluorouracil. Ann Pharmacother. 2004; 38: 1089-1090.

10. Chiewchanvit S, Noppakun K, Kanchanarattanakorn K. Mucocutaneous complications of chemotherapy in 74 patients from Maharaj Nakorn Chiang Mai Hospital. J Med Assoc Thai. 2004; 87: 508-514.

11. Minisini AM, Tosti A, Sobrero AF, et al. Taxane-induced nail changes: incidence, clinical presentation and outcome. Ann Oncol. 2003; 14:333-337.

12. Spazzapan S, Crivellari D, Lombardi D, et al. Nail toxicity related to weekly taxanes: an important issue requiring a change in common toxicity criteria grading? J Clin Oncol. 2002; 20:4404-4405.

13. Kuroi K, Bando H, Saji S, et al. Protracted administration of weekly docetaxel in metastatic breast cancer. Oncol Rep. 2003; 10:1479-1484.

14. Borecky DJ, Stephenson JJ, Keeling JH, et al. Idarubicin-induced pigmentary changes of the nails. Cutis. 1997; 59:203-204.

15. Naumann R, Wozel G. Transverse leukonychia following che?mother?apy in a patient with Hodgkin?s disease. Eur J Dermatol. 2000; 10:392-394.

16. Uede K, Furukawa F. Skin manifestations in acute arsenic poisoning from the Wakayama curry-poisoning incident. Br J Dermatol. 2003; 149:757-762.

17. Herrero F, Fernandez E, Gomez J, et al. Thallium poisoning presenting with abdominal colic, paresthesia, and irritability. J Toxicol Clin Toxicol. 1995; 33:261-264.

18. Onder M, Oztas MO, Oztas P. Isotretinoin-induced nail fragility and onycholysis. J Dermatolog Treat. 2001; 12: 115-116.

19. Abrams CK, Siram SM, Galsim C, et al. Selenium deficiency in long-term total parenteral nutrition. Nutr Clin Pract. 1992; 7:175-178.

20. Carmel R. Hair and fingernail changes in acquired and congenital pernicious anemia. Arch Intern Med. 1985; 145: 484-485.

21. Derrick EK, Price ML. Primary systemic amyloid with nail dystrophy. J R Soc Med. 1995; 88:290-291.

22. Mancuso G, Fanti PA, Berdondini RM. Nail changes as the only skin abnormality in myeloma-associated systemic amyloidosis. Br J Dermatol. 1997;137:471-472.

Answers: 1. D; 2. B; 3. A; 4. D; 5. C.



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