Patients on chemotherapy can often experience changes in the toenails and although some of these changes may be tolerable, others are more serious and require treatment. Accordingly, this author reveals how one can recognize common nail changes such as Beau’s lines and subungual abscesses, and provides a pertinent guide to prevention and treatment. Nail apparatus changes are an increasingly common adverse effect of multiple antineoplastic chemotherapeutic drugs. The type and severity of nail changes vary depending on the drug, dose, duration and frequency of treatment, the affected nail structure, and the environmental factors. Nail changes can affect all or some of both the fingernails and toenails. Taxanes, anthracyclines, epidermal growth factor receptor inhibitors and small molecule multikinase inhibitors are the chemotherapeutic drugs most commonly associated with nail changes.1-3 Nail changes are frequent. They reportedly occur in up to 44 percent of patients undergoing treatment with taxane drugs and 10 to 15 percent of patients undergoing treatment with epidermal growth factor receptor inhibitors.1,4,5 Authors have reported numerous chemotherapy-induced nail pathologies. These include nail color changes, Beau’s lines, Mees’ lines, growth reduction, onycholysis, onychodystrophy, Muehrcke’s lines, onychodermal bands, paronychia, subungual abscess and subungual hematoma.6 While some chemotherapy-induced nail changes are benign, others have significant morbidity. The National Cancer Institute’s Common Terminology Criteria for Adverse Events classifies two grades of nail changes.7 Grade 1 changes are mild and include pitting, ridging and or discoloration. Grade 2 changes are more severe and include nail bed pain and partial or complete nail loss.
What You Should Know About Nail And Nail Apparatus Pathologies Associated With ChemotherapyThe nail matrix epithelium is formed by highly proliferating cells that differentiate and keratinize to produce the nail plate. Numerous changes to both the nail plate and surrounding soft tissue structures can be adverse effects of chemotherapeutic drugs. Chemotherapy-induced nail pathology can involve nail color changes, changes in the surface of the nail plate, disruption of the bond between the nail plate and the underlying nail bed, and damage to soft tissue structures surrounding the nail. The nail matrix epithelium contains numerous melanocytes that are normally quiescent but can become activated by toxins, resulting in nail plate color changes. Researchers have reported multiple nail color changes following chemotherapy including dyschromia (alteration of nail color including yellow, brown, black, gray, white, red discoloration), melanonychia (dark nail pigmentation), hyperchromia (hyperpigmentation of the nail plate) and hypochromia (hypopigmentation of the nail plate).8 Chemotherapy-induced nail color changes can affect the entire nail plate or can occur as isolated or multiple bands. Mees’ lines, also known as leukonychia striata, are commonly visible following chemotherapeutic treatment. Mees’ lines present as white bands traversing the width of the nail.9 Mees’ lines exist in the nail plate and eventually grow out to the end of the nail. Muehrcke’s nails are also frequently visible following chemotherapy and present similarly with transverse white lines in the nail (leukonychia). In contrast to Mees’s lines, the color alteration in Muehrcke’s nails exists in the vascular nail bed and does not change position with nail growth. In addition to nail color changes, several alterations in the surface and structure of the nail plate have reportedly occurred following chemotherapy treatment. Structural nail plate changes result from the defective nail plate production caused by toxins damaging the nail matrix. Beau’s lines, which are deeply grooved transverse lines in the nail plate, are a common adverse effect of chemotherapeutic agents. Beau’s lines in theory result from a temporary arrest of cell division in the nail matrix.10,11 Nail plate thickening and crumbly nails have also reportedly occurred as adverse effects of chemotherapeutic agents.8,12 Several chemotherapeutic agents have adverse effects on the bond between the nail plate and nail bed. Onycholysis is a frequently reported chemotherapy-induced pathology involving the separation of the nail plate from the underlying nail bed. Onycholysis frequently leads to loss of a portion or all of the nail plate. Subungual hematoma and subungual abscess are also complications of chemotherapy that cause nail plate separation and potential loss of the nail plate. Onycholysis, subungual hematoma and subungual abscess can cause significant pain to the affected digits and create a portal for infection, which increases sepsis risk in immunocompromised patients undergoing chemotherapy treatment. Several chemotherapeutic drugs also frequently alter the skin and soft tissue structures surrounding the nail plate. Acute paronychia resulting from chemotherapeutic agents can be very painful and mimic ingrown nails. Severe cases of paronychias can lead to the development of pyogenic granulomas of the nail fold. Paronychia and pyogenic granuloma are reportedly relatively common adverse effects of many chemotherapeutic drugs.4
Current Insights On The Pathophysiology Of Chemotherapy-Induced Nail ChangesThe underlying etiologies of many chemotherapy-induced nail changes are unknown. Multiple mechanisms can affect the nail plate and nail apparatus including direct changes to both the nail plate and surrounding soft tissue structures, increased sensitivity to environmental factors, and secondary infection. Frequently, more than one pathologic process is present, leading to multiple changes in the nail apparatus. Direct nail apparatus changes. Chemotherapeutic treatments can cause several pathologic processes that directly affect both the nail plate and the surrounding soft tissue structures. Chemotherapy-induced structural nail plate changes hypothetically result from many factors, including defective nail plate production resulting from acute damage to the nail matrix, disruption of the nail plate secondary to a medication’s toxic effects on cellular maturation and direct toxicity to structures of and surrounding the nail apparatus.13 Nail color changes secondary to chemotherapeutic treatment theoretically result from toxin-induced activation of normally quiescent melanocytes in the nail matrix epithelium.8 Multiple chemotherapeutic drugs cause disruption of the bond between the nail plate and bed and resultant onycholysis. Disruption of the bond between the nail plate and bed is a theoretic result of two mechanisms: acute toxic damage to the nail bed and toxin-induced subungual edema.13 Toxic damage to the soft tissue structures surrounding the nail plate can result in paronychias with subsequent nail matrix exposure and damage.4 Splinter hemorrhages, subungual hematoma and hemorrhagic onycholysis result from chemotherapy-induced thrombocytopenia and vascular abnormalities.5 A case study by Wasner and colleagues suggests that peripheral nerve fibers play a role in the development of chemotherapy-induced nail abnormalities.14,15 In this case study, a patient undergoing docetaxel (Taxotere, Sanofi Aventis) treatment for advanced breast cancer had complete peripheral nerve palsy of the right arm due to tumor infiltration of the brachial plexus. During treatment, the patient developed docetaxel-induced onycholysis of all extremities with the exception of the paralytic hand. The authors postulated two mechanisms to account for the absence of nail changes in the paralytic extremity: release of neuropeptides by activation of nociceptive C-fibers as is present in cases of neurogenic inflammation, or release of prostaglandins by sympathetic postganglionic fibers. In accordance with the hypothesis that chemotherapy-induced onycholysis is an inflammatory process that is maintained by postganglionic sympathetic terminals and nociceptive c-fiber afferents, the authors of the case study treated the patient with a cyclooxygenase-2 inhibitor.14,15 The patient experienced improvement in nail alterations in the neurologically intact limbs. Dose and frequency of chemotherapy drug administration. For many drugs, there is a dose-specific effect related to chemotherapy-induced nail changes. Hussain and coworkers studied 91 patients receiving treatment with paclitaxel (Abraxane, Celgene).16 Patients receiving more than six weekly doses of paclitaxel developed onycholysis while patients who received fewer weekly treatments did not develop onycholysis. Further, Spazzan, Mourad and their respective colleagues report a higher incidence of adverse effects on the skin and nail apparatus with weekly versus every three weeks treatment with paclitaxel.17,18 Segaert and Van Cutsem additionally report a dose-dependent effect on the development of skin and nail changes following treatment with epidermal growth factor receptor inhibitors.4 Environmental factors affecting chemotherapy-induced nail changes. In addition to the direct toxic effects that chemotherapy drugs may have on the nail plate and surrounding soft tissues structures, researchers have shown that environmental factors have an effect on chemotherapy-induced nail changes.16 Authors have suggested that chemotherapeutic agents increase sensitivity of the nail apparatus to ultraviolet light. Hussain and colleagues found that onycholysis secondary to paclitaxel treatment for breast carcinoma increases by exposure of the hyponychium to sunlight.16 The researchers additionally found that protecting the nails from sunlight prevented nail loss in a large percentage of patients despite continued chemotherapy treatment. The hypothesis is that the hyponychium may be more sensitive to UV light following chemotherapy treatment and that UV light may induce nail changes by rupturing the bond between the nail plate and the hyponychium directly or by inhibiting cellular maturation in this area.16 In addition to increased sensitivity to UV light, the toxic effects of chemotherapeutic drugs can make nail plates thin, brittle and more prone to mechanical trauma. Secondary fungal and bacterial infections. Both bacterial and fungal infections may contribute to chemotherapy-induced nail changes. Researchers believe that nail plate abnormalities combined with immunosuppression may allow colonization of the nail apparatus and surrounding soft tissue structures.13 Several case reports have shown bacterial and fungal infections of the nail apparatus associated with chemotherapeutic treatment.5,16,19 Numerous additional case studies have shown chemotherapy-induced nail changes leading to secondary bacterial and fungal infections of the nail plate and surrounding soft tissue structures.4,16,18-21 For example, Mackay-Wiggan and coworkers report the case of a 70-year-old male who receivied long-term, low dose chemotherapy treatment with paclitaxel and carboplatin (Paraplatin, Bristol-Myers Squibb) for lung adenocarcinoma and developed onycholysis of both his fingernails and toenails.22 The patient developed purulent drainage from below the separated nail plates with cultures growing Staph aureus, beta-hemolytic Strep species and E. coli. Following treatment with oral antibiotics and resolution of the bacterial infection, the patient shed multiple nail plates. A Periodic Acid-Schiff (PAS) stain was positive for Candida fungal spores and fungal culture later grew Candida as well. The patient received ciclopirox (Loprox) and complete resolution of both fungal infection and chemotherapy-induced nail changes occurred one year following treatment. Segaert and Van Cutsem report the development of paronychia in 10 to 15 percent of patients treated with epidermal growth factor receptor inhibitors and a high incidence of secondary pyogenic granulomas and Staphylococcus aureus infections in many of these patients.4
A Guide To The Prevention Of Post-Chemo Nail ChangesSeveral modalities may prevent or lessen chemotherapy-induced nail changes. Physicians have used cryotherapy to prevent several adverse effects of chemotherapy including mucositis, alopecia and nail changes.23-25 The hypothesis is that cryotherapy causes local vasoconstriction, temporarily decreasing blood flow to the specific tissue and reducing the exposure to the drug and the associated adverse effects.24 Scotté and coworkers conducted two multicenter studies examining the effect of frozen gloves and frozen socks for the prevention of docetaxel-induced onycholysis and skin toxicity.26,27 The glove study showed an approximately 40 percent reduction in both Grade 1 and Grade 2 onycholysis of the fingernails while the frozen sock study showed a 21 percent reduction in Grade 1 and grade 2 onycholysis of the toenails. Researchers have recommended advising patients, especially those who are being treated with taxanes and anthracyclines, to use gloves, opaque tape, artificial nails or reflective sunscreens to avoid exposure of their nails to UV light due to the potential to develop onycholysis, dyschromia and other nail changes with these medications.16 Authors have suggested additional protective measures, including appropriate nail trimming, avoiding environmental irritants, antimicrobial treatment, and stopping or reducing the offending chemotherapeutic drug.23 Segaert and Van Cutsem report several measures that are recommended to lessen and treat the skin and nail changes that occur with epidermal growth factor receptor inhibitors.4 These include ensuring maximum hydration of the skin with bath oil instead of soap, tepid water and emollient cream; avoiding sun exposure; avoiding friction and pressure on the nail fold from shoe gear; and regular use of antiseptic soaks and antibiotic cream.
Managing Chemotherapy-Induced Nail ChangesChemotherapy-induced nail changes warrant treatment depending on their severity and impact on patient well-being and function. Patients may well tolerate nail changes such as discoloration or irregularity in the nail plate, and require no treatment other than monitoring and patient assurance. Other adverse effects, such as a subungual abscess in an immunocompromised patient, create a much more serious condition, necessitating rapid and aggressive treatment. Multiple case studies have shown that eliminating or suspending the causative chemotherapeutic agent for four to six months can resolve some, if not all, of the chemotherapy-induced nail changes.8,13,28 While not specifically studied, several modalities are reportedly effective for the management of several of the chemotherapy-induced nail and skin changes. Seagert and colleagues found a combination of drying paste containing antiseptic (chlorhexidine), an anti-yeast (nystatin) and, in severe cases, a topical corticosteroid, to be an effective treatment for paronychia and pyogenic granuloma resulting from epidermal growth factor receptor treatment.4 Additionally, silver nitrate application on a weekly basis is reportedly an effective treatment for chemotherapy-induced pyogenic granuloma.4 The previously discussed case study reported by Wasner and colleagues suggests that onycholysis is an inflammatory process.14,15 The fact that the authors found that treatment with a cyclooxygenase-2 inhibitor led to improvement in nail alterations supports this theory and suggests a potential role for anti-inflammatory medication in the treatment of some chemotherapy-induced nail pathologies.14,15 Cases of chemotherapy-induced subungual abscess require formal drainage with nail plate avulsion if purulence does not freely drain.21 If infection remains localized, one should initially use oral antibiotics empirically to treat both subungual abscess and paronychia with secondary bacterial infection, and then use tailored antibiotics pending culture and sensitivity results.5 Advanced infections may require hospitalization, IV antibiotic therapy and surgical drainage.21 Given the immunocompromised nature of patients undergoing chemotherapy, researchers recommend rapid and aggressive antibiotic treatment to prevent secondary sepsis.
In ConclusionWith the rapid development of new chemotherapeutic drugs and decreasing mortality with new treatment protocols, we can expect that more and more patients will present with chemotherapy-induced nail apparatus changes. It is important to have an understanding of these adverse effects as many can cause significant patient morbidity. Many of the chemotherapy-induced nail changes are mild and do not necessitate treatment other than patient assurance and monitoring. However, other chemotherapy-induced changes, such as subungual abscess, pose significant risk in these immunocompromised patients. Dr. Hoffman is in private practice in Boulder, Colo. References 1. Fenniche S, Hammami H, Badri T, Mokhtar I, Benmously R. Subungueal haemorrhages following docetaxel (taxotere) treatment. Curr Drug Saf. 2012; 7(3):247-249. 2. Choi JN. Chemotherapy-induced iatrogenic injury of the skin: new drugs and new concepts. Clin Dermatol. 2011; 29(6):587-601. 3. McLellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and sunitinib. Dermatol Ther. 2011; 24(4):396-400. 4. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005; 16(9): 1425-33. 5. Minisini AM, Tosti A, Sobrero AF, Mansutti M, Piraccini BM, Sacco C, Puglisi F. Taxane-induced nail changes: incidence, clinical presentation and outcome. Ann Oncology. 2002; 17(2):333-337. 6. Susser WS, Whitaker-Worth DL, Grant-Keis JM. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol. 1999; 40(3):367-98. 7. NCI, NIH, DHHS. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE). Version 3.0, DCTD. 2009. Available at http://ctep.cancer.gov/forms/CTCAEv3.pdf . Accessed October 30, 2013. 8. Ranawka RR. Patterns of chromonychia during chemotherapy in patients with skin type V and outcome after 1 year of follow-up. 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