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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 1  |  Page : 24-28

Pigmentary adverse effects of chemotherapeutic agents


Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication4-Jul-2019

Correspondence Address:
Dr. Shekhar Neema
AFMC, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/Pigmentinternational.Pigmentinternational_

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  Abstract 


Introduction: Skin and mucosa are most susceptible to the adverse effects of chemotherapeutic agents due to rapid rate of proliferation. A wide array of these adverse effects has been reported in patients undergoing chemotherapy. Although mostly of cosmetic significance, few of these side effects may require alteration or suspension of therapy and reduce the likelihood of therapy completion. This study was undertaken to know the spectrum of skin pigmentary issues seen in these patients. Material and Methods: A total of 153 patients on chemotherapy for various malignancies from oncology department of the hospital were screened for cutaneous adverse effects over a period of 3 months. Relevant details and chemotherapy protocol followed were assessed. Cutaneous examination was done in daylight and photographs were taken. The data was analyzed at the end of 3 months. Results: Ninety-one (59.4%) patients had cutaneous adverse effects due to chemotherapeutic agents. Colorectal carcinoma was most common malignancy seen in 27 (29.6%) patients. Hand–foot hyperpigmentation was most common adverse effect seen in 67 (73.6%) patients followed by supravenous hyperpigmentation in 14 (15.3%), oral hyperpigmentation in four (4.3%), and flagellate hyperpigmentation and melisma-like pigmentation in three (3.2%). Capecitabine was most common drug resulting in hand–foot hyperpigmentation in 29 (43.2%) patients whereas docetaxel resulted in supravenous hyperpigmentation in five (35.4%) patients. Flagellate hyperpigmentation was seen with bleomycin and oral pigmentation exclusively noticed with capecitabine. Conclusion: Cutaneous adverse effects of chemotherapy are common but rarely reported. It is important to understand the entire spectrum of these side effects and allay the anxiety associated with them.

Keywords: Capecitabine, chemotherapeutic agents, flagellate hyperpigmentation, hand–foot syndrome


How to cite this article:
Saraswat N, Neema S, Sengar K. Pigmentary adverse effects of chemotherapeutic agents. Pigment Int 2019;6:24-8

How to cite this URL:
Saraswat N, Neema S, Sengar K. Pigmentary adverse effects of chemotherapeutic agents. Pigment Int [serial online] 2019 [cited 2019 Oct 19];6:24-8. Available from: http://www.pigmentinternational.com/text.asp?2019/6/1/24/262042




  Introduction Top


Chemotherapy has revolutionized the management of carcinoma all over the world and increased the longevity of cancer patients. As the use of these life-saving drugs has increased, the incidence of both systemic and cutaneous adverse effects because of these agents have also tremendously increased.[1] Common adverse effects reported with chemotherapeutic agents are anagen effluvium, hand–foot syndrome (HFS), extravasation injuries, papulopustular eruptions, and xerosis.[2] A wide variety of these adverse effects are known to have a negative impact on quality of life and may result in interruption or discontinuation of therapy.[3] The aim of this study is to find the spectrum of skin pigmentary changes along with their frequency of association with chemotherapeutic agents.


  Materials and Methods Top


This study was conducted at a tertiary care hospital in Western India over a period of 3 months from July 2018 to October 2018 in the Department of Oncology. All the patients with malignancies on chemotherapy with adverse effects due to chemotherapeutic agents were screened in the Department of Oncology. A total of 153 consecutive patients were screened out of which 91 (59.4%) had pigmentary adverse effects. Only the pigmentary adverse effects were taken into consideration whereas other common nonpigmentary adverse effects such as hair loss, xerosis, papulopustular eruptions, patients on concurrent radiotherapy, or denied permission to be part of the study were excluded. The patients who had only nail pigmentation without any hyperpigmentation of palms and soles were also excluded. Written informed consent was taken from patients or their families and they were explained regarding the nature of the study. Permission of Institutional Ethics Committee was also obtained.

In all the patients, protocol of chemotherapy was recorded. A detailed systemic and cutaneous examination was done in natural light after exposing the patient. The data was analyzed at the end of 3 months.


  Results Top


Out of 153 patients studied, 91 (59.4%) had pigmentary complaints. Males comprised 52 (57.1%) whereas females were 39 (42.8%). The age ranged from 18 to 68 years. Most common malignancy seen in these patients was colorectal carcinoma in 27 (29.6%). The spectrum of malignancies noted is detailed in [Table 1]. Palms and soles hyperpigmentation [[Figure 1],[Figure 2],[Figure 3]] were the most common pigmentary changes seen in 67 (73.6%) patients. Hyperpigmentation of palms and soles was diffuse involving both dorsum of the hands and palms bilaterally in all the patients and was seen between day 3 and 2 weeks of initiation of chemotherapy. Supravenous hyperpigmentation (SVH) was seen in 14 (15.3%) patients, clinically presenting as linear streaks of hyperpigmentation along the veins, which started as linear erythematous lines along veins seen between day 2 and 1 month of chemotherapy infusion [[Figure 4] and [Figure 5]]. Oral pigmentation [[Figure 6]] was seen in four (4.3%) patients between day 10 and 30 of intake of capecitabine and presented as brownish to black macules on tongue, buccal and labial mucosae, and palate. Three (3.2%) patients who had flagellate hyperpigmentation [[Figure 7]] presented with linear hyperpigmented streaks in criss-cross and whip-like pattern across trunk in all the patients and were seen between day 3 and 1 month of bleomycin administration. Another three (3.2%) patients developed melisma-like hyperpigmentation [[Figure 8] and [Figure 9]] between second and third month of imatinib therapy. All the three patients with melasma presented with hyperpigmented macules over bilateral cheeks and forehead in one patient. None of the patient had extrafacial melisma-like patches. The chemotherapeutic agents associated with these pigmentary changes is shown in [Table 2].
Table 1 Distribution of malignancies

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Figure 1 Capecitabine-induced palms and soles hyperpigmentation.

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Figure 2 Palm hyperpigmentation with paclitaxel and carboplatin.

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Figure 3 Palmar hyperpigmentation with gemcitabine and oxaliplatin.

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Figure 4 Supravenous hyperpigmentation induced by docetaxel.

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Figure 5 Supravenous hyperpigmentation by 5-fluorouracil.

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Figure 6 Capecitabine-induced oral hyperpigmentation.

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Figure 7 Flagellate hyperpigmentation induced by bleomycin.

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Figure 8 Imatinib-induced melasma-like hyperpigmentation.

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Figure 9 Melasma-like pigmentation in a patient due to imatinib.

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Table 2 Chemotherapeutic agents associated with pigmentary adverse effec

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  Discussion Top


Chemotherapeutic agents have a narrow therapeutic index and are known to be toxic for rapidly proliferating cells of skin, hairs, and nails resulting a wide array of adverse effects. Unlike older agents, newer molecules have specific target in the pathogenesis of malignancies resulting in better side-effect profile.[4],[5] Pigmentary adverse effects of chemotherapeutic agents are often ignored as they are not life threatening and rarely require any alteration in the course of the chemotherapy.

In the present study, palms and soles hyperpigmentation was most common pigmentary adverse effect noted in 67 (73.6%) patients on chemotherapy. It has been reported earlier that patients with HFS can have hyperpigmentation of hands and feet and it is hyperpigmentation rather than erythema considered to be an initial manifestation of HFS; this is considered to be Grade 1 HFS by many authors.[6],[7],[8] Of 67 cases with hyperpigmentation, 26 (38.8%) had complaints of associated dysesthesia or paresthesia that further support the proposition that palms and soles hyperpigmentation might be the initial presentation of HFS. Capecitabine was most common drug associated with the hyperpigmentation of palms and soles in 29 (43.2%) patients. The possible cause of this can be excess collection and secretion of drug by eccrine glands that are concentrated on palms and soles.[9] The fact that palms and soles hyperpigmentation was seen with drugs like doxorubicin and cyclophosphamide, paclitaxel and carboplatin, gemcitabine and oxaliplatin, and a combination of cyclophosphamide/doxorubicin/paclitaxel that are associated with HFS also emphasize the fact that this hyperpigmentation is a part of HFS.[10],[11] The incidence and severity of HFS is highly varied among chemotherapeutic agents with capecitabine amounting to upto 64% cases. The present study also had capecitabine as most common cause of HFS, which is consistent with this finding.[12]

Other pigmentary adverse effect seen in the present study were supravenous hyperpigmentation, flagellate hyperpigmentation, and oral pigmentation that has been reported earlier also with chemotherapeutic agents.[13],[14],[15]

SVH was seen in 14 (15.3%) patients on chemotherapy. Five (35.7%) developed SVH due to docetaxel therapy that has been reported earlier also.[13] SVH is a rare sequel of infusion of chemotherapeutic agents like cyclophosphamide, actinomycin, doxorubicin, vinca alkaloids, taxanes, and bortezomib that is in alignment with the findings of the present study.[16] Although the exact mechanism of this peculiar pigmentation is not known, it is postulated to be the result of loss of integrity of vascular endothelium by these cytotoxic drugs.[17] Another theory proposed for this pigmentation is the accumulation of drug within the skin overlying the blood vessels that result in localized or generalized hypersensitivity reaction and hyperpigmentation.[18],[19]

Bleomycin-induced flagellate hyperpigmentation is a rare entity seen as diffuse, patchy, or linear pigmentation predominantly on the trunk or proximal extremities. The term flagellate has been used because of the typical shape of presentation derived from the Latin word “flagellum.”[20] It is reported in 8% to 66% patients receiving bleomycin.[21],[22] All three cases who developed flagellate hyperpigmentation were on bleomycin in the present study, which is again consistent with the earlier findings.

All four patients who developed oral hyperpigmentation were on capecitabine. All these patients had isolated oral involvement without palms and soles hyperpigmentation. The combination of oral mucosa involvement and palmar–plantar hyperpigmentation has been reported in literature, although it is quite rare.[22],[23],[24] Although it is known that oral pigmentation is an entity, whether it is a part of HFS or separate from it is widely debated. Neither the grading nor the etiopathogenesis of HFS can explain the cause of oral hyperpigmentation in these patients. Clinicians have to be aware about this entity as it may unnecessarily alarm the patients or the treating physician.

We also had three (3.2%) patients who developed melasma-like hyperpigmentation while on imatinib therapy, which has been reported with imatinib earlier also.[25] Although the etiopathogenesis is elusive, it is thought to be the result of drug-melanin metabolite in the skin. Another widely debated mechanism of this pigmentation is drug-induced cytotoxic response to epidermal “neo-antigen” and the presence of KIT (proto-oncogene receptor tyrosine kinase) mutation along with its interaction with another receptor.[26],[27] Pigmentation associated with imatinib can involve palatal mucosa, nails, teeth, hair, and gums as observed by various studies.[28],[29],[30]


  Conclusion Top


Pigmentary adverse effects are common but underreported with chemotherapeutic agents. Although mostly these are of cosmetic significance, at times these are challenging because of associated patient anxiety and lack of awareness of the treating oncologists. It is absolutely prudent for the dermatologists and the treating physician to be aware that these side effects alter the possibility of treatment completion if not addressed adequately and in time. A thorough counseling of the patient and their families about these side effects would be of immense help in continuing the therapy with these life-saving drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2]



 

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