Case Report: Non-infectious causes of palmoplantar rashes, what to consider

Background: Palm and sole skin eruptions have a broad differential diagnosis. It is particularly important to recognize common causes as well as their association with certain chemotherapy regimens such as Capecitabine. Case report: A 79-year-old woman presented with a painful rash on her hands and feet for 1 week. She had metastatic colon cancer and was in her third week of treatment with capecitabine. Her diagnosis was a medication side-effect from chemotherapy. Capecitabine was stopped and she had some clinical improvement over the next two days. She was discharged with oncology follow up for resumption of Capecitabine at a lower dose with improvement in her rash 3 weeks later.  Discussion: Skin rashes are a commonly encountered complaint in patients in the inpatient and outpatient setting. It is important to maintain a broad differential diagnosis in those with rashes of the palmoplantar surfaces of the hands and feet. Recognizing skin changes as a possible manifestation of underlying malignancy or a medication side-effect is key in appropriate diagnosis and treatment.

Most likely causes include Type IV hypersensitivity reactions (i.e.contact dermatitis), tinea pedis/manuum, psoriasis, and dyshidrotic dermatitis.These rashes may also be associated with underlying malignancies, especially gastrointestinal malignancies or can be associated with a medication side-effect 1 .Palmoplantar erythrodysesthesia (PPE), also known as hand-foot syndrome is a toxic, cutaneous side effect of well-associated chemotherapeutic agents, especially capecitabine [2][3][4] .The pathophysiology of this condition is not well understood and is an active area of investigation.It is important to recognize this side effect early in patients treated with oral capecitabine chemotherapy and to differentiate it from similar presentations in other disease entities.We present a case of a woman on chemotherapy for metastatic colon cancer with a palmoplantar rash.

Case report
A 79-year-old Hispanic woman presented with a one-week history of painful rash on her palms and soles.She reported no recent viral illness, travel, previous rashes, joint pains, new lotion, soap or fabric use.She had metastatic colon cancer previously treated with radiation and hemicolectomy three years prior.She currently completed her second week of Capecitabine therapy (1,250mg/m2 twice a day).She had no other contributory medical history or family history and was on no other medications.She describes never having a similar rash in the past.
On physical exam, she was afebrile, normotensive and appeared chronically ill.Her palms and soles were tender to touch, erythematous, and diffusely edematous with desquamation over the fingertips and toes (Figure 1 and Figure 2).Biochemical testing including complete metabolic panel and complete blood count were normal.Given her recently administered chemotherapy, it was suspected that the patients' palmoplantar rash was a result of a medication side-effect from Capecitabine.Other less likely diagnoses were contact dermatitis, tinea pedia/mannum, or dyshidrotic dermatitis.
After Capecitabine was stopped, she had mild clinical improvement over the next two days.She was discharged with resumption of Capecitabine at a lower dose (565 mg/m2 twice daily) and had complete clinical resolution of her rash 3 week later.

Discussion
Palmoplantar skin eruption carries a varied differential diagnosis.
Other palmoplantar rashes such as palmoplantar keratoderma (PPK), Acanthosis Nigricans (AN), Tripe palm, and Acquired Ichthyosis are also associated with underlying malignancies 5,6 .PPK presents with a yellow, wax-like hyperkeratosis of the palms and soles.AN, seen in patients with insulin resistance, presents as palmoplantar plaques which can be a sign of internal gastric cancer 6 .Tripe palm, also associated with gastric and lung malignancies, presents with wrinkled velvety hyperkeratosis of the palmoplantar surfaces 7 .Lastly, acquired ichthyosis is a symmetric scaling of the skin, associated with Hodgkins lymphoma 8 .
Since our patient had a temporal relationship between initiation of a new medication and her presentation, it was likely related, if not the cause of her palmoplantar rash.Chemotherapy, such as Capecitabine, is an important cause of palmoplantar skin eruption known as palmoplantar erythrodysesthesia (PPE).It is characterized by pain, swelling and desquamation, which can progress to ulceration and blistering (Figure 1 and Figure 2).In total, 7%  of patients treated with Capecitabine may experience PPE.
Other commonly encountered chemotherapy regimens may also cause PPE, such as Cytarabine, Fluorouracil, and Doxorubicin.
Treatments include either withdrawal of the chemotherapy or dose reduction, and supportive measures.In our patient's case, we were limited by not being able to completely stop chemotherapy given her limited therapeutic options; however resuming treatment at a lower dose helped to resolve her symptoms as well as provide a longer life-expectancy.
Common diagnoses aside, medication side-effect and malignancy should be considered in the differential diagnosis of palmoplantar skin eruption to guide appropriate therapy.

Consent
Written informed consent was obtained from the patient for the publication of the patient's clinical details and accompanying images.
There are other diagnoses to be considered in patients with these clinical findings.Only some of them are mentioned by the authors.For the readers a table with differential diagnoses and typical clinical and anamnestic criteria would have been helpful to differentiate between these diagnoses.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
No competing interests were disclosed.

Competing Interests:
Referee Expertise: Pediatric dermatologist, dermatologist I have read this submission.I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Mohamed Badawy Abdel-Naser Department of Dermatology and Venereology, Ain Shams University Hospital, Cairo, Egypt
The case report is well written.
The title is not addressing the case.Perhaps it can be reformulated to directly refer to the case.
The statement "however resuming treatment at a lower dose helped to resolve her symptoms as well as provide a longer life-expectancy" -how does reduction of the dose provide longer life-expectancy?
The provided figures, particularly Figure 2, are not clear.
Was any local treatment given to the patient?

Is the case presented with sufficient detail to be useful for other practitioners? Yes
No competing interests were disclosed.

Competing Interests:
I have read this submission.I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.The title could have been better -"Non-infectious causes of palmoplantar rashes, what to consider" would have been more apt in a case where there was diagnostic confusion based on history and/or examination.In this case, the history of malignancy and the ongoing chemotherapy was forthcoming.Emphasizing upon the fact that one MUST investigate for concurrent malignancy and chemotherapy, to consider non-infectious cause of the hand and foot syndrome (HFS) in a patient who is presenting with the classical clinical features of HFS and history of capecitabine, the most 2.

7.
who is presenting with the classical clinical features of HFS and history of capecitabine, the most common chemotherapeutic agent responsible for this condition.
Although, despite a strong evidence (history of malignancy and capecitabine) of the etiology of palmo-plantar erythrodysesthesia or HFS, the authors mention that they were considering other less likely diagnoses such as contact dermatitis, dyshidrotic eczema and tinea pedis/manuum.But no confirmatory investigations were done to rule them out.A 10% KOH smear and a punch biopsy should have been taken if these conditions were still being suspected.
Ideally, the authors should have mentioned about the state of the nails of the patient also, which often become dystrophic alongwith HFS.
It would have been better if the authors had also graded the patient's HFS; in view of the three well-established grading systems in place (WHO, NCI, and one system proposed by Nikolaou et al. especially for darker skin types) that have also been documented to guide regarding the therapeutic approach.Similarly, it would have been better if the patient's quality of life (QoL) affected by HFS was quantified using the simple HFS-14 scale.Nikolaou et al have demonstrated that HFS-14 scale may identify differences in QoL impairment between patients with HFS of same clinical grade and may serve as a valuable tool for anticancer treatment management and assessment of clinical efficacy of treatments used for this condition.
The authors should have at least made a mention of an important differential of HFS, i.e.HFS reaction (HFSR) that predominantly involves the pressure-prone areas of the soles and typically arises as a reaction to multiple kinase inhibitors (MKI).
Since the HFS was not quantified, nor the patient's morbidity due to pain (limitation of instrumental vs self-care activities) has been mentioned, based upon the relatively scarce data on physical examination, the patient seems to qualify for NCI grade 2 HFS.The approach to management in grade 2 has been recommended to stop the chemotherapy for a short duration till the condition improves to grade 1 or 0 (which was done in the current case) followed by resumption at lower doses.However, there are many practical measures and simple drugs/topical applications which if followed could have expedited the improvement such as avoidance of mechanical stress, use of cold compresses, generous moisturization with a urea-containing cream, and potent topical corticosteroids for a short duration.In fact prophylactic oral pyridoxine and celecoxib (COX-2 inhibitor) have also been suggested for a patient with NCI grade 2 HFS.
It is true that in this particular patient, as per the authors' description, uneventful remission occurred within 2-3 weeks of 2-day cessation followed by resumption at low doses of capecitabine, the report would have given out a more wholesome message to the readers if the treatment modalities other than the stoppage of the chemotherapeutic agent were at least mentioned.The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias You can publish traditional articles, null/negative results, case reports, data notes and more The peer review process is transparent and collaborative Your article is indexed in PubMed after passing peer review Dedicated customer support at every stage For pre-submission enquiries, contact research@f1000.com

1 ©Introduction
2018 Advani R and Arad D. This is an open access article distributed under the terms of the , Copyright:Creative Commons Attribution Licence which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The author(s) declared that no grants were involved in supporting this work.Palmoplantar skin eruption is a commonly encountered diagnosis in the inpatient and outpatient setting.

References 1 .
Nikolaou V, Syrigos K, Saif MW: Incidence and implications of chemotherapy related hand-foot syndrome.Full Text Is the background of the case's history and progression described in sufficient detail?Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Partly Is the case presented with sufficient detail to be useful for other practitioners?Partly No competing interests were disclosed.Competing Interests: Referee Expertise: Systemic dermatology, dermoscopy, pigmentary disorders I have read this submission.I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.