An unforeseen reaction: Pyogenic granuloma induced by drug therapy

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Pyogenic granuloma (PG) refers to a common, acquired, benign vascular tumor that arises in the skin and mucous membranes. PG can arise spontaneously, in sites of injury, or within capillary malformations. Histologically, PG is composed of capillaries and venules with plump endothelial cells separated into lobules by fibro-myxoid stroma. The development can be classified into (i) cellular phase, (ii) capillary phase or vascular phase, and (iii) involutionary phase.¹

A 45-year-old female presented with hyperkeratotic plaques and scaling on her palms and soles for a decade, diagnosed as palmoplantar psoriasis. Despite intermittent treatment, her condition saw minimal improvement, and her joints and nails remained unaffected. We initiated treatment with acitretin 25 mg once daily and scheduled a follow-up after a month. Surprisingly, she returned within 3 weeks, reporting painful, shiny pink tumors on her ring finger and great toes, which bled with minor trauma. Examination revealed raspberry-like growths around the ring finger’s lateral nail fold [Figure 1] and tender swellings with ingrowing nails on the great toes, clinically suggestive of PG [Figure 2]. On histopathology, lobules of capillary sized vessels and dense mix infiltrate were revealed [Figure 3]. Notably, she had no history of such lesions before starting acitretin, leading us to suspect the drug as the culprit. Consequently, we discontinued acitretin and transitioned her to methotrexate. Remarkably, within 2 weeks, the PGs completely resolved [Figures 1 and 2].

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Figure 1:

(a) A 45-year-old female presented with excessive periungual granulation tissue with tender swelling present on the middle fingers. (b) Regression of PG post acitretin withdrawal.

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Figure 2:

(a) A 45-year-old female presented with ingrowing nails on bilateral great toes. (b) Regression of PG post acitretin withdrawal.

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Figure 3:

Histopathology (hematoxyline and eosin, 10x) showing multiple lobules of capillary sized vessels (red stars) with dense mixed inflammatory infiltrate (green arrows).

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Another, a 57-year-old female known case of breast carcinoma receiving capecitabine since last 14 days, reported to us with a red painful lesion with a tendency to bleed easily over the right index finger and a severe burning sensation over both the feet since last 7 days [Figure 4a]. On clinical grounds, a diagnosis of PG was made. In view of the above complaints, capecitabine was discontinued, and chemical cauterization was done with a silver nitrate stick in two applications 3 days apart, resulting in resolution of the lesion within 1 week [Figure 4b].

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Figure 4:

(a) A 57-year-old female presented with excessive granulation tissue over the right index finger. (b) Regression of PG post acitretin withdrawal and chemical cauterization with silver nitrate stick.

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PG has been associated with certain medications such as oral contraceptives, retinoids, gefitinib, capecitabine, and afatinib.² Retinoids cause release of vascular endothelial growth (VEGF), which activates Signal Transducer and Activator of Transcription-3 (STAT-3) in endothelial cells. The overexpression of the transcription factors STAT-3 and phosphorylated-activated transcription factor-2 have been implicated in the formation of PG.³

It is also postulated that the action of retinoids leads to increased skin fragility of the periungual tissue, increasing the likelihood that local trauma or infection will induce the formation of granulation tissue.⁴

Capecitabine is a novel orally administered fluoropyrimidine carbamate derivative of 5-fluorouracil. The underlying mechanism for the development of capecitabine-induced PG is poorly understood. Several studies observed an increase in VEGF and upregulation of decorin, an extracellular proteoglycan regulating the angiogenesis of capillary endothelial cells.⁵ As a cytotoxic agent, capecitabine can cause local tissue damage, which may trigger a reparative process that leads to excessive granulation tissue formation. This reparative hyperplasia can manifest as PG.

A plausible explanation for our case of acitretin- and capecitabine-induced PG could be the synergistic relationship between the increased risk of mechanical trauma (in our case, due to the location of PG on the hands, which might be considered more prone to injury than other body parts) and the proliferative actions of the above drugs, which can cause keratinocytes to detach from one another and become lodged in the nail folds.

Hence, it can be concluded that capecitabine and acitretin share a similar proangiogenic target or, alternatively, that they somehow favor nail trauma, resulting in the formation of PGs. The case suggests a synergistic effect between the increased fragility of skin (caused by both drugs) and the proliferative actions of acitretin and capecitabine. This combination may increase susceptibility to mechanical trauma, which can lead to PG formation, especially in vulnerable areas like the periungual tissue. This case highlights the importance of knowing drugs like acitretin and capecitabine can cause PG, particularly in patients with compromised skin or mucosal surfaces. Early identification can lead to prompt cessation of the offending drug and management of the lesions. Discontinuing the causative drug and utilizing local treatments like chemical cauterization or switching to an alternative medication can result in the complete resolution of PG, as demonstrated in both cases.