Serpentine supravenous hyperpigmentation related to carboplatin and vinorelbine chemotherapy: A case report

Fatma Tuncez Akyurek1, Nihal Sari1, Ceyhan Ugurluoglu2, Gulcan Saylam Kurtipek1

Abstract

Serpentine supravenous hyperpigmentation (SSH) is a unique type of chemotherapyassociated drug eruption, characterized by hyperpigmentation along the superficial venous network. Histopathology reveals an increase in melanin production without destruction of basal cells of the epidermis or dermal inflammatory infiltrate. Herein, we describe a patient who developed SSH after repeated intravenous infusions with carboplatin and vinorelbine; two medications that have been uncommonly reported in association with SSH previously.

KEYWORDS
carboplatin, chemotherapeutic agent, serpentine supravenous hyperpigmentation

1 | INTRODUCTION

Hyperpigmentation is an established cutaneous adverse effect of chemotherapeutic agents (Reyes-Habito, 2014). Serpentine supravenous hyperpigmentation (SSH) is a novel and specific type of cutaneous pigmented drug eruption caused by intravenous injection or infusion of some chemotherapeutic agents (Jamalpur, 2017; Payne, 2006). It is a rare complication of chemotherapy, clinically characterized by linear or serpentine streaks of hyperpigmentation following the traces of veins through which the antineoplastic agent has been infused or injected. As the clinical presentation is unique, it can easily be distinguished from other types of drug-induced pigmentation (Roach, 2015). The most commonly reported offender medication for SSH in medical literature is 5-flourouracil monotherapy. However, other antineoplastic agents including alkylating agents, antibiotics, antimicrotubules, and proteasome inhibitors or a combination of these agents have also been reported as culprits (Geddes, 2010). In our case, carboplatin and vinorelbine were held responsible for SSH; two medications that have rarely been associated with SSH.

2 | CASE REPORT

A 52-year-old male patient undergoing chemotherapy with carboplatin and vinorelbine for non-small cell lung cancer was admitted to our outpatient clinic with complaints of redness, pain, and exuding wounds on the hands and arms. Approximately 2 weeks after the first course of chemotherapy, the patient had developed painful erythematous lesions beginning from the infusion site and spreading to the right arm. This initial presentation has been interpreted as drug extravasation. Topical treatment of this condition led to regression in erythema; however, the pigmentation remained. Two days after the second course of chemotherapy, painful erythematous lesions developed on the dorsal aspect of the left hand, extending from the infusion site to the left forearm. Dermatologic examination revealed tender erythematous and bullous lesions in a linear and serpentine pattern of distribution conforming to superficial venous network, over the dorsum of the left hand and left arm (Figures 1 and 2). There was no evidence of lymphadenopathy, superficial venous thrombosis, thrombophlebitis, or extravasation injury in the axillary region. A skin biopsy sample obtained on the fifth day following the second infusion showed loss of superficial epidermis, perivascular and dermal lymphocytic infiltration, focal edema, and scant extravasated erythrocytes (Figure 3). Topical steroids, boric acid dressings, and oral nonsteroidal anti-inflammatory therapy led to amelioration of erythematous and bullous lesions within a few days, at site of which linear hyperpigmented tracts remained corresponding to the veins of left forearm (Figure 4).

3 | DISCUSSION

Erythematous or hyperpigmented linear eruptions following trauma to superficial veins at the injection site have been reported with various chemotherapeutic agents. The terms “persistent supravenous erythematous eruption” (PSEE), “persistent supravenous hyperpigmented eruption” (PSHE), and “serpentine supravenous hyperpigmentation” (SSH) have been used to define such drug eruptions (Aydogan, 2005; Payne, 2006). PSEE is characterized by erythematous streaks or red-violet-colored papules and plaques in a linear or serpentine pattern following the superficial venous network near the infusion site (Aydogan, 2005; Chen, 2005; Ghosh, 2011; Spencer, 1984). It is most commonly seen over the forearm (Geddes, 2010). Lesions develop within 24 hr to 15 days after intravenous cytotoxic drug infusion and spontaneously transform into residual hyperpigmented bands overlying the venous network within 1–3 weeks; this phase of the eruption is reminiscent of PSHE/SSH (Aydogan, 2005; Koehn, 1982; Payne, 2006). Unlike superficial venous thrombosis or thrombophlebitis, the veins involved in PSEE or PSHE/SSH remain patent (Chan, 2010; Ghosh, 2011). The eruption may resolve within 1 to few months after termination of chemotherapy, although persistent eruptions have also been reported (Aydogan, 2005; Chan, 2010; Payne, 2006). After repeated intravenous exposure to the responsible drug, the eruption may recur or hyperpigmentation may increase in intensity (Aydogan, 2005; Chen, 2005; Fine, 1986; Koehn, 1982; Marcoux, 2000;
Spencer, 1984). In our case, the reaction developed after both the first and second courses of carboplatin and vinorelbine chemotherapy, starting as PSEE and progressing into PSHE/SSH after a few days.
Although the histological features of PSEE and PSHE/SSH are not diagnostic, biopsy in PSEE reveals isolated necrotic keratinocytes at all levels of the epidermis, vacuolar change of basal epithelium, mild edema of the underlying papillary dermis, and perivascular infiltrate in the papillary dermis (Aydogan, 2005). It has been reported that spongiosis and occasional dyskeratotic cells might have been in the epidermis (Spencer, 1984). Given this histopathological appearance, some authors have described PSEE as an erythema multiforme-like drug reaction. In contrast, PSHE/SSH displays diffuse basilar melanin pigmentation, marked basilar dendritic melanocytes, occasional necrotic keratinocytes, scant melanophages in the papillary dermis, and slight perivascular lymphocytic infiltrates (Aydogan, 2005; Ghosh, 2011; Jain, 2005; Rao, 2010).
Thus, clinically and histologically PSEE is distinguished from PSHE/SSH by the presence of a painful or pruritic erythematous inflammatory phase, vacuolar change, destruction of basal cells, necrotic keratinocytes, and perivascular inflammatory infiltrate in the former. In contrast, PSHE/SSH is characterized by an asymptomatic pigmented rash, with a histological portrait of increased dendritic melanocytes, increased melanin granules, and lack of basal cell destruction or prominent inflammatory infiltrate (Aydogan, 2005; Cecchi, 1994; Ghosh, 2011; Jain, 2005; Rao, 2010). However, PSEE lesions become hyperpigmented by time and eventually take the look of PSHE/SSH clinically (Aydogan, 2005). We believe that the distinction between PSHE and PSHE/SSH is blurred and that the latter represents the abortive (or invisible subclinical) phase of the former.
SSH has a gender predilection as it is nine times more frequently reported in men than in women. The age range varies between 7 and 85 years, with a mean of 46 years (Geddes, 2010). SSH was initially described by Hrushesky in 1975 as a rare side effect of intravenous 5-fluorouracil administration (Hrushesky, 1976). Thereafter, other agents have also been implicated as a cause of this eruption (Ghosh, 2011; Payne, 2006; Rao, 2010). The list of medications reported in association with PSEE, PSHE/SSH encompasses 5-fluorouracil, docetaxel, paclitaxel, fotemustine, bromodeoxyuridine, vinorelbine, vinblastine, vincristine, nitrogen mustard, cyclophosphamide, dactinomycin, doxorubicin, daunorubicin, 6-mercaptopurine, bleomycin, dacarbazine, and bortezomib (Ghosh, 2011; Jamalpur, 2017; Payne, 2006; Rao, 2010). To our knowledge, there have been three cases vinorelbineinduced SSH (Cecchi, 1994; Marongiu, 2009; Roach, 2015) and no report of carboplatin-associated SSH in the literature. Our case represents the fourth case of vinorelbine-associated SSH and first case of carboplatin-associated SSH.
The mechanism of this peculiar drug-induced supravenous pigmentation pattern is obscure. Theories involve direct toxic effect of the medication on the vascular endothelium that enhances loss of vascular integrity and increased vascular permeability, possible extravasation/leakage of the medication from traumatized vein(s), and its direct toxic and/or stimulating effects over the surrounding neighboring epidermal melanocytes (Chan, 2010; Lang, 2002; Payne, 2006; Rao, 2010; Susser, 1999). In fact, most of the offender medications have been linked to significant extravasation injuries previously (Chen, 2005; Payne, 2006). Inadequate venous washing may be responsible for the injury to vascular endothelium (Aydogan, 2005). Adequate venous washing has been reported to prevent the occurrence of SSH. Along with termination of the offender medication, pentoxifylline has been recommended as a potential hemorheologic therapeutic option (Aydogan, 2005; Chen, 2005).
Parallel to an increase in the frequency of malignancies and emergence of new chemotherapeutic agents, dermatologists will more frequently encounter SSH and other chemotherapy-induced cutaneous adverse effects in clinical daily practice. Being aware of rare and novel cutaneous chemotherapy-associated reactions will enable physicians to guide management and treatment of affected patients accordingly.

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