Leukocytoclastic Vasculitis as an Initial Indicator of Prostate Cancer: A Case Report

Introduction

Paraneoplastic syndromes are estimated to affect up to 8% of patients with cancer [1]. Malignancies associated with paraneoplastic syndromes are small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies [1]. The underlying mechanisms of these conditions involve release of hormones from tumors, peptides, cytokines, or immune cross-reactivity between malignant and healthy tissues. Thus, successful treatment of the underlying tumor often improves the condition [2].

Cutaneous manifestations are relatively common among the various clinical presentations of paraneoplastic syndromes. Approximately 1% of patients exhibit skin manifestations as the initial diagnostic indication of a neoplastic disease [3].

Cutaneous vasculitis is a heterogeneous group of rheumatological disorders characterized by inflammation of blood vessels in the skin, which leads to vascular damage. This condition can present with palpable purpura, erythematous papules, nodules, ulcers, and vesicles. It can be associated with malignancies and can manifest as a paraneoplastic syndrome, suggesting a potential link between the skin manifestations and underlying cancer [2].

The etiopathogenesis of cutaneous vasculitis involves immune complex deposition, direct infection of the vessel wall, or autoantibody-mediated processes. Diagnosis typically relies on clinical evaluation, histopathological examination through skin biopsy, and laboratory investigations to identify potential systemic involvement and underlying causes. Management of cutaneous vasculitis requires addressing the primary cause, if identified, and may involve immunosuppressive therapies, corticosteroids, and supportive care [3].

Leukocytoclastic vasculitis (LCV) is a prevalent type of small-vessel vasculitis, which can manifest in different forms, affecting both the skin and internal organs [4]. Diagnosis relies on histopathological examination, showing neutrophil infiltration with fibrinoid necrosis and leukocytoclasia [5].

There is limited evidence in the literature of leukocytoclastic vasculitis (LCV) associated with malignancies. We present a clinical case diagnosed at our institution to emphasize the importance of differential diagnosis in paraneoplastic syndromes, and the need for prompt and accurate identification of the etiology of LCV as a paraneoplastic syndrome.

Case Report

A 60-year-old White man who was a heavy smoker (with a history of 40 packs/year), with a medical history of hypertension, mitral insufficiency, tachycardia, dyslipidemia and peripheral arterial disease, was referred to the urology service after having dysuria and persistent nycturia for 4 months. Prostate-specific antigen (PSA) level revealed 69 ng/ml. Following a thorough urological evaluation, including a clinical examination and direct rectal examination, pelvic magnetic resonance imaging (MRI) was recommended. The scan revealed a tumoral mass in the prostate gland, evaluated as Prostate Imaging-Reporting and Data System (PI-RADS) 5.

Subsequent prostatic biopsy was performed using transrectal ultrasound-guided biopsy (TRUS-biopsy). All 12 fragments were consistent with adenocarcinoma, revealing a Gleason score of 8(4+4) and evidence of perineural invasion. After completing staging through chest computed tomography (CT) scans and osseous scintigraphy, metastatic prostate adenocarcinoma stage IVB (cT3b cN1 and multiple lymphatic metastases M1LYM) was confirmed in October 2023. Following the investigations, the patient presented in our clinic to start oncological treatment.

Upon clinical examination in our service, 2 non-specific cutaneous lesions were identified on the upper right arm and left hip (Figure 1) The cutaneous lesions appeared 3 weeks prior to investigating the malignancy, with a gradual increase in dimensions. At the time he presented in our institution, the lesions were stable (no dimensional growth, no other lesions identified). He denied taking any medication, use of topical creams, or excessive sun exposure, and said that the lesions were neither pruritic nor painful. A dermatology consult was indicated.

One month after presenting in the oncology service, he started volumetric modulated arc therapy- external beam radiation therapy (VMAT-EBRT) up to a total dose of 54 Gray (Gy) in target volume prostate, seminal vesicles, and lymph nodes, followed by a boost to a total dose of 76 Gy in target volume prostate, together with hormonotherapy with the gonadotropin-releasing hormone (Gn-Rh) analog Goserelin 3.6 mg, 1 subcutaneous administration every 28 days. Given the clinical aspect of the cutaneous lesions of unidentified etiology, a multidisciplinary team decided to start him on Gn-Rh analog only, until dermatology evaluation.

During clinical examination in the first days of radiation and hormonal treatment, the cutaneous lesions rapidly grew and slowly became necrotic and ulcerated (Figure 1). He was referred to a dermatologist and rheumatologist for a complete evaluation.

The patient related no systemic symptoms such as fever, myalgias, arthralgias, or swelling of the joints. Complete blood counts, liver function, and renal function tests, along with urinalysis, performed at baseline, revealed a non-specific inflammatory syndrome. A more extensive workup was pursued to rule out lupus erythematosus and Sjogren syndrome. The immunology profile was negative for rheumatoid factor, anti-cyclic citrullinated peptides (anti-CCP) antibody, serum complement, anti-neutrophil cytoplasmic antibodies (ANCA) antibodies, antinuclear antibodies (ANA) antibodies, and anticardiolipin antibodies, and there was no evidence of cryoglobulinemia.

Viral hepatitis panel and human immunodeficiency viruses (HIV) testing was also negative, ruling out a diagnosis of a possible infectious trigger of the lesions. Although the clinical appearances of the cutaneous lesions seemed like polyarteritis nodosa disease, 2 biopsies from 2 separate lesions were taken for an accurate diagnosis. The histopathological results suggested leukocytoclastic vasculitis with secondary extension of the ulceration (Figure 2). Considering the recent diagnosis of prostate cancer, the early onset of the cutaneous lesions, no specific symptoms described, and no evidence of rheumatological affliction or infection, the patient was diagnosed with cutaneous leukocytoclastic vasculitis of paraneoplastic etiology.

The indicated treatment consisted in topical corticosteroids for the affected skin and systemic corticoid therapy with methylprednisolone (Medrol) 16 mg twice daily for 30 days. Prophylactic topic antibiotic therapy with neomycin ointment was also initiated, considering the ulceration. A delay of the hormonal treatment was suggested. The lesions improved through continuing the radiotherapy course and the corticosteroid treatment (Figure 1) Hormonal therapy was withheld for 2 months, and the patient completed 5 weeks of radiation therapy.

Radiotherapy was very well tolerated and no immediate toxicities were identified. Two weeks after completing the VMAT-EBRT and concluding the corticosteroid treatment for the leukocytoclastic vasculitis lesions, the patient returned for a follow-up appointment and to continue hormonal therapy.

He presented in February 2024 with a good performance status, no urological symptoms, a PSA value of 2 ng/ml, and a good clinical response of the dermatological lesions. No ulceration was identified on the lesions, as both of them gradually decreased in size; however, the cutaneous lesions did not disappear completely. The patient was cleared by the rheumatologist to resume the hormonal treatment. While continuing the treatment for 4 months, he had stable residual dermatological lesions and maintained an excellent performance status and treatment adherence. Clinical workup findings in May 2024 revealed evidence of clinical partial response confirmed through whole-body CT scan and through biochemical response (PSA value decreased to 0.51 ng/ml). However, the skin lesions did not disappear completely, with residual pigmentation.

Discussion

Paraneoplastic syndromes involve a range of localized or diffuse pathological symptoms that can develop in individuals with cancer, even those with hidden forms. Skin-related manifestations of paraneoplastic syndromes often stem from vascular irregularities. Patients with solid tumors can experience migratory thrombophlebitis and increased blood clotting, while hematological cancers can trigger vasculitis and erythromyalgia [3]. In the clinical case presented here, the patient exhibited atypical lesions without any symptoms related to the paraneoplastic syndrome, which made it challenging to assess and accurately diagnose the condition.

Leukocytoclastic vasculitis (LCV) has rarely been reported in the literature as a paraneoplastic syndrome associated with hormonal and radiotherapy treatment, especially in solid malignancies such as prostate cancer. However, there is scant evidence of prostatic cancer associated with paraneoplastic syndromes, which highlights the rarity of the case. Some other cases of paraneo-plastic syndromes such as eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) have been presented in the literature, mostly in patients with prostate cancer, cervical cancer, endometrial cancer, and breast cancer [3].

In leukocytoclastic vasculitis, skin lesions frequently are the earliest sign of the underlying disease. A skin biopsy, along with direct immunofluorescence, is the main diagnostic approach [2], and this method was also used to diagnose our patient, emphasizing its critical role in identifying the condition.

The characteristic histopathological features, including fibrinoid necrosis of the vessel wall, red blood cell extravasation, and the presence of perivascular polymorphonuclear leukocytes with fragmentation and nuclear dust formation (leukocytoclasis) [7], were also observed in our case, underscoring its consistency with leukocytoclastic vasculitis.

Determining the primary cause of this disease can be challenging, as other factors such as radiotherapy, hormonal therapy, drug reactions, or viral infections can also play a role. Generally, before confirming the diagnosis, it is essential to rule out any systemic involvement and consider other potential causes of vasculitis, such as drug reactions, infections, or rheumatological conditions. For this reason, extensive testing was conducted in our case to eliminate any other secondary diagnoses.

There is little evidence in the literature regarding LCV diagnosed in the context of a paraneoplastic syndrome, especially pertaining to prostate cancer and scant evidence of gonadotropin-releasing hormone (Gn-Rh) analog as a primary trigger for LCV. A case of LCV was described by Turk et al [8] in a patient undergoing hormonal treatment with a Gn-Rh analog – leuproleide acetate – for endometriosis, but there is no evidence in the literature regarding prostate cancer cases that developed LCV under hormonal treatment with goserelin.

In 2010, Gnanaraj et al [9] reported the first case of serum sickness associated with use of a Gn-RH synthetic analog (leuprolide) as the primary hormonal therapy for prostate cancer. In our patient, however, the condition was confined to the skin, and a different Gn-RH analog was used for prostate cancer treatment.

Considering the limited clinical manifestation of the disease (skin lesions), corticosteroid therapy was initiated in accordance with the general treatment recommendations for LCV [2] and adjusted based on the severity of the condition, with a gradual tapering regimen implemented to prevent rebound effects. The episode resolved over 4 weeks, resulting in residual pigmentation, and there has been no recurrence since completing the corticosteroid treatment as per dermatologist recommendation.

According to the literature, leukocytoclastic vasculitis (LCV) is generally a self-limiting condition with high overall survival rates (99% at 1 year and 83% at 3 years) and a relapse rate of under 20% [2]. Whether our patient will experience a recurrence remains to be determined.

Conclusions

Based on the clinical and pathological features of this case, we can infer that in this case the etiology of LCV was paraneoplastic. The literature does not describe LCV associated with prostate cancer as a paraneoplastic syndrome, nor does it mention Gn-RH analog treatment triggering LCV in prostate cancer cases. Our case underscores the importance of thorough diagnostic evaluation and multidisciplinary collaboration to provide tailored treatment for each patient. Despite the limited number of LCV cases reported in the literature, clinicians should remain vigilant to ensure prompt and accurate diagnosis, particularly in the context of solid tumors.