COVID-19 Hepatic Prodromal Syndrome in Patient with Non-Clear Cell Metastatic Renal Cell Carcinoma: A Case Report

Giovanni Lo Re^1*, Paolo Doretto², Massimiliano Balbi³ and Sandro Sulfaro^4
*Correspondence: Giovanni Lo Re, Department of Medical Oncology and Immune-Related Tumors, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Gallini 2 Aviano, (PN), 33081, Italy, Tel: 0039434399788, Email:

Keywords

Renal carcinoma • COVID-19 • Interleukin-2 • Immune homeostasis • Liver injury

Introduction

After one year from the first case of COVID-19 reported in Wuhan, the capital of Hubei (China), on December 2019, on April 9th 2021 global cases and deaths are 133.146.550 and 2.888.530 respectively. We are currently going through the third pandemic wave and from COVID-19 vaccination campaign 669.248.795 vaccine doses are administered. Excluding the majority of cases presenting a mild SARS-CoV-2 infection, moderate and severe forms occur in 10%-20% of cases, symptomatic mainly following up into pneumonia which causes hypoxia and requires hospitalization. Severe forms are linked to hyperinflammation and mainly result in acute respiratory distress syndrome (ARDS). It can be complicated by Disseminated Intravascular Coagulation (DIC) phenomena and septic shock, which require hospitalization in an intensive care unit, with a poor prognosis in about 2% of cases [1-3].

However from other organ injury, liver involvement is frequent in patients who are COVID-19 positive. Liver injury (LI) is mostly often mild or moderate, whereas severe grade is present on among the 6.4% of patients, which is predictive of unfavorable disease course [4,5]. The frequent hepatic injury is related to the presence of ACE2 receptors, functional host receptor for SARS-CoV-2, especially in 60% of cholangiocytes whereas it has a minimal extent in hepatocytes and it is absent in Kuppfer cell [6]. In addition to hepatic toxicity linked to the drug administration for COVID-19 [7,8]. Varying degrees of hepatic involvement may present a higher rate of serum elevations of alanine aminotransferse (ALT). Mild liver involvement occurs in more than one-third of infected patients who can show elevated ALT or aspartate aminotransferase (AST), abnormal prothrombin time and low albumin level [9-11]. These serologic abnormalities are more frequent in COVID-19 positive patients than in negative patient ones [12,13]. Furthermore in positive patients, especially in those who have undergone auto transplantation or with primary liver cancer, their grade is related to the disease outcome, risk of complications, clinical worsening and the need for hospitalization in an intensive care unit and intubation [14]. Furthermore, a correlation between LI, use of drugs and its p possible negative impact on COVID-19 was found [15,16].

From the anatomo-pathological point of view, in the context of multiorgan involvement, LI is characterized by the presence of thrombi and neutrophilic plugs in the advanced stage of the disease, an expression of hyper-inflammation linked to IL-6 [17]. In the cancer patient, elevation of hepatic function indices can mainly be an expression of drug-related toxicity or hepatic progression. If these occurrences are excluded, this picture could be defined as idiopathic. Another explanation could be the prodromal value of the clinical picture of a subsequent pathological manifestation of COVID-19. The purpose of this paper is to describe the therapeutic approach in a heavily pretreated patient with metastatic kidney cancer and to discuss the possible role of chemo-immunotherapy in warding off COVID-19 positivity after an intermediate phase of hepatic injury.

Case Description

Clinical case

A Caucasian 59-year-old male patient with previous duodenal ulcer, diverticulosis of the colon and sclerotic heart disease on past medical history, was recognized as having locally advanced neoplasia of the right kidney with atrial cavity thrombosis, pulmonary embolism and lung metastases. After renal biopsy, the diagnosis of clear and oxyphilic renal cell carcinoma with nuclear grade 4 according to Fuhrman classification was made. Its immunophenotypic profile was: CK7⁺ (very rare elements), racemase⁺, CD117^-, CAIX⁺ focal, EMA⁺, CD10⁺, Vimentina-, RCC⁺ focal, CEA m⁺ CEA m focal, A-Meltri-. From, June 2014 the patient underwent a neoadjuvant therapy with Sunitinib 50 mg/ day for 28 days and repeated on day 42nd. After three cycles of therapy, as far as the size was concerned, the increase in size of large solid lesion to right kidney (about 19 × 17 × 16 cm) although with uneven density due to the presence of solid and large hypodense-necrotic colliquated component and bleeding suspect regarding peripheral mass in the perirenal space in correspondence of doubtful infiltration of ipsilateral psoas muscle was detected. Inferior vena cava, resulted unchanged, markedly ectasic (maximum caliber of about 55 mm) and occupied by thrombotic material, which extends into the thoracic tract of superior vena cava, with endocardiac involvement. There was an improvement of thromboembolic picture both in left renal vein and in the branch for the right lower pulmonary lobe. Bilateral lung nodules (up to about 13 mm) and hypervascular lesion to 2, 6 and 7 segments (S) of 8-18 mm of probable angiomatous appearance were stable.

Thereafter, he underwent a right nephrectomy with caval-atrial thrombectomy in extra-corporeal circulation and the pathological diagnosis was papillary variant of clear cell carcinoma pT3c pN0 according to WHO. Post-operatively treatment with Sunitinib was resumed for one cycle with stabilization. After PD to lungs and bone of left ischial tuberosity, recurrence of vena cava thrombosis and post-surgical outcome picture improvement, from December 2014 treatment with Axitinib 5 mg twice a day was then administered with disease control (DC). However on July 2015 bone scintigraphy showed areas of hypercaptation to lower right acetabular and ischio-pubic branch, and to lesser trochanter and the intertrochanteric region of left femur. This was confirmed by skeletal X-Ray, which showed a large osteolytic lesion of about 7 cm to left greater trochanter with extension to proximal shaft of the femur, and presence of reparative callus to right ischio-pubic branch, outcomes of doubtful pathological fracture. Radiotherapy 1300 cGy/2 fractions was performed and Axitinib was continued behind disease progression until December 2015 lacking of more effective alternative therapies and waiting for expanded access program with new agent anti-PD-1. After CT scan detection of liver PD on S1 (13 mm), S4 (15 mm), S5 (15 mm) e S6 (6 mm) and stabilization on lung nodal lesions and on extension of caval thrombosis of 7 cm × 3,5 cm, third line therapy with Nivolumab as compassionate use was delivered from December 2015 and performed until June 2016. Patient demonstrated good tolerance to therapy, obtaining stabilization to lung and nodal lesions and size reduction of liver metastases.

After PD on caval thrombosis which projects to atrial cavity, on liver mainly of two hypodense in S7, partially confluent, of 4.5 × 5 cm × 4,5 cm diameter and of hepatic hypodensity to S2 of about 2 cm, pulmonary thromboembolism recurrence, and stabilization on other sites of disease, Sorafenib 400 mg twice a day was administered from June 2016 to December 2017. During Sorafenib therapy an improvement of lung thromboembolism, low size reduction of liver metastases, and a stabilization of cavo-atrial thrombosis and lung lesions was detected. Radiotherapy (880 cGy/1 fr and 1000 cGy/2 fr) on right and left femur respectively stabilized bone metastatic lesions. From October 2017 Zoledronic acid 4 mg/3 months was administered for 4 times only for the onset of osteonecrosis of the jaw and was treated with sequestrectomy. After subsequent lung PD due to the appearance of 9 mm nodule in paraesophageal of right lower lobe, of two lymph nodes of 12 × 11 mm in left axillar, liver PD for increased S7 (30 mm vs. 17 mm) and progression of solid component of proximal meta-epiphyseal of the left femur (46 mm vs. 37 mm), he was treated with radiotherapy 1200 cGy/2 fr and Cabozantinib 60 mg/day from February 2018. After eight months, on October 2018 the patient reported pathological fracture of the subtrochanteric left femur and he underwent a surgery reduction and synthesis with PFN-A long intramedullary nail. Cabozantinib was administered until September 2019 for 19 cycles with a fair general DC. On September 2019 PD was detected due to the replacement of cavitated lesions in the right lung with areas of parenchymal consolidation (largest in apical segment of the upper lobe of 24 × 6 mm). Furthermore liver PD to S7 (40 mm diameter), increase of two hypodense oval retroperitoneal masses of about 22 × 16 mm, new appearance of soft tissue nodules to trunk of about 2 cm maximum diameter, bone progression on right ischio-pubic branch (50 × 34), on left proximal epiphysis of femur and stabilization in other sites, femoral re-irradiation (800 cGy/1 fr) and Everolimus 10 mg/day was administered from January 2020 to September 2020 with symptoms stabilization and moderate reduction in size of the nodules in the soft tissue of the trunk.

Subsequently, in light of the progression of predominantly pulmonary, hepatic and subcutaneous disease, after proven negativity of the nasopharyngeal swab for COVID-19, he started therapy with intravenous Cyclophosphamide 300 mg/m2, Fluorouracil 500 mg/m² day 1 and low doses Interleukin (IL)-2 4.5 MUI subcutaneously day 3-6 and 17-20 every 4 weeks. During therapy he presented flu-like syndrome which regressed promptly after discontinuation of treatment. Following the onset of dyspnea, he went to the emergency room, where COVID-19 negativity was confirmed, and he was hospitalized for investigations and supportive care. Chest CT scan performed in suspicion of disease progression demonstrated a reduction in size of cavitated metastatic lung lesion and appearance of small new ones (Figures 1 and 2).

After antibiotic and steroid therapy with clinical improvement, the patient was discharged. At a subsequent control visit, he complained asthenia, anorexia, pain in the right shoulder and on biochemistry serum elevation of ALT, AST, LDH, alkaline phosphatase, bilirubin and INR were highlighted (Figures 3 and 4). After persistence of the symptoms, appearance of acute retention of urine and worsening of pain in the right shoulder, he was hospitalized again after proved negativity of the nasopharyngeal swab for COVID-19. During hospitalization he experienced tachycardia, hypotension by haemorrhagic anemia due to rectorrhagia. Biohumoral tests shown persistence of INR lengthening and of cholestatic hepatitis picture and reduction level of albumin (Figures 3 and 4).

From a hematological point of view, following the immunophenotype trend during single cycle of chemo-immunotherapy, the initial increase in the CD3⁺, CD4⁺, CD8⁺ and Treg cells count is highlighted with a marked reduction of B lymphocytes (Figures 5-7). This is followed by evidence of absolute monocytosis, eosinophilia and lymphocyte activation and normalization of T and B lymphocyte counts. After a few days it is followed by progressive decrease mostly in Tregs, CD3⁺, CD4⁺ and CD8⁺ cells count and activation of neutrophilic granulocytes which ends with the positivity for COVID-19. Furthermore, increase of N/L ratio, decrease of P/L ratio and increase of PCR levels were observed (Figures 8-10). Despite discontinuation of cumarol therapy, plasma administration and blood transfusion, no clinical improvement was obtained. The patient died and the nasopharyngeal swab was positive for COVID-19.

Conclusion

It is worth noting how the immunophenotype trend during the single course of chemo-immunotherapy, with an initial increase in the CD3⁺, CD4⁺, CD8⁺ and Treg cell counts, is followed by lymphocyte activation and how the hyperinflammation follows the subsequent decrease mainly of Tregs, CD3⁺, CD4⁺ and CD8⁺ cell counts. In conclusion, this prodromal hepatic picture, above quoted, could be an expression of the negative feedback due to the increase of regulatory T lymphocytes, stimulated by IL-2, on hyper-inflammation linked to hyper-cytokinemia with attempt to control and counter viral infection and resulting in the delaying of the disease course culminating with final worsening until COVID-19 positivity. This is a hypothesis generating a further study aiming to be proved, prospectively, on an adequate cohort of cancer patient with the support of the immunophenotype, cytokine and metabolomic profile.

Acknowledgments

We warmly thank Dr. Federica G. Ravizza for editing. Finally, we thank the doctors and nurses who supported us in this study.

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