Treatment, further Work-up and Follow-up.
On admission, intravenous (IV) Ringer Lactate (1 L), IV Ceftriaxone (1 g), IV Acetaminophen (1 g/100 mL), and IV Ketorolac (30 mg/mL) were administered. Informed consent was obtained, and preoperative preparations that included negative viral markers (Hepatitis B surface antigen and Hepatitis C antibody), a normal chest x-ray, and blood grouping were done. Left radical nephrectomy via transabdominal approach was done. Postoperative recovery was satisfactory without any complications; appropriate pain, nausea, and pyrexia management were given in the form of IV Ketorolac (30 mg/mL), IV Acetaminophen (1 g/100 mL), IV Nalbuphine (20 mg/mL), and IV Metoclopramide (10 mg/2 mL).
The patient was discharged on the fifth postoperative day on oral medications, including Amoxicillin + Clavulanic acid (1 g) twice a day, Tramadol + Acetaminophen (37.5/325 mg) twice a day, and Acetaminophen (500 mg) as needed. Adequate counselling to the family about daily dressing change, the importance of compliance with medication, and follow-up was given. On a one-week follow-up, the staples were removed, and no complaints were reported. The patient was also referred to the oncology department for further management and follow-up.
Specimen findings included the left kidney measuring 13 x 11 x 7.0 cm, along with hilar vessels and easily detachable perirenal fat that were identified. A tan reddish-white tumour at the upper pole of the kidney measuring 7.5 cm in diameter was also appreciated. The specimen was sent for histopathology and immunohistochemical assay that proved the diagnosis of papillary RCC with a tumour causing microscopic capsular invasion without involving the perirenal fat, hilum, vein, and Gerota’s fascia. Histological type was papillary type two due to papillary architecture showing cells containing abundant eosinophilic granular cytoplasm. Histological grade two, according to the International Society of Urologic Pathologists (ISUP), as tumour cell’s nucleoli were conspicuous and clearly visible at 400x magnification. Pathological Tumour-Node-Metastasis (pTNM) Staging was pT2a as the tumour was limited to the kidney. On immunohistochemical assay, the tumour cells were negative for TFE3 (Transcription Factor Binding To IGHM Enhancer 3) and positive for CK7 (cytokeratin 7), AMACR (Alpha-methylacyl-CoA racemase), PAX8 (Paired-box gene 8), CKAE1/AE3 (cytokeratin AE1/AE3), and Vimentin.
Discussion.
Mancilla-Jiminez et al. initially identified papillary renal cell carcinoma as a separate subtype of renal cell carcinoma in 1976 [10]. Many studies have compared PRCC with non-PRCC in terms of pathological stages and five-year survival rate and reported that PRCC has lower pathological stages with better five-year survival rates [11-16], but some studies found the five-year survival rate to be as low as 50% and 61% [17, 18]. This difference in clinical behavior gave the concept of two distinct morphological subtypes of PRCC, type 1 and type 2 with type 2 having increased tendency of locally advanced disease and higher rates of metastasis [19, 20] and this is supported by the our case report as tumour had microsopic capsular invasion along with multiple suspicious looking pulmonary nodules and other similar case reports that presented a case of repetitive bladder carcinoma after one and half of years of  radical nephroureterectomy, done for type 2 PRCC of  left renal pelvic carcinoma [21] and spleeno-hepatic metastatic lesions were diagnosed after four months of left partial nephrectomy and right adrenalectomy for type 2 PRCC [22]. However, in this case, the metastatic lesions were identified on imaging at the time of diagnosis.
The genetic basis of the sporadic types of papillary renal-cell carcinoma is not well understood; hence, most of the information is derived from studying the inherited form of the disease. Hereditary papillary renal-cell carcinoma that increases the risk of type 1 PRCC is caused by germline mutations of the MET proto-oncogene, while type 2, which is related to hereditary leiomyomatosis and renal-cell cancer syndrome [9], is caused by germline mutations in the fumarate hydratase (FH) gene [23]. However, somatic mutations of the MET gene have been identified in 13 to 15% of non-hereditary cases as well [24, 25]. Similarly, somatic mutations were also found in the FH gene in six out of 10 specimens of leiomyomas [26] and a reported case of FH-deficient RCC, subtype chromophobe, post-hysterectomy for multiple leiomyomas with negative family history [27]. Negative family history was also present in our case. Apart from FH gene mutations, some less-known gene mutations have also been explored, such as increased expression of TopBP1-interacting checkpoint and replication regulator (TICRR), which not only plays a role in tumorigenesis but also has prognostic value [28]. Similarly, CDKN2A alteration was found in 25% of type 2 PRCC; mutations were also found in chromatin-modifying genes: SETD2, BAP1, and PBRM1 [29]. In a large cohort study that did tumour profiling of 169 PRCC specimens, these common alterations were identified in type 2: CDNK2A/B (18%), TERT (18%), NF2 (13%), and FH (13%) [30], so these findings suggest that type 2 tumours, especially sporadic ones, are more genetically complex. The immunohistochemical profile of most of the type 2 PRCC revealed positivity for CK7, AMACR, Vimentin, and Cytokeratin AE1/AE3 [31], and this finding was consistent with our case report.
Besides the risk factors linked to RCC, such as male sex, obesity, smoking, hypertension, and family history, PRCC has a special correlation with the different phases of renal failure [32, 33]. Preoperative chronic kidney disease stage and/or glomerular filtration rate have been found to positively correlate with the probability of papillary histology upon resection in retrospective data [34]. Additionally, PRCC is more common in haemodialysis patients with end-stage renal illness, which is believed to be caused by acquired renal cystic disease that subsequently develops malignant degeneration [35, 36]. Surgery is the mainstay of treatment for PRCC, like many other renal cancers, and the extent of surgery depends on the stage, grade, and location of cancer. Common surgical options are radical and partial nephrectomy. In radical nephrectomy, the whole kidney is removed along with surrounding tissues and regional lymph nodes, preferred in cases of locally advanced disease; hence, in our case, radical nephrectomy was the best option. While in partial nephrectomy or nephron-sparing surgery, only the area affected by the tumour is resected so that normal renal function is still maintained. It is a good option for small tumours without local spread or in cases where by birth there is a single kidney or the patient’s renal function is already compromised. Both surgeries can be performed as open or laparoscopic; the choice depends upon the surgeon’s expertise, the patient’s choice, affordability, and availability.
For advanced or metastatic PRCC, pharmacological options are considered. Since PRCC is a rare subtype of RCC, currently there are no specific medicines to treat it; hence, medicines that are approved for other common subtypes are used but have varying degrees of success. Pharmacological options are immunotherapy, targeted therapy, and monoclonal antibodies. Cabozantinib, crizotinib, and savolitinib as vascular endothelial growth factor (VEGF) inhibitors have been tested in clinical trials to treat advanced PRCC, but only cabozantinib proved effective in improving survival rate and is the only licensed medicine among them to treat PRCC [37]. Similarly, combination therapies in the form of savolitinib plus durvalumab and cabozantinib plus atezolizumab have also been tested with varying degrees of success but are only available in clinical trials [37]. Most kidney cancers are radio-resistant, but radiotherapy is helpful in controlling and alleviating the symptoms of advanced disease by shrinking large tumours and relieving pressure on nearby nerves and organs. Radio-surgery or stereotactic body radiotherapy (SBRT) or gamma knife surgery can also be used to treat distant small metastatic lesions of the lungs or liver [37].
Regardless of the type, cytogenetics, and possible risk factors, there is a significant need for public awareness, as renal cancers are often asymptomatic in their early stages, and there is an alarming rise in kidney cancer in young adults, as reported by 17 types of cancers that are prevalent in the young population. Kidney cancer is one of them, and the main culprits behind this rise are obesity [38]. Hence, the identification of risk factors is important for promoting healthy life choices like avoiding smoking and sedentary lifestyles. In case of familial risk, awareness regarding early screening will help in early detection and treatment thereby reducing mortality rates. Moreover, it also emphasises the need for improved imaging technology and its frequent use in high-risk profiles to promote early detection and hence improve patient outcomes.