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.