Uromodulin as a radiographic mimicker of renal cell carcinoma recurrence after partial nephrectomy

Abstract

Tamm-Horsfall protein (THP) is the most abundant protein in urine, yet its function remains incompletely understood. It has been hypothesized that THP contributes to the maintenance of urinary homeostasis. We report a case of a 71-year-old male with a history of renal cell carcinoma treated with partial nephrectomy in 2017. He represented 8 years later with an enlarging, enhancing renal mass concerning for recurrence. A radical nephrectomy was performed and revealed a benign specimen with a positive PAS stain, consistent with THP. To our knowledge this is the first report of THP deposition in the renal parenchyma after partial nephrectomy.

1. Introduction

There are approximately 400,000 newly diagnosed cases of kidney cancer every year, the vast majority of which are clear cell renal cell carcinomas (RCC).¹ Management of localized renal masses include surveillance, ablation or surgery in the form of partial or radical nephrectomy. When treated, prognosis is generally excellent with a 5-year survival of greater than 90 %.² It is widely accepted that partial nephrectomy is an oncologic safe treatment option for smaller renal masses (i.e T1 and T2). Given the benefit of nephron sparing surgery, partial nephrectomy is being increasingly utilized for larger and more complex renal masses (i.e > T2 and >grade 2/4 Fuhrman). The risk of recurrence after partial nephrectomy in clinically localized masses is about 5 %.³ These typically present as enhancing masses during follow-up surveillance imaging. In this case, we present an enhancing renal lesion following partial nephrectomy suspicious for recurrence with a discordant benign final pathology.

2. Case presentation

A 71-year-old man was referred to our facility with chief complaint of recurrent left renal mass. The patient has a history of left inguinal hernia, psoriasis, nephrolithiasis, and psychiatric disorder. He also has a history of a 3.1 cm exophytic left lower pole renal mass that was incidentally found during a work-up for nephrolithiasis. He subsequently underwent an open left partial nephrectomy in 2017 at an outside hospital; final pathology pT3aNX Fuhrman grade 2/4 clear cell renal carcinoma with extension into renal sinus fat and without communication to the collecting system. He underwent negative surveillance until 2020 – the last surveillance CTAP without contrast in 2020 showed no masses concerning for recurrence with a wedge-shaped defect at the resection bed and findings consistent with typical granuloma formation. Unable to assess for enhancement due to lack of contrast in the study. He was then lost to follow-up. The patient then presented to our emergency room in 2024 with increasing pain and bulging of his left groin. He underwent a CT scan of the abdomen and pelvis with IV contrast that showed a moderate-sized inguinal hernia. There was also an incidental finding of a 3.3 cm exophytic and heterogeneously enhancing lesion in the lower pole concerning for recurrence (Fig. 1). This mass was clearly increased in size compared to the granuloma seen on the last surveillance scan in 2020. There was no evidence of metastatic disease in the chest. The patient did not have any new hematuria or flank pain. The patient subsequently underwent an CT-guided biopsy revealing acellular material, overall nondiagnostic. Further management options were discussed including repeat biopsy, surveillance, and radical nephrectomy. Given the initial pathology with renal sinus fat invasion and the patients normal kidney function, the patient opted to undergo robotic-assisted laparoscopic radical nephrectomy. The patient declined repeat partial nephrectomy given concern for perinephric fat invasion on cross-sectional imaging. The patient's operative and post-operative course were unremarkable. Gross examination revealed an encapsulated smooth-walled collection (6.4 cm) filled by dark brown waxy material (Fig. 2). There was no communication to the collecting system. Microscopic examination revealed a benign specimen with encapsulated glassy eosinophilic acellular material positive for PAS stain and negative for amyloid stain favoring Tamm-Horsfall (THP)/uromodulin protein (Fig. 3). Background renal tubules leading to the collection are dilated by the same material.⁴ The patient will be followed with cross-sectional imaging per the standard American Urologic Association surveillance protocol.

Fig. 1.

A) axial and B) sagittal CT AP with IV contrast images of 3.3 cm left lower pole enhancing mass concerning for renal cell carcinoma recurrence into perinephric fat after remote history of ipsilateral partial nephrectomy. Hounsfield unites ∼65.

Fig. 2.

Gross appearance of Uromodulin collection seen on the outer surface of the bisected kidney.

Fig. 3.

PAS stain with diastase treatment40x. Uromodulin collection is identified at the top of the page separated from kidney by a band of chronic inflammation.

Purple PAS stain highlights renal tubules clogged by Uromodulin Protein below.

3. Discussion

In this case, we describe a 71-year-old male who was incidentally noted to have an enhancing, enlarging renal mass 8 years after partial nephrectomy. The patient had no clinical signs of recurrent disease such as flank pain or hematuria but his initial pT3a disease did increase his risk for recurrence.³ Fortunately, his final pathology after radical nephrectomy was negative for malignancy. The final pathology was instead consistent with benign tissue with an accumulation of Tamm-Horsfall protein (THP).

THP or uromodulin is the most abundant protein in normal urine. THP is almost exclusively made in the thick ascending loop of henle (TAL). It is made in abundance and therefore its physiologic function has been extensively studied. Despite this, its clear biologic role is uncertain and researchers have proposed roles in many aspects of both cell homeostasis and immune function such as maintaining water impermeability in the nephron. Despite its rigorous study, the biologic function of THP is still incompletely understood. Studies of THP knockout mice have suggested that its presence in the TAL may be important for electrolyte transport and as a binding agent to prevent urinary tract infections and calcium crystals in nephrolithiasis. In humans, extremely rare mutations in THP exist and clinically manifest with tubulointerstitial disease with chronic kidney dysfunction, hypertension, and eventual renal failure.⁵

Due to its diverse functionality in urinary homeostasis, THP has been studied as a biomarker in various disease states. Because it is synthesized and secreted in the TAL, serum THP levels closely correlate with GFR and therefore are low in CKD or in acute disease states with acute kidney injury (AKI). Serum THP can theoretically be serially measured to monitor recovery after AKI. Similarly, a decreasing THP level in the context of chronic CKD could indicate progression of disease. Alternatively, serum THP can also be increased in other inflammatory states of the kidney. Due to its variability, the practicality of performing enzyme-linked immunoassays to measure serial THP to monitor disease states is clinically questionable.⁶ THP has also been historically studied in the context of RCC. The presence of THP in RCC has produced mixed results, with some studies finding strong THP staining⁷ while others have found no evidence of THP in renal tumor specimens.⁸ One large series that looked at 114 tumor specimens and found THP in only 31 neoplasms.⁹ There have been no contemporary studies investigating the presence of THP in RCC. It appears that there is no clear association between THP and RCC, as RCCs primarily form from the proximal convoluted tubule whereas THP is made and excreted in the TAL. It has been previously postulated that the distortion and compressive activity of RCCs may induce secretion of THP in the urine/serum but may not actually be related to the pathophysiology of the malignancy itself.⁸

While there appears to be no clear relationship between THP and RCC, THP has occasionally been found in some genitourinary tissues during the work-up of other pathology. In one study, THP was identified in ∼7 % of patients who underwent bladder biopsy or cystectomy (n = 247). Interestingly, they found THP in 60 % of cystectomy specimens (versus 3.9 % in bladder biopsy) with surrounding areas of cellular necrosis, inflammation, and fibrinous exudate.¹⁰ It has been hypothesized that THP is deposited in the bladder as a protective mechanism of the urothelium mucosa in response to inflammation.¹¹ Other case reports have found more rare deposits of THP in the peri-renal/peri-pelvic fat and even in the ureter causing obstruction.¹²,¹³ One case report by Higgins et al. described a non-traumatic hematoma with refractory gross hematuria that required nephrectomy and final pathology showing polyps of THP. This was similar to a historical case by Solez et al., 1978 that described THP deposition in cases of unilateral obstruction and gross hematuria.¹⁴,¹⁵ It has been hypothesized that urinary or venous obstruction in the kidney results in tubular rupture and spillage of THP into the renal parenchyma. In this report, it is possible that the index partial nephrectomy induced adjacent cellular injury (possibly increased with open technique) resulting in tubular rupture, spillage, and collection of THP. Similarly, it is presumable that inflammatory processes such as cancer or infection induce secretion of THP that are then observed in pathology specimens in the bladder, ureter, and other organs. This hypothesis requires further study and has not been studied in the literature.

In our report, we describe the first known THP deposit in the renal parenchyma with increasing extension into the perinephric fat after partial nephrectomy. In this case, the mass was enhancing and suspicious for recurrence particularly in the setting of high-risk initial pathology. Pre-operative discussion included surveillance, partial nephrectomy, and radical nephrectomy. In this case the patient was otherwise healthy with a normal GFR, therefore, he opted to proceed with radical nephrectomy. In cases with increased morbidity and/or chronic kidney disease, it is possible that MRI or repeat biopsy may be helpful to delineate malignancy vs a benign process.

While the biologic function of THP is still under investigation, THP is generally accepted as one mediator of urinary homeostasis. As described above, it has been seen to deposit in genitourinary organs after trauma or inflammation. In this case it is plausible that THP deposition occurred following the trauma of the partial nephrectomy and was slowly increasing in size over time.

The patient in this report gave permission to publish the clinical data described in this case.

CRediT authorship contribution statement

Kathryn E. McGonagle: Writing – review & editing, Writing – original draft. Vikram S. Lyall: Writing – review & editing, Writing – original draft, Validation, Supervision, Conceptualization. Cristina E. Taylor: Writing – review & editing, Formal analysis, Data curation, Conceptualization. Michael E. Rezaee: Writing – review & editing, Writing – original draft, Supervision, Investigation, Data curation, Conceptualization.