Keywords Bosniak - cystic disease - end-stage renal disease - pyelonephritis
Introduction
Multilocular cystic renal neoplasm of low malignant potential (MCNLMP) is a multiloculated
benign cystic lesion separated by a thin septum.[1 ] Incidence of MCNLMP ranges from 0.5 to 2.5% of all renal tumors and approximately
10% of all cystic tumors. This tumor was previously referred as multilocular cystic
renal cell carcinoma (RCC) as it shares a similar genetic profile and histopathological
features to that of clear cell renal cell carcinoma (ccRCC), but differs entirely
in its prognostic features. Till date no data of its metastasis has been reported
in English literature. Historically grouped under multilocular/multicystic RCC (World
Health Organization [WHO] 2004 classification), these lesions are now subclassified
as a distinct entity (WHO 2016 classification) due to their low malignant potential,
no incidence of metastasis, and having a favorable outcome.[2 ] Renal cysts are formed due to abnormal microtubules formation and primary cilia
destruction, owing to von Hippel-Lindau (VHL) germline mutations. These are known
to play a pivotal role in MCNLMP pathogenesis via cyst dependent pathway. The WHO
defines these cysts to be lined by a single layer of tumor cells with abundant clear
cytoplasm and small nucleoli (WHO/ ISUP grade 1 or 2) with absence of expansile growth.[1 ]
Chronic kidney disease and end-stage renal disease (ESRD) are frequently associated
with renal cystic diseases, including a wide spectrum of tumors with cystic changes.
However, only few resemble those in sporadic cases (ccRCC, chromophobe RCC), others
being unique to ESRD (acute cystic disease associated renal cell carcinoma [ACD-RCC],
clear cell papillary RCC [ccPRCC]).[3 ] Differentiation between tumors with cystic change and acquired cystic lesions are
difficult preoperatively by imaging. An enhanced computed tomography (CT) and magnetic
resonance imaging is helpful in evaluating the possibility of malignancy in cystic
renal masses on radiograph as per Bosniak classification.[4 ] We present a case of MCNLMP detected incidentally on histopathology in a background
of chronic pyelonephritis and ESRD. Even though the literature search showed occurrence
of acquired cystic disease of the kidney and RCC with ESRD[3 ]
[5 ] however, there have been only two previous case reports[6 ]
[7 ] documenting MCNLMP co-existing in a setting of chronic pyelonephritis and ESRD in
the literature. We, thus, like to add a third case report with these distinctive features.
Case Report
A 74-year-old male patient presented to the urology outpatient department with complaints
of right-side loin pain radiating to the back, with no association with nausea and
vomiting. There was no history of fever, hematuria, pyuria, or lithuria. No other
significant medical history was identified.
Hematological (hemoglobin: 12.6 g/dL, total leucocyte count: 4.55 × 1000/cumm, prothrombin
time: 9.8 seconds, international normalized ratio: 0.91) and biochemical parameters
(total bilirubin: 1.13 mg/dL, direct bilirubin: 0.21 mg/dL, serum glutamic-pyruvic
transaminase: 22 U/L, serum glutamic-oxaloacetic transaminase: 17 U/L, alkaline phosphatase:
102 U/L, creatinine: 1.37 mg/dL) were almost within the normal range. Urine routine
examination revealed calcium oxalate crystals with trace proteins. Urine culture grew
Enterococcus faecalis . Viral markers were nonreactive. Noncontrast computed tomography (NCCT) of the kidney,
ureter, bladder region showed right ureteric (7mm × 4.5mm) and renal calculi (2.7cm × 1.5cm)
with gross hydroureteronephrosis. No mass lesion was detected. Diethylenetriamine
pentaacetate (DTPA) scan of the right kidney showed 7% split function and 4.1 mL/min
glomerular filtration rate (GFR) suggesting impaired renal function; however, DTPA
scan of the left kidney was normal. A clinical working diagnosis of poorly functioning
kidney due to nephrolithiasis was made following which right open simple nephrectomy
was done under general-epidural anesthesia and the specimen was sent for histopathological
examination.
Right nephrectomy specimen measuring 9 × 6 × 4.5cm with attached ureter was received
in the department of pathology. The outer surface of lower pole of the kidney showed
multiple tiny surface cysts of varying sizes ranging from 0.5 to 1.0 cm in diameter.
Serial sections through the specimen revealed markedly dilated pelvicalyceal system
with loss of corticomedullary differentiation and dilated pelviureteric junction ([Fig. 1A ]). A cortical cyst was identified at the upper pole measuring 1 × 0.7 × 0.7 cm having
a multiloculated cut surface separated by thin fibrous septa containing gelatinous
material ([Fig. 1B ]). The attached ureter measured 7 cm in length and showed no gross abnormality.
Fig. 1 Gross photograph showing (A ) multiple dilated calyces with loss of corticomedullary differentiation and multilocular
cyst (arrow) seen in the cortex at the upper pole; (B ) The cyst is separated by thin septae, measuring 1 × 0.7 × 0.7 cm and contain gelatinous
material (arrow).
Histopathological examination from the upper pole cystic lesion revealed a multilocular
cyst lined by a single layer of clear cells with grade I nuclei and absent nucleoli.
Focal aggregates of clear cells were also seen within the fibrous septae ([Fig. 2 ]). Cyst lumen showed eosinophilic secretions. No necrosis, vascular invasion or sarcomatoid
change was noted. Sections from the dilated pelvicalyceal system exhibited focal squamous
metaplasia of lining epithelium. The compressed renal parenchyma showed global sclerosis
of more than 50% of the glomeruli along with periglomerular fibrosis. Majority of
the tubules were atrophied and exhibited thyroidization and tubulitis. The interstitium
showed marked fibrosis with infiltration by intense chronic lymphoplasmacytic infiltrate
along with foci of dystrophic calcification. Few medium sized vessels showed vascular
wall thickening. Sections from the lower pole cysts were seen lined by flattened epithelium
without any atypia.
Fig. 2 Photomicrograph showing (A ) multilocular cyst separated by fibrous septae (hematoxylin and eosin [H&E], 40x)
and (B ) cyst lined by a single layer of tumor cells with abundant clear cytoplasm and small
nuclei (arrow) (H&E, 400x).
Immunohistochemistry was done with tumor cells showing immunoreactivity with vimentin,
epithelial membrane antigen (EMA), CK-7, and negative staining for CD-10 ([Fig. 3 ]). The histopathological features along with immunohistochemistry confirmed the diagnosis
of MCNLMP existing in a background of chronic pyelonephritis and ESRD. The patient
has been on a close follow-up over the last 7 months and has not shown any recurrence.
Fig. 3 Photomicrograph showing (A ) diffusely negative CD-10, (B ) CK-7 positivity (arrow), (C ) diffuse membranous epithelial membrane antigen positivity (arrow), and (D ) diffuse vimentin positivity (arrow) (immunohistochemistry, 400x).
Discussion
MCNLMP is a rare subtype of RCC having a low malignant potential and a relatively
favorable outcome with majority of them being asymptomatic. These are discovered incidentally
on imaging as multiloculated cystic lesion with septations. Radiological findings
for these tumors are variable making their preoperative diagnosis a challenge. Bosniak
classification helps to predict malignancies in these complex cystic lesions. MCNLMP
mostly qualifies as Bosniak category IIF to IV.[4 ] However, the final diagnosis can be made only after histopathological examination.
In the present case, no cystic lesion was reported on NCCT imaging. However, a multilocular
renal cortical cyst measuring 3 cm was identified on gross examination and the diagnosis
confirmed on histopathology. Grossly, these neoplasms have been reported to be ranging
from 6 to 150 mm, unilateral, containing clear, serous or gelatinous fluid with hemorrhagic
debris, and are composed of multiple cysts of variable sizes separated by thin septa.
Microscopically, the cysts are lined by a single layer of tumor cells with abundant
clear cytoplasm and small nucleoli (WHO/ ISUP grade 1 or 2). The septae may contain
tumor cells comprising of abundant clear cytoplasm in nests and scattered singly.
However, they do not show any expansile mass or exceed 20x (1mm) microscopic field
of view.[1 ]
[2 ]
A large number of cystic lesions enter the differential diagnosis of MCNLMP that include
benign renal cortical cyst (absence of clear cells within the wall of cyst), ccRCC
with cystic and/or regressive changes (cysts filled with hemorrhage, necrosis and
hemosiderin deposits; keyboard like arrangement of nuclei), cystic nephroma (cysts
lined by bland non-clear cells with presence of ovarian stroma), cystic clear cell
papillary RCC (contains clear cells with low-grade nuclei, but differentiating feature
is the presence of papillary architecture), MiT family of tumors (high grade tumors
with focal solid areas), and tubulocystic carcinoma (cells have eosinophilic cytoplasm
with high-grade nuclei instead of clear cells).[8 ] MCNLMP is genetically related to ccRCC demonstrating 3p loss by fluorescence in
situ hybridization and VHL mutations. However, next-generation sequencing identified
six genes namely SETD2 (SET domain-containing 2), GIGYF2 (GRB10 interacting GYF protein
2), FGFR3 (Fibroblast Growth factor Receptor 3), BCR (Breakpoint Cluster Region),
KMT2C (lysine methyltransferase 2C) and TSC2 (Tuberous Sclerosis complex 2) for differentiating
MCNLMP from ccRCC with cystic change.[9 ]
The present case presented in a background of chronic pyelonephritis and ESRD. Cystic
diseases and tumors are common in a setting of ESRD. Oxidative stress has been thought
to be one of the important etiologies that promote carcinogenesis in patients with
ESRD.[5 ] The morphological diagnosis of MCNLMP in a background of ESRD is difficult, when
neoplastic cystic conditions like ccRCC, ACD-RCC, ccPRCC, and other acquired cystic
diseases of kidney need to excluded. Immunohistochemistry can play a crucial role
in the differential diagnosis. The tumor cells in MCNLMP show reactivity for PAX 8,
PAX 2, CA-IX, CK7, EMA, CAM5.2, and focal positivity in CD10, whereas they are negative
for AMACR, CK 34βE12, HMB45, A-103, and synaptophysin.[2 ]
[8 ] The immunohistochemical profile of our case was found to be in concordance with
that reported in the literature.
Most MCNLMP can be cured by surgical resection, as evident from literature search,[10 ]
[11 ]
[12 ]
[13 ]
[14 ] advocating a prognostically favorable outcome of these neoplasms. The good prognosis
can also be advocated by the fact that only two case reports of recurrence have been
reported.[15 ]
[16 ] Majority of the cases of MCNLMP have been reported as low-stage tumors (ranging
from T1, 90%; T2, 8–10% and T3, 1–3%) with only two previous case reports[17 ]
[18 ] demonstrating renal sinus fat involvement (T3). Therefore, current tumor staging
system is not applied to these tumors.[1 ] MCNLMP has shown to have an excellent prognosis, irrespective of tumor stage, with
negligible risk of recurrence or metastasis. Nephron sparing surgery can be offered
to patients if MCNLMP is suspected preoperatively and gets confirmed intraoperatively.[9 ] Radiology plays an important role in the workup of cystic renal neoplasms; however,
tumors with size less than 3 cm have been misinterpreted as solid lesions,[19 ] turning out to be MCNLMP advocating the importance of histopathology, concurring
with features studied in our case.
Conclusions
Pathologists should be aware of this rare entity, which is usually diagnosed incidentally.
This case highlights the importance of adequate grossing technique, as a small lesion
can easily be missed out as renal cysts and not get sampled. In literature, only two
MCNLMPs have been described in a setting of ESRD; herein we describe one more such
case. These tumors bear an excellent prognosis and therefore need to be separated
from other tumors with a cystic component and the tumors commonly encountered in a
setting of ESRD.
