Keywords
autosomal dominant polycystic kidney disease - tubulocystic renal cell carcinoma -
papillary renal cell carcinoma - mTOR inhibitors - sunitinib
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder linked
to mutations of PKD1 (16p) or PKD2 (4q) genes in 85% and 15% patients, respectively,
with incidence varying from 1 in 400 to 1 in 1,000.[1] The condition is characterized by multiple renal cysts with or without extrarenal
manifestations such as hepatic/pancreatic cysts and vascular abnormalities (intracranial
aneurysms, aortic root aneurysms, mitral valve prolapse, etc.), with variable familial
expression. Familial involvement and early renal failure are more common with PKD1
mutations.[1]
[2] As the fluid-filled cysts in ADPKD replace normal renal tissue, progressive loss
of renal function leading to chronic kidney disease (CKD) may develop over time.[3] There is more than twofold higher risk of developing renal cell carcinoma (RCC)
in patients with ADPKD in large national databases over a 14-year follow-up period.[4] Surgical specimens of ADPKD patients on dialysis showed 5 to 12% harboring RCC.[5]
[6] A possible direct association of ADPKD with RCC is, however, controversial, and
is more often deemed a coincidence except in those with end-stage renal failure where
genetic mutations may trigger malignant transformation.[7]
We discuss the clinical course of two patients who presented to us with metastatic
RCC with a background of ADPKD.
Case Report
Case 1
A 26 year-old male with past history of bilateral ADPKD diagnosed at the age of 10
years based on renal biopsy and on irregular follow-up with imaging, presented with
left-sided abdominal pain, backache, and weight loss for 6 months. Examination revealed
both hepatomegaly (15 × 10 cm) and splenomegaly (7 × 6 cm). Positron emission tomography
(PET)-computed tomography (CT) demonstrated 18F-fluorodeoxyglucose (FDG) avid mass
involving upper pole of left kidney (4.9 × 7.4 × 7.2 cm) with metastatic retroperitoneal
lymph nodes, hepatic and D12 vertebral metastases ([Fig. 1A–E]). Magnetic resonance imaging (MRI) of spine showed a soft tissue mass involving
left side of D12 vertebral body with neural foramen narrowing. Biopsy from vertebral
lesion suggested metastatic papillary RCC. After review of all blood parameters that
returned normal and a discussion with the patient regarding possible treatment options
in intermediate risk disease, systemic therapy with sunitinib was initiated. Partial
morphologic and metabolic response was observed on interim PET-CT performed after
4 months. A single fraction of palliative radiotherapy (RT; 8 Gy) was delivered when
the backache recurred (approximately 9 months after initiating sunitinib). The patient
experienced complete response in backache after 4 weeks. He needed evaluation for
recurrent episodes of massive ascites causing breathing difficulty after 18 months
of initiating sunitinib. Ascitic fluid cytology was consistently negative for malignant
cells but showed hypoproteinemia, which was managed conservatively. He received palliative
re-irradiation (20 Gy in 5 fractions) to dorsolumbar spine for worsening backache
(1 year after initial RT). After being stable clinically and on imaging for 29 months,
a follow-up PET-CT showed an increase in size and avidity of liver lesions, although
bilateral renal masses did not show any disease progression. Ascites, right pleural
effusion, and pericardial effusion were seen (negative for malignancy on cytology).
Systemic therapy was changed to axitinib 5 mg twice daily, with symptomatic improvement
and partial response at a follow-up of 15 months following initiation of axitinib.
Review of renal biopsy (done at 10 years of age) and vertebral biopsy (done at diagnosis
of metastatic disease) revealed that both specimens showed tubulocystic RCC (TCRC),
a rare variant of RCC ([Fig. 2]).
Fig. 1 (A) Sagittal section of contrast-enhanced computed tomography (CECT) abdomen showing
bilateral polycystic kidneys (Right 26.5 × 14 cm, Left 25.5 × 13 cm) with peripheral
and chunky calcification, and multiple liver cysts. (B) Sagittal and (C) axial sections of magnetic resonance images of dorsolumbar spine showing a large
T2 hyperintense lobulated soft tissue metastatic lesion involving D12 vertebra on
left side of body, pedicle, and transverse process with involvement of adjacent costovertebral
joint, epidural space extension, cord compression, and left neural foramina narrowing
at D11-12 and D12-L1 levels. (D) Axial sections of corresponding positron emission tomography (PET)-CECT images showing
multiple cystic liver metastases with fluorodeoxyglucose (FDG) uptake, largest in
right lobe (largest11.2 × 7.3 cm) with peripheral enhancement on arterial phase, and
(E) multiple bilateral renal cystic masses with soft tissue component and FDG avidity,
and left D12 vertebral metastases. (F) Axial PET-CECT image on follow-up showing progressive necrotic liver metastases;
many new liver lesions had developed (not shown in image), and (G) progression in extent of D12 vertebral lesion and soft tissue component with cord
compression.
Fig. 2 Renal biopsy specimen obtained at the age of 10 years with a clinical diagnosis of
autosomal dominant polycystic kidney disease. (A) Low power images of kidney biopsy showing cystic spaces separated by fibrous septae.
(B) At places they are mixed with closely packed tubules. (C) Lining cells are lined by cuboidal cells showing prominent hobnailing with uniform
nuclei, minimal atypia, and mitosis. (D) These tumor cells are positive for alpha methyacyl CoA racemase (AMACR) immunostains.
At the age of 26 years, the patient was evaluated for low backache and biopsy from
D12 vertebral soft tissue mass was obtained. (E) Small biopsy fragments showing metastatic deposit of tumor with same morphology
as renal biopsy taken 16 years ago. (F) High power shows hobnailing, with abundant eosinophilic cytoplasm and low atypia
and mitosis. (G) These cells show nuclear staining for PAX8, and (H) cytoplasmic staining for AMACR.
After 1 year of stable disease on axitinib, he developed visible and palpable increase
in the soft tissue mass on his back at D12 level, but no change in power or sensorium
of lower limbs. His Karnofsky Performance Status was 80 with no new symptoms. Repeat
PET-CT showed new liver lesions, new retroperitoneal nodes, progression of D12 vertebral
lesion with cord compression, and persistent pleural effusion ([Fig. 1F, G]). Neurosurgical intervention for decompression was sought but not considered due
to overall poor prognosis of the disease. Treatment options including immunotherapy
and tyrosine kinase inhibitors were discussed, and the patient opted for third-line
therapy with cabozantinib 60 mg daily. Palliative radiation therapy (12 Gy in 4 fractions)
was given after discussion of risks of demyelination. The vertebral disease responded
to palliative RT and the visible bulge on his back disappeared, but he developed a
seizure episode and progressive weakness of lower limbs within 4 weeks of palliative
RT. MRI brain ruled out any intracranial cause for the weakness and renal/liver functions
and electrolytes were normal. His oral intake progressively declined and he was unable
to tolerate cabozantinib; a dose reduction was attempted but he could not continue
the drug due to continuous decline in intake and general health. He succumbed to progressive
disease and cachexia within 3.5 months of palliative RT, and approximately 4 years
from the first diagnosis of metastatic disease.
Case 2
A 56 year-old-patient, diagnosed radiologically to have ADPKD while being evaluated
for hypertension 3 years previously, presented with oliguria for 3 months and azotemia
(serum creatinine 11.87 mg/dL) with a diagnosis of CKD stage V on maintenance hemodialysis
two to three times per week. Ultrasound and CT abdomen suggested bilateral renal exophytic,
solid-cystic lesions, suggestive of RCC ([Supplementary Fig. S1]). In view of preexisting poor renal function, bilateral laparoscopic radical nephrectomy
was performed. On histopathology, left upper pole renal mass was suggestive of papillary
RCC, type1 (pT1N0) with ADPKD. Right renal mass showed oncocytoma with ADPKD. Six
months postoperatively, he developed extensive skeletal and abdominal nodal metastases.
He was determined to have intermediate risk disease. Systemic therapy with pazopanib
was initiated but within 6 months, there was progression of bony lesions and development
of new pulmonary nodules and pleural effusion. He received palliative RT to painful
pelvic bone metastases (8 Gy in single fraction) and switched to second-line therapy
with lenvatinib/everolimus combination. However, there was rapid deterioration in
his general health, and he succumbed to his illness within 3 months of initiating
second-line systemic therapy.
Discussion
The first description of RCC and ADPKD together was given in 1934 by Walter and Braasch.[8] Since then, over 60 cases of this association have been published in English literature.
The diagnosis of RCC in a background of ADPKD poses several challenges. An evolving
focus of RCC in a background of multiple renal cysts and distorted architecture may
be difficult to discern in early stages even on regular follow-up. Many patients have
end-stage renal disease and may not have any additional symptoms related to malignancy
before progression to advanced disease or development of metastases. Symptoms from
malignancy such as pain, hematuria, mass effect, or hypertension may be confused with
cyst rupture or hemorrhage.
A literature review of 25 cases of RCC in background of ADPKD compared to RCC in general
population reported no gender predilection, earlier age at presentation (45 vs. 61
years), higher occurrence of fever as a presenting symptom (32% vs. 7%), with higher
incidence of bilaterality, multicentricity, and sarcomatoid features.[9]
Surgical series in ADPKD have also documented multifocality and bilateral renal involvement
with RCC. Papillary and clear cell RCC were the most common reported pathologic diagnoses
in these series and nearly a third of patients had more than one histologic subtype.[5]
[6] Metastatic disease is noted in nearly 20 to 23% patients with RCC in the setting
of ADPKD, possibly due to a delay in diagnosis.[9]
[10]
Distinguishing new RCC within ADPKD is particularly challenging. The only definitive
suspicion could arise from symptoms and findings related to metastatic disease. Ultrasound
of kidneys may show complex cysts with or without internal debris or hemorrhage. ADPKD
cysts have variable size and appearance on CT or MRI. Hemorrhage within these cysts
can appear as higher density on CT or high intensity on MRI. However, none of these
features are specific to development of malignancy. A serial change in appearance
of a cystic lesion (more asymmetry, parenchymal change, or appearance of solid component)
may indicate a malignant change. Contrast enhancement within the cyst wall that is
thick and irregular, enlarged renal vein or inferior vena cava indicating possible
venous tumor thrombus, para-aortic lymphadenopathy, or other lesions in liver or soft
tissues may be soft pointers toward RCC. MRI may show high signal on T1-weighted images,
low signal on T2, and diffusion restriction on diffusion-weighted imaging; these findings
may also occur in cyst infections, and if fever is the presenting symptom, there may
be more confusion than clarity.[10]
[11] When suspicion is high and both CT and MRI are indeterminate, open biopsy or nephrectomy
may be necessary to exclude malignancy. Role of PET-contrast-enhanced CT (CECT) in
diagnosis is also limited since kidneys physiologically excrete FDG as well and malignant
cysts may not appear very different from ADPKD cysts and FDG uptake is only slightly
higher than normal renal parenchymal uptake; however, it is definitely useful in metastatic
disease.[12] Despite advances in imaging, most of the RCCs are noted not on imaging but incidentally
at autopsy, nephrectomy before kidney transplant, or during excision of symptomatic
cysts. Among our patients, case 1 was picked up due to metastatic disease; however,
renal function was normal. Case 2 had end-stage renal disease and diagnosed with RCC
within 3 years of CKD. The diagnosis of renal masses on CT in case 1 was challenging
but PET-CECT helped in distinguishing malignant cysts from ADPKD cysts, while in case
2, the renal tumors were solid and exophytic on CT.
On biopsy, normal kidney, ADPKD cells, and RCC cells may be differentiated on morphology.
ADPKD cysts may be seen as fluid-filled abnormal cavities or membrane-lined sacs with
compression of adjacent parenchyma. The fluid arises from glomerular filtrate. In
RCC, however, the cyst fluid may show neoplastic cells.[13] Both ADPKD and RCC may have overexpression of vascular endothelial growth factor
(VEGF) and its receptors. Hypoxia is seen in both with consequent overexpression of
hypoxia inducible factor-1-alpha signaling. In ADPKD as well as RCC, cyst and tumor
cell growth and proliferation may be related to two important pathways: PI3K/AKT/mammalian
target of rapamycin (mTOR) and Ras/Raf/ERK.
Additionally, majority of polycystic kidney tissue expresses the epithelial developmental
antigen Exo1 while normal kidney and RCC do not.[14] RCC cells have highly increased expression of epidermal growth factor receptor and
transforming growth factor-alpha; these are also expressed in ADPKD and normal kidney
but to a much lesser degree.
The postulated hypotheses of RCC development in ADPKD include chronic renal injury
favoring renal parenchymal genetic mutations with consequent malignant change, or
hyperproliferation in ADPKD acting as a precursor to RCC.[15]
[16] None of these theories have been substantiated yet. Some studies also demonstrate
increased apoptosis in cystic and noncystic structures in ADPKD, negating the malignant
potential in this condition.[17]
Clinical series documenting the clinical course of RCC in ADPKD are sparse. A Japanese
study of 10 patients with a mean age of 61.2 years (80% men) and on hemodialysis for
a mean of 11.2 years showed that clear cell carcinoma was the most common histologic
subtype.[15] Three patients had bilateral disease, and four had multiple metastases. At a median
follow-up of 20 months, 60% had died.
TCRC is a recently established rare histologic type recognized by the American Joint
Committee on Cancer in 2010 and formally included as an independent subtype of RCC
classification by The World Health Organization in 2016.[18]
[19] These tumors were earlier clubbed with collecting duct carcinomas, but now deemed
a distinct entity, with a male predilection, indolent behavior, and diagnosis at early
stage. Immunohistochemistry with vimentin, p53, and alpha methyacyl CoA racemase overexpression
and negative high molecular weight cytokeratin, distinguishes them from other RCCs.[20] Metastases are rare and reported in less than 5 cases of the total 80 cases reported
so far. Case 1 in this report is the first instance of an association between the
rare TCRC and ADPKD. Indolent behavior is evident in this case—although TCRC was not
identified initially in biopsy at 10 years and noted in biopsy review later, metastases
took nearly 16 years to develop without any anticancer therapy. Surgery is the recommended
therapy for TCRC. Targeted therapy has no documented role but a few case reports suggest
partial response to sunitinib and everolimus.[21] The role of RT in RCC is largely palliative (for control of brain metastases or
painful bone metastases) except in situations where oligometastatic disease is present
and may be addressed with stereotactic body radiation therapy with or without immunotherapy.[22]
The surgical and pathology details of the second case have been discussed in a prior
publication.[23] Association with papillary RCC has been hypothesized due to pathologic similarity
of papillary epithelial cells to cyst lining hyperplastic cells that often manifest
papillary-like change.[24] Although papillary RCC is believed to have a better prognosis than clear cell RCC,
our patient (case 2) developed metastases fairly early (within 6 months of diagnosis).
Treatment for localized RCC in ADPKD would essentially include surgical management—partial
nephrectomy in those with normal renal function and radical nephrectomy, often bilateral,
for those with end-stage renal disease on dialysis. Some authors suggest that detection
of RCC in one kidney in ADPKD should prompt aggressive search for tumor in the opposite
kidney as well.[25] Patients who are not candidates for surgery may be considered for other local ablative
therapies such as radiofrequency ablation to the gross tumor.[26] Follow-up for recurrence is again as big a challenge as initial diagnosis but periodic
imaging (abdominal CT) is recommended. The European Society of Medical Oncology guidelines
recommend annual CT scan of chest and abdomen in low-risk patients and CT every 3
to 6 months for initial 2 years in high-risk patients. Metastatic RCC patients on
systemic therapy should undergo CT imaging every 2 to 4 months.[27] Systemic therapy for patients with metastatic disease is guided by the International
Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification, comorbidities,
and financial arrangements of insurance or reimbursement (especially if immunotherapy
is being considered).
mTOR pathway undergoes activation after acute renal injury (or diabetes, progressive
renal disease, etc.) and is responsible for repair and regeneration of injured renal
tissue.[28] mTOR is inappropriately active in renal epithelial cells lining the cyst walls in
ADPKD and mediates formation and enlargement of cysts. In normal kidneys, mTOR pathway
inhibitors delay renal function recovery after acute insult, leading to chronic renal
disease. In ADPKD, however, mTOR inhibitors have shown reduction in cyst volume and
slowing of renal function decline.[29] mTOR inhibitors are also shown to be effective either alone or in combination with
VEGF-targeted agents in metastatic RCC. Theoretically, this should be the preferred
therapy especially in nonclear cell poor risk RCCs in background of ADPKD because
of their dual activity.[30]
Both our patients received VEGF-targeted therapy as first line—case 1 due to financial
challenges with immunotherapy chose oral tyrosine kinase inhibitor even for second
and third line; moreover, the diagnosis of TCRC does not have a clearly defined systemic
therapy. Our first patient did reasonably well on two lines of multikinase inhibitor
therapy but progressed rapidly on third line, while the second patient had a rapid
decline following initiation of second-line therapy that included mTOR inhibitor.
Conclusion
RCC in background of ADPKD is a difficult diagnosis and needs a high index of suspicion
for clinical symptoms and signs, as well as imaging findings on screening of patients
with known ADPKD. The association seems sporadic at present although several genetic
mutations and pathways are being explored. RCCs in ADPKD kidneys are more often bilateral,
multicentric, and metastatic compared to those in general population. Although various
histologic types are described, the association of ADPKD with TCRC has been described
for the first time in this report. Management of ADPKD essentially includes surveillance
for renal function, and dialysis if CKD develops. RCC local management is guided by
stage at diagnosis and baseline renal function, and systemic therapy by IMDC risk
group as well as logistics. For those with localized disease and preserved renal function,
partial nephrectomy is considered with surveillance imaging for recurrence.
