Keywords
crizotinib-associated renal cyst - anaplastic lymphoma kinase - nonsmall-cell lung
cancer - complex cyst
Introduction
Nonsmall-cell lung cancer (NSCLC) constitutes 85% of all lung cancers.[1] Rearrangements of the anaplastic lymphoma kinase (ALK) gene are present in 3 to
5% of NSCLCs.[2] Crizotinib is a first-generation orally active ALK inhibitor, which has revolutionized
the treatment of ALK-positive NSCLC since receiving Food and Drug Administration approval
in November 2013.
The development of renal cysts as an adverse effect of crizotinib has been described
since clinical trials in 2011, with a reported incidence of 4 to 42%.[3]
[4]
[5]
[6]
[7] With crizotinib assuming the center-stage in the treatment in NSLCs, the radiologist
needs to be familiar with this entity so as to avoid misdiagnosing a new renal “lesion”
as a metastasis. In this case series, we describe the imaging appearance and evolution
of renal cysts in four cases of ALK-positive NSCLC treated with crizotinib at our
institute.
Case Reports
-
A 64-year-old man was diagnosed with metastatic ALK-positive adenocarcinoma of the
lung. He was started on crizotinib. In the baseline scan, both the kidneys were normal
([Fig. 1A]). Two months after initiation of crizotinib, the response assessment computed tomography
(CT) scan ([Fig. 1B]) revealed a new complex cystic lesion in right kidney, which almost doubled in size
in next 3 months ([Fig. 1C]). The patient’s primary and metastatic disease otherwise responded well to the chemotherapy.
This was correctly identified as a crizotinib-associated complex renal cyst and remained
stable through the rest of therapy.
-
A 57-year-old woman with ALK-positive metastatic large cell neuroendocrine carcinoma
was started on crizotinib. Response assessment CT scan done after 1 month ([Fig. 2A]) showed a new thick-walled cystic lesion in left kidney. This was labeled a crizotinib-associated
renal cyst (CARC) and followed up. The renal lesion remained stable after the subsequent
follow-up scans ([Fig. 2B]). There was partial response of the primary tumor.
-
A 40-year-old woman with ALK-positive metastatic NSCLC was started on crizotinib.
Both kidneys were normal in the baseline scan. On follow-up CT after 2 months ([Fig. 3A1]
[A2]), two new complex cystic lesions were seen, one each in either kidney.
Fig. 1 (A) A 64-year-old patient with anaplastic lymphoma kinase-positive lung cancer. Axial
baseline contrast-enhanced computed tomography (CECT) image shows normal kidneys.
(B) Axial CECT image after 3 months of therapy shows a new simple cyst in the lower
pole of right kidney. (C) Axial CECT image at 5 months follow-up scan shows interval increase in the size
of right renal cyst, which now looks more complex with mild wall enhancement and mean
Hounsfield unit 50 is seen (Bosniak IIF).
Fig. 2 (A) A 57-year-old woman with anaplastic lymphoma kinase-positive metastatic large cell
neuroendocrine carcinoma. Baseline computed tomography (CT) (images not shown) demonstrated
normal kidneys. Axial contrast-enhanced computed tomography (CECT) image after onemonth
of initiation of crizotinib shows a hypodense lesion with thin imperceptible wall
in theleft kidney (Bosniak I). (B) An 8-month follow-up axial CECT shows new thick peripheral wall enhancement with
stable cyst size (Bosniak III cyst). (C) Further follow-up scan at 2 months interval showed mild increase in the size of
left renal cyst, with persistent thick enhancing wall.
Fig. 3 (A) A 57-year-old man, diagnosed with anaplastic lymphoma kinase positive metastatic
adenocarcinoma lung. Baseline scan demonstrated normal kidneys (not shown). Axial
contrast-enhanced computed tomography (CECT) image after 3 months following initiation
of therapy shows a new simple Bosniak I cyst in the left kidney. (B) CECT performed at 6 months follow-up shows increase in the size of the cyst with
wall enhancement (Bosniak IIF cyst).
After 4 more months, she developed flank pain and fever spikes. CT scan showed massive
increase in the size of both the renal lesions with abscess formation and invasion
into the renal bed ([Fig. 3B]). Both the lesions were drained percutaneously. Aspirated fluid was negative for
malignancy. The dose of crizotinib was halved and empirical broad-spectrum antibiotics
were started; however, the symptoms did not resolve. It was decided to withhold crizotinib
in view of nonresolving infection.
Subsequent CT scan done after 2 months demonstrated near complete resolution of the
bilateral renal lesions and perirenal inflammatory changes ([Fig 3C]). The patient was restarted on crizotinib after 3 more months at a lower dose. Unfortunately,
this again led to an increase in the size of bilateral renal lesions and the formation
of a large right iliopsoas abscess ([Fig 3D]). The abscess was drained by pigtail insertion and crizotinib was stopped till symptomatic
improvement and then reinitiated. The patient is stable on follow-up since then.
-
4. A 57-year-old man, diagnosed with ALK-positive metastatic adenocarcinoma lung,
was started on crizotinib in June 2017. The baseline CT showed unremarkable kidneys.
On CT scan done after 3 months (September 2017), new simple cysts were seen in left
kidney ([Fig. 4A]). On 6 months (December 2017) follow-up scan, the cysts showed increase in size
([Fig. 4B]). The patient was asymptomatic for any renal issues and is on routine follow-up.
Fig. 4 (A) A 40-year-old woman with anaplastic lymphoma kinase-positive metastatic nonsmall
cell carcinoma lung. Baseline axial computed tomography (CT) showed a tiny hypodensity
in the left kidney, too small to characterize. The right kidney was normal. (B) Contrast-enhanced computed tomography (CECT) performed 3 months after starting crizotinib
shows increased size of the left renal cyst without other worrisome features. (C) Another new exophytic complex cystic lesion is seen in the right renal upper pole.
(D) Axial CECT image after another 3 months shows massive increase in size of both the
renal cysts with abscess formation which invades the renal beds bilaterally. Aspiration
showed suppurative inflammation. (E and F) Axial CECT image performed after withholding crizotinib for 2 months shows marked
regression in the renal abscesses with a small residual component. (G and H) Axial CECT image performed after reinitiation of crizotinib shows a recurrent large
septated iliopsoas collection and bilateral perinephric abscesses with thick enhancing
walls.The right-sided collection was drained by pigtail insertion (not shown).
Scan Protocol
Please note that these cysts were identified on routine follow-up CT done for these
patients. CT scans were performed on 16 slice Siemens Somatom emotion CT scanner,
manufactured in Erlangen, Germany. Following parameters were used to perform the contrast-enhanced
CT scan: collimation, 4 × 2.5 mm; slice thickness, 1.5 mm; reconstruction interval,
1.5 and 5 mm; table feed, 12 mm/rotation. Kilovolt potential and milliampere seconds
were adjusted in each case by using the automatic exposure control. Patients were
given intravenous noniodinated contrast medium, either Ultravist (iopromide 300) or
Omnipaque (iohexol 300) at a dose of 1.2 mL/kg body weight with the scan performed
at 70 seconds after the injection, using automatic pressure injector at a flow rate
2.8 mL/s.
Discussion
The historical standard of care for treating NSCLCs has been platinum-based double
agent chemotherapy.[8] However, there has been paradigm shift in the treatment of NSCLC in the last decade,
as a result of significant advances in molecular pathology and better understanding
of heterogeneous tumor biology. Specific oncogenic driver mutations have been identified
that lead to uncontrolled tumor proliferation, with epidermal growth factor receptor
(EGFR) mutation being the most common, followed by ALK mutation. Targeted therapeutic
agents have been developed to target these mutations by either small molecule inhibitors
or receptor monoclonal antibodies.[9] The successful targeted inhibition of these using EGFR tyrosine kinase inhibitors
and crizotinib respectively has revolutionized the treatment of adenocarcinoma lung,
with significantly improved progression free and overall survival in these patients.[10]
The association between crizotinib and development of renal cysts has been known since
the drug was in phase III clinical trials. However, its pathogenesis is still not
clearly understood. Tyrosine kinase receptor (c-mesenchymal to epithelial transition)
is normally present in renal tubular epithelium and their inhibition by crizotinib
could represent the responsible pathway.[11]
Crizotinib-associated cysts are usually simple but can be complex. They can present
in the form of de novo appearance of new cysts, or as enlargement or increased complexity
in preexisting cysts. The incidence of the various patterns of crizotinib-associated
cysts as reported in literature is summarized in [Table 1].[3]
[4]
[5]
[7]
[10] By far, the dominant pattern of evolution of CARCs is asymptomatic cysts that enlarge
and spontaneously regress without the need for discontinuation of crizotinib or intervention.[7]
[12] In our cases, the patients had stable cysts or progressively enlargement of cysts
or transformation into complex cysts, without any impairment in renal function.
Table 1
Patterns of evolution crizotinib-associated renal cysts
|
Pattern of evolution of crizotinib-associated renal cysts
|
Incidence (%)
|
|
Complex cysts[3]
[4]
[5]
[7]
|
9–27
|
|
Enlargement of cysts[3]
[4]
[7]
|
2–32
|
|
Septations[7]
|
25
|
|
Mixed cystic and solid appearance[7]
|
29
|
|
Psoas/abdominal wall extension[5]
[7]
|
7–41
|
Although ultrasonography (USG) can detect and characterize these cysts, CT usually
forms the mainstay in characterization of these lesions, as it is anyway performed
for response assessment in patients on crizotinib. On USG, CARCs may appear as ovoid,
anechoic lesions with smooth well demarcated walls. Internal echoes and septations
may be present in complex cysts and may sometimes cause a “pseudosolid” appearance.
In such cases, posterior acoustic enhancement and lack of internal vascularity would
favor complex cysts.
Similarly, CT may demonstrate a simple or complex cyst. It is important to obtain
pre- and postcontrast images so that calcifications and hemorrhage can be accurately
identified, and high-density nonenhancing renal cysts are not mistaken as solid metastases.
Simple cysts are near water density with an upper threshold of 20 Hounsfield units
(HU).[13] Complex features include hyperdense contents, septations, mixed solid cystic appearance,
poorly defined margins, or extension into renal bed. The two commonest complex features
in these CARCs are the development of multiple septations and a mixed cystic and solid
appearance. The apparent solid appearance of some of these cysts may be due to the
underlying inflammatory process.[7] These cysts can fall into categories IIF, III, and IV of Bosniak classification.[14] It must be remembered that although Bosniak III/IV cysts usually need surgical resection,
crizotinib-associated complex cysts are not known to have malignant potential and
therefore resection is not recommended.
The differential diagnosis of renal cysts demonstrating complex features in a patient
with NSCLC includes infections such as pyelonephritis and renal abscess, renal metastases,
and primary renal malignancy. Infection can be excluded clinically based on lack of
symptoms and urinalysis. Renal metastasis and primary renal neoplasm are rare; knowledge
of CARC is, however, essential to avoid misinterpretation. Metastasis can have similar
imaging morphology as the primary lesion in lung.[15]
[16] Renal metastases have been described as small, multiple, bilateral, and located
within the renal capsule.[15]
[16] Delayed contrast-enhanced CT can help to distinguish renal cell carcinomas (RCC)
and non-neoplastic cysts by measuring decrease in HU on delayed phase. RCC shows significant
decrease in HU on delayed phase as opposed to benign cysts which remain unchanged.[17] CT and magnetic resonance imaging findings of complex cysts are similar; no significant
difference is present between the two modalities in characterization of these lesions.[14]
Our case series highlights the importance of recognizing the imaging features of new
renal cysts as an adverse effect of crizotinib treatment. Misinterpretation of such
complex cysts as metastasis or disease progression may lead to futile invasive investigations,
or worse, may lead to cessation of an otherwise effective chemotherapy. In cases in
which complex renal cysts extend into adjacent extrarenal spaces, percutaneous drainage
becomes necessary to hasten resolution. Existing case reports in literature and our
own experience suggest that stopping crizotinib leads to their spontaneous regression.[7]
[12]
Conclusion
Development of renal cysts is not an uncommon side effect of treatment with crizotinib.
Cysts are typically benign and remain stable on continued crizotinib therapy. They
may, however, rarely enlarge over time or get complicated by infection or abscess
formation. Such cases may even require dose reduction or withholding crizotinib. Complex
cysts can mimic infection, primary renal malignancy or metastasis, or Bosniak IIF-IV
category cysts. It is imperative that radiologists are aware of this entity in order
to avoid wrong interpretation and mismanagement.
