Papillary Renal Cell Carcinoma Presenting with Hemoptysis

Papillary Renal Cell Carcinoma Presenting with Hemoptysis

Michael Dougan, PhD, HMSIIIGillian Lieberman, MD

July 2009

Our patient

• 57 y.o. man with a previous smoking history, and an 8 month

history of COPD presenting with worsening dyspnea

on

exertion, cough, and wheezing

• A chest X‐ray was performed to look for lung processes that

could be acutely exacerbating his condition– Pneumonia

– Obstruction/collapse– Pneumothorax

– Pleural effusion

Our patient’s initial evaluation by chest X-ray is shown below

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Frontal Upright Chest X-Ray Left Lateral Upright Chest X-Ray

ABCs of CXR : quality control

Is this our patient? Do we have the standard views?Is the entire region of interest covered? Exposure?

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ABCs of CXR : aberrant air

ABCs of CXR : bonesBIDMC PACS


ABCs of CXR : cardiac silhouette

ABCs of CXR : diaphragmBIDMC PACS



depressed diaphragm


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small effusion


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ABCs of CXR : extras

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outside the patient

ABCs of CXR : fields

ABCs of CXR : gastric bubble and hilaBIDMC PACS


Increased markings

Our patient’s course: worsening COPD

• Our patient was released with a diagnosis of worsening COPD– no acute lung problem

• 2 months later, he returned with a new COPD exacerbation, this time complicated by hemoptysis

• Because of his acutely worsening condition, a CT scan was ordered

Chest CT for to evaluate hemoptysis

yellow oval: airspace filling

DDx: water, blood, cells, protein

orange oval: focal densitycould this be malignant?

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axial chest CT: lung window

Right bronchial mass on CT

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Yellow circle:density in the right bronchus

malignancy?mucus plug?

coronal reconstruction CT of the chest: soft tissue window

Incidental finding in the abdominal portion of the CT

axial CT through the abdomen: soft tissue window

post-contrast

yellow circle: exophytic posterior left kidney cyst

pre-contrast

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Overview of normal renal anatomy

www.nlm.nih.gov/medlineplus/ency/imagepages/1101.htm

Exophytic kidney cyst

www.nlm.nih.gov/medlineplus/ency/imagepages/1101.htm

common incidental findings

DDxBenign Cyst (common)Renal Tumor (RCC, TCC, other)AbscessVascular AbnormalityMetastasisCystic Kidney Syndrome

follow-up is determined by specific radiographic features

Bosniak Classification System• Bosniak I: hairline thin wall; no septa, calcification, or solid components.

Water density, no enhancement.

• Bosniak II: a few hairline thin septa, fine calcification in wall or septa.

• Bosniak IIF: more hairline septa. Minimal septa or wall enhancement, minimal wall thickening. Nodular or thick calcifications. No soft tissue enhancement.

• Bosniak III: cystic masses with thickened irregular walls, or septa with enhancement

• Bosniak IV: Cystic lesions with enhancing soft-tissue elements

Generally Benign Cysts (I, II)• Bosniak I: hairline thin wall; no septa, calcification, or solid components.






Potentially Malignant (IIF – IV)• Bosniak I: hairline thin wall; no septa, calcification, or solid components.






Follow-up Required

Evidence that Bosniak

criteria are clinically meaningful

BosniakClassification

% Malignant

I 1.8% (2/114)

II 18.5% (20/108)

III 33% (218/660)

IV 92.5% (148/160)

Analyzing our patient’s cyst using the Bosniak criteria

pre-contrast post-contrast

yellow circles: exophytic cyst, soft tissue density, some regions of inhomogeneity, question of rim enhancement, calcified rim, accessory nodule.

axial CT through the abdomen: soft tissue window

How should we classify our patient’s cyst?

• Bosniak IIF: follow-up recommended– MRI can provide greater soft tissue detail

Further diagnostic steps for our patient

• Multiple pulmonary/bronchial nodules identified– Concern for primary pulmonary malignancy– Bronchial nodule was resected and sent to pathology

• Follow-up MRI of the kidneys was performed to further characterize the mass

Follow-up MRI was ordered

Sagittal abdominal MRI: T1 pre-contrastfat suppressed

Sagittal abdominal MRI: T1 post- contrast fat suppressed

yellow circle: posterior exophytic left kidney masshigh signal regions suggest focal hemorrhage

orange circle: hyper-intensity in the posterior renal fatmalignant invasion? inflammation?

pink arrows: enhancing papillary nodules

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Coronal MRI of the kidney

coronal abdominal MRI: T1 pre-contrast, fat suppressed

coronal abdominal MRI: T1 post-contrast, fat suppressed

pre-contrast images can be mathematically subtracted from post-contrast images to confirm regions of enhancement, outlining areas of blood flow

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Further analysis of blood flow by MRI

coronal abdominal MRI: post-contrast subtraction view

pink arrows: enhancing papillary nodules

MRI aided diagnosis• MRI imaging findings are characteristic of papillary RCC

– Cystic mass– Well encapsulated– Relatively low/homogenous enhancement with gadolinium– Enhancing, papillary projections into lumen

• Diagnosis was confirmed by bronchoscopy– The mass in his bronchus was confirmed to be papillary RCC

Renal cell carcinoma• Most common tumor of the kidney

• Subtypes of RCC– Clear Cell (75% – 85%)– Chromophilic/papillary (10% – 15%)– Chromophobic (5% – 10%)– Oncocytic (rare)– Collecting Duct (rare)

http://pathologyoutlines.com

Clear Cell RCC

http://pathologyoutlines.com

Papillary RCC

RCC staging and prognosis

• Staging– Stage I: < 7 cm– Stage II: > 7 cm but limited to kidney– Stage III: invasion into veins, adrenal, perirenal space– Stage IV: invasion beyond perirenal fascia, including distant

metastases

Stage Prognosis (5 year survival)

I 91% ‐

100%

II 74% ‐

96%

III 59% ‐

70%

IV 16% ‐

32%

Use of CT for staging RCC

• Detect invasion of perirenal structures (Stage III disease)– Veins (renal, IVC)– Adrenal Gland– Perirenal fasica

• Identify distant metastases (Stage IV disease)– e.g. the pulmonary masses in our patient?

• Other modalities include:– MRI, metabolic bone scan, PET

• Clear cell RCC is more common than the papillary variant, and has a more typical, malignant presentation by CT using the Bosniak criteria as demonstrated by companion patient 1

Companion patient 1: typical presentation of clear cell RCC

Yellow circle: complex cystic mass (Bosniak IV)Orange rectangle: area of detail (next slide)

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Post contrast axial CT through the abdomen: soft tissue window

Magnification view

complex cystic mass(Bosniak IV)

Yellow oval: tumor thrombus in the IVC (stage III disease)

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Post contrast axial CT through the abdomen centered on IVC: soft tissue window

Renal cell carcinoma treatment• Surgical Resection (Stage I – III only)

• Standard chemotherapy has not been found to be effective

• Immune Therapy– IL-2, Interferon alpha, bevacizumab

• Targeted Therapy (Stage III, IV)– mTOR (temsirolimus), VEGF Receptor (sunitinib, sorafenib)

• Clinical Trials– response rates to current therapeutic regimens are poor

Immune therapy for RCC• Tumors often express proteins that can be recognized as

foreign by the immune system– Mutated proteins, developmental/tissue restricted proteins, etc.

• Spontaneous anti-tumor immune responses do occur, but are rare and often insufficient to clear tumors

• Immune therapy is used to augment nascent anti-tumor immune responses– cytokines, monoclonal antibodies

Cytokine therapy mechanism of action

• Both IL-2 and interferon alpha are important factors in promoting immune responses

• IL-2: potent T cell growth factor

• Interferon alpha: critical in for anti-viral responses, makes infected cells (or tumors) more susceptible killing by cytotoxic cells (CD8 T cells, and NK cells)

Cytokine therapy efficacy and side effects

• Objective response rates are currently low (~10%), and durable responses are rare

• Adverse effects are significant, and resemble those of influenza infection– Malaise, fever, night sweats, joint pain, nausea

Monoclonal antibody therapy for RCC

• Vascular Endothelial Growth Factor (VEGF) is an important growth factor in RCC– important in renal tumors associated with VHL disease

• VEGF can be directly targeted by monoclonal antibody therapy (bevacizumab)– Also targeted by new small molecule inhibitors (currently the

treatment of choice for many patients due to improved tolerability)

Follow up on our patient• Diagnosed with Stage IV papillary RCC with intra-

bronchial metastases

• Poor prognosis, limited response to current therapies

• Entered into a clinical trial investigating a novel small molecule inhibitor

Conclusion• Incidental renal cysts are a common finding

• Renal cysts are classified radiographically using the Bosniak system to separate benign findings from probable malignancies

• MRI can play an important role in correctly diagnosing cysts with indeterminate features on CT

• RCC is the most common tumor of the kidney, and, in early stage disease (stage I and II), can be treated by surgery alone

• Advanced RCC has a poor prognosis, and is managed using immune therapy or using targeted molecular therapy

Acknowledgments• Erica Gupta• Maryellen Sun• Gillian Lieberman

• Glenn Dranoff• Richard Haspel• Adam Jeffers• Jay Pahade• Rich Rana• Aarti Sekhar• Jennifer Son

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Papillary Renal Cell Carcinoma Presenting with Hemoptysis