191 Understanding Genitourinary System Cytology: From Morphology to Molecular Pathology

191 Understanding Genitourinary System Cytology: From
Morphology to Molecular Pathology
Guliz Barkan MD
Eva Wojcik MD
2011 Annual Meeting – Las Vegas, NV
AMERICAN SOCIETY FOR CLINICAL PATHOLOGY
33 W. Monroe, Ste. 1600
Chicago, IL 60603
191 Understanding Genitourinary System Cytology: From Morphology to Molecular Pathology
This session will provide a comprehensive review of the morphologic criteria and guidelines for the cytologic
diagnosis of genitourinary neoplasms and non-neoplastic lesions using real cases to segue into discussion. The
subject matter is comprised of 2 sections: Urinary tract cytology and renal FNA cytology. The salient
morphological features of genitourinary tract cytology , the current state-of-the-art ancillary tests, and the
pitfalls associated with them will be addressed. The practical integration of ancillary tests (DNA ploidy,
biomarkers, FISH, and other novel tests designed to detect malignancy) in urine cytology and renal FNA's will
be discussed. Approach to differential diagnoses and diagnostic role of ancillary studies in renal cytology will
be covered in light of the newer sensitive imaging techniques and personalized treatment modalities of the 21st
century.
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Learn the indications, cytomorphologic features, and potential pitfalls of urine cytology.
Recognize normal renal cytology, common, and uncommon lesions in renal aspirations, and understand
limitations in diagnosing renal FNA's.
Understand the current role and potential pitfalls of emerging new technologies and ancillary techniques
in urine and renal cytology.;and review integrated approach (using biochemical, molecular tests,
morphological and clinical findings) the in the diagnosis of genitourinary tract cytopathology.
FACULTY:
Guliz Barkan MD
Eva Wojcik MD
Entire Pathology Team
Cytopathology
Cytopathology (Non-Gynecologic)
2.0 CME/CMLE Credits
Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the
Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for
physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical Education (ACCME).
Credit Designation: The ASCP designates this enduring material for a maximum of 2 AMA PRA Category 1
Credits™. Physicians should only claim credit commensurate with the extent of their participation in the
activity. ASCP continuing education activities are accepted by California, Florida, and many other states for
relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of
Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to
meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance
Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing
medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s
Maintenance of Certification Program.
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GU Cytology Handout
ASCP 2011
Understanding Genitourinary System Cytology:
From Morphology to Molecular Pathology
ASCP 2011
October 21, 2011
Eva M. Wojcik, M.D., MIAC
Chair, Department of Pathology
The Helen M. and Raymond M. Galvin Professor of Pathology
and Urology Loyola University Medical Center
Department of Pathology, Bldg 103
2160 South First Ave.
Maywood, IL 60153
E-mail: [email protected]
Güliz A. Barkan, M.D., FIAC
Assistant Professor of Pathology
Program Director, Anatomic and Clinical Pathology Residency
Director of Cytopathology
Loyola University Medical Center
Department of Pathology, Bldg 110
2160 South First Ave.
Maywood, IL 60153
E-mail: [email protected]
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The authors do not have a financial disclosure
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I. URINE
Introduction to Urinary Tract Cytopathology
Urothelial carcinoma (UC) of the bladder is a challenging condition for both
urologists and pathologists. For the urologist, the challenge is to predict at an early stage
which patient will have further tumor occurrences or will develop invasive properties.
For the pathologist, the challenge is mainly to detect low grade lesions. By definition, the
nuclear differences between low grade urothelial carcinoma and normal urothelium are
subtle and very subjective. Additionally, reactive processes due to treatment, lithiasis of
the urinary tract or viral infections may be difficult to distinguish from neoplastic
processes.
A sensitive non-invasive test to detect bladder cancer remains an elusive but
highly desirable goal. Although urine cytology is highly sensitive for detection of high
grade UC, its sensitivity for low grade cancer remains unacceptably low. Consequently,
invasive cystoscopy remains the mainstays for the diagnosis of bladder urothelial
carcinoma and it is used to monitor patients with high risk for recurrence and
progression.
Therefore there is an obvious need for a development of additional more sensitive
tests that could detect urothelial neoplasia. In this context, a number of techniques,
including DNA ploidy by image analysis, flow cytometry, or laser scanning cytometry,
image analysis-based morphometry, immunohistochemistry, cytogenetics or urine
chemical assays such as NMP-22 and BTA have been proposed to be used in conjunction
with cytologic examination.
New technologies, however, should not diminish the need for a proper cytologic
evaluation. Successful urine cytology depends upon numerous factors:
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Basic knowledge of anatomy, histology and function of the GU tract
Availability of clinical information: sex, age, type of specimen, symptoms,
cystoscopic and radiographic findings, previous history
“Common language” with surgical pathologist and clinician
Application of adjunct tests
Understanding and acceptance of limitations
Cellular and non-cellular components of normal urine specimens
A specialized type of epithelium (transitional epithelium or, currently recommended
name, urothelium) is lining a lower collecting system which includes bladder and urethra,
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and upper collecting system which includes renal pelvis, calyceal system and ureters.
Urothelium is a multilayer epithelium, composed of 6 to 7 layers of cells. The main role
of the urothelium is to form a blood/urine barrier.
Cells normally found in urine:
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Urothelial cells – basal cells, intermediate cells, superficial (umbrella) cells
Squamous cells – contaminant, trigone, squamous metaplasia
Other cells found in urine:
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Glandular cells – prostatic, endometrial, cystitis glandularis, paraurethral glands
Renal tubular cells
Leukocytes, lymphocytes and RBC’s
Seminal vesicle cells
Sporadically, degenerated seminal vesicle cells can be seen in urine specimens,
particularly from older patients. Seminal vesicle cells in urine specimens often have a
bizarre appearance, with greatly enlarged nuclei and foamy, fragmented cytoplasm.
The chromatin is hyperchromatic, degenerated and smudgy. In contrast, the
chromatin of malignant cells is coarse. As in prostatic specimens, seminal vesicle
cells may be distinguished from cancer cells by the presence of a golden-brown
lipofuscin pigment. Often, spermatozoa accompany seminal vesicle cells. These cells
also have an abnormal DNA content.
Non cellular elements:
• Crystals
• Casts
• Sperm
• Corpora Amylacea
• Lubricant
• Mucus
• Fibrin
• Pollen
• Alternaria
• Microconidia
Types of Urinary Tract Specimens
Voided Urine:
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the most convenient and easily obtained
contamination from external genitalia and vagina
degenerated epithelial cells (eosinophilic inclusions)
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Catheterized urine:
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Bladder washing/barbotage: -
Ileal conduit:
lack of contamination from external genitalia
more cellular – pseudopapillary fragments
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more cellular
better preservation
monolayered sheets, pseudopapillary fragments and
single cells
multinucleated cells
columnar intermediate and deep cells
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hypercellular
dirty background of mucus and bacteria
columnar cells of ileal epithelium
degenerated urothelial cells with cytoplasmic inclusions
karyorrexis
Renal pelvis washing/brushing:
-high cellularity
-well-preserved
-sampling of a specific area
Inflammatory Conditions
A. Noninfectious
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Interstitial cystitis:
Eosinophilic cystitis:
Hemorrhagic cystitis:
Non-specific cytologic findings
Eosinophils and reactive urothelial cells
Non-specific cytologic findings, abundant erythrocytes
Could be infectious or non-infectious
Etiology: Escherichia coli; adenoviruses, papovavirus;
influenza A; cyclophosphamide, and radiation induced.
B. Infectious
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Viral
Human Polyoma Virus: Human polyoma viruses are small, non-enveloped, doublestranded DNA viruses that are classified into two main strains, BK and JC. The JC
strain of the virus is associated with progressive multifocal leukoencephalopathy.
The BK strain of the virus affects the kidney and can be detected in the urine. A
primary BK virus infection occurs during childhood and is usually subclinical. Over
90% of adults are seropositive for BK viral antibodies. The BK virus generally
remains latent in the kidney, but intermittent viruria is demonstrable in 0.3% of
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healthy adults. The infection is reactivated in individuals with various degrees of
immunological deficits. BK virus-infected cells are characterized by the presence of
single, large, homogenous, basophilic inclusions occupying most of an enlarged
nuclear area. Because of the nuclear abnormalities, the infected cells can easily be
misclassified as malignant cells, and have been previously described as “decoy
cells”. The other type of cells commonly seen in PV infection are the “empty cells”,
described by Koss. In addition, urothelial cells affected by BK virus have an
abnormal DNA content.
Cytomegalovirus: Larger cell with perinuclear halo and both cytoplasmic and
nuclear inclusions
Adenovirus: Homogenous basophilic intranuclear inclusion, with multiple small
irregular inclusions, and nuclear clearing
Herpes: Multinucleation, margination of the chromatin, and molding of the nuclei
 Fungal:
Candida: is the most common fungal organism affecting the bladder. More common
in immunosuppressive patients and diabetes. If seen accompanied by numerous
squamous cells, bacterial organisms in women possibility of vaginal contamination
should be raised.
 Parasitic:
Trichomonas: Rare sexually transmitted infection, frequently associated with
genital coinfection. The organisms is a light gray, pear shaped protozoan ranging in
size between 15- 50μm, with cytoplasmic eosinophilic granules.
Schistosoma: Endemic in Africa and some parts of Asia. The organisms are
transmitted via fresh water snails. The eggs are oval, ranging between 100-150 μm,
with a terminal (S. hematobium) or lateral (S. mansoni) spine.
•
Bacterial
Fecal flora and malakoplakia (rarely - blue targetoid calcosherules (MichaelisGutmann bodies)
Urolithiasis:
This one of the most common pitfalls in urinary cytology. Patients may present with
hematuria and/or filling defect. Cytology specimens may be cellular and three
dimensional fragments composed of cells exhibiting significant pleomorphism may be
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seen. Often clinical history is crucial to avoid a false positive diagnosis. However, stones
can co-exist with a neoplasm.
Treatment Related Changes
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Cyclophosphamide:
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high N/C ratio
large nuclei
hyperchromasia and degeneration
granular and wispy cytoplasm
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Mitomycin and Thiotepa:
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umbrella cells mostly affected
marked nuclear enlargement
multinucleation
hyperchromatic, granular chromatin
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Radiation:
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cytomegaly
nucleomegaly
preserved N/C ratio
multinucleation
nuclear and cytoplasmic vacuoles
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BCG:
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granulomas
inflammation
multinucleated giant cells, histiocytes
Urothelial Carcinoma
The American Cancer Society predicts that approximately 131,000 new cases of
bladder cancer will be diagnosed in the year 2009 in the United States and approximately
28,100 people will die of the disease. Only about 50% of these new cases will be detected
by routine cytologic examination. At presentation, the majority of bladder cancers (75%)
will be superficial. Of these, 50% - 70% will recur and 10% - 20% will progress. This
natural history of bladder cancer results in a very high overall disease prevalence. As a
matter of fact, the urinary carcinoma is described as the most prevalent form of cancer.
This is mainly due to two factors typical of superficial disease. The recommended
frequent follow up and the duration of this because of low risk of mortality due to
disease.
Epidemiology
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Highest rate in North America, Western Europe
Lowest rate in Japan
Male:Female – 3:1
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•
Median age at Dx - > 65 years
WHO/ISUP consensus classification (1998) of urothelial neoplasms
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Papillary Noninvasive
- Papilloma
- Inverted papilloma
- Papillary urothelial neoplasm of low malignant potential - PUNLMP
- Papillary urothelial carcinoma, low grade
- Papillary urothelial carcinoma, high grade
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Invasive Neoplasms
- Lamina propria invasion (superficial urothelial carcinoma)
- Muscularis propria (detrusor muscle) invasion
WHO
WHO/ISUP
Papilloma
Papilloma
TCC I
Low malignant potential
TCC II
Low grade UC
TCC III
High grade UC
Urothelial Carcinoma – Low Grade
Low grade tumors are characterized by:
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Increased cellularity
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Presence of papillary, cohesive clusters
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Mild to moderate pleomorphism
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Eccentric, mildly enlarged nuclei
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Mild irregularity in nuclear membrane
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Granular, even chromatin
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Homogenous cytoplasm
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Inconspicuous nucleoli
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Low – moderate sensitivity and specificity
The cytologic and architectural criteria are unreliable in diagnosing low grade lesions.
Also low grade lesions having very little chance of progression, and if there is a papillary
low grade lesion the chance of the urologist seeing it in cystoscopy is very high.
Therefore, in practice, unless papillary fragments are seen with intact fibrovascular cores,
low grade urothelial carcinoma should not be diagnosed on cytology.
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Urothelial Carcinoma – High Grade
High grade tumors are characterized by:
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Increased cellularity
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Presence of loose clusters and single cells
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Moderate to marked pleomorphism
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Eccentric, enlarged, pleomorphic nuclei
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Irregular nuclear membrane
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Coarse chromatin
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+/- prominent nucleoli
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Squamous or glandular differentiation
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High sensitivity and specificity
Other bladder neoplasms
Primary
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Squamous cell carcinoma
Adenocarcinoma
Small cell carcinoma
Squamous cell carcinoma
This is a rare tumor, accounting for less than 5% of all bladder carcinomas.
It is most frequently associated with schistosomiasis, chronic inflammation, and
urolithiasis. Well differentiated squamous cell carcinoma shows cells with dense
cytoplasm, and orangophilia (if keratinizing), hyperchromatic small nuclei. In
contrast, poorly differentiated carcinoma has pleomorphic, hyperchromatic cells with
high N:C ratio, prominent nucleoli and a necrotic background. The co-presence of
urothelial carcinoma and dysplastic cells arising in the genital tract can not be
reliably distinguished cytological from squamous cell carcinoma arising in the
bladder. In the presence of dysplastic squamous cells in the urine a differential
diagnosis of urothelial carcinoma with squamous differentiation, squamous cell
carcinoma, and dysplastic cells arising in the genital tract should be raised.
Adenocarcinoma
Adenocarcinoma is also a rare tumor, accounting for less than 2% of all bladder
carcinomas. May arise in the bladder or urachus. Well differentiated adenocarcinoma;
forms glandular structures, or sheds as isolated columnar cells with hyperchromatic
nuclei and amphophilic, finely vacuolated cytoplasm. Poorly differentiated carcinoma
could have signet ring cells or cells with high N:C ratio, and prominent nucleoli.
Tumors cells are usually positive for Cytokeratin 20 and Cytokeratin 7 (CK7 has a
varying range of positivity 0-82%).In general CDX-2 and villin are negative in
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adenocarcinoma arising in the bladder, however, there are reports stating otherwise as
well.
Small cell carcinoma
As in other areas of the body this is a highly aggressive malignancy, accounting for
less than 1% of the bladder carcinomas. Majority of small cell carcinomas are seen in
combination with urothelial carcinoma, and the most common symptoms are
hematuria, dysuria, and paraneoplastic syndromes. The cytyomorphology is identical
to small cell carcinomas seen elsewhere; small round to oval cells, with high N:C
ratio, scant cytoplasm, hyperchromatic nucleus with coarse- ‘salt and pepper’
chromatin, nuclear molding, and occasional mitotic figures. The tumor cells are
usually positive for at least one of the following chromogranin, synaptophysin, and
CD 56.
Secondary
• ~ 10% of bladder tumors
• Majority (~ 70%) – direct invasion: prostate, cervix, uterus, GI tract
• Distant metastases – malignant melanoma, carcinomas of stomach, breast,
kidney and lung
Ancillary Techniques in Urine Cytology
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DNA ploidy
 Flow cytometry
 Static image analysis
 Laser Scanning Cytometry
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Morphometry
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Cytogenetic alterations and urothelial tumor markers
 Microsatellite Instability Assays
 FISH
 Blood (ABO) group antigens and Lewis X
 Urothelial tumor-associated monoclonal antibodies
 CK 20
 E-cadherin
 P53
 The BARD Bladder Tumor Antigen - BTA
 The Nuclear Matrix Protein- NMP22
 Telomerase
 Multiprobe FISH Assay – UroVision
 Cyfra 21-1
 ImmunoCyte
 Survivin
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DNA Ploidy
The evaluation of DNA ploidy in urinary specimens is becoming accepted adjunct
test used for both diagnostic and prognostic purposes. In general, low grade urothelial
carcinomas are diploid and high grade tumors are aneuploid. As a result, aneuploidy
is a strong indicator of high grade malignancy as well as carcinoma in situ. Also
aneuploidy in conjunction with suspicious cytology is highly predictive of tumor
recurrence. In addition, it has been shown that DNA ploidy analysis provides
independent prognostic information.
Definitions:
DIPLOID:
Normal (2c or 2N) amount of DNA corresponding
to 46 chromosomes; cells in G0/G1 stage of the cell
cycle; DNA index –
DI = 1
ANEUPLOID:
Abnormal (increased or decreased) amount of DNA
TETRAPLOID:
Double amount of DNA (4c or 4N DNA)
HYPERPLOID:
DNA content > 5c
Diploid histogram
Aneuploid histogram
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DNA Ploidy – Flowcytometry
Flow cytometry (FCM) was first applied to study bladder washings from patients
with urinary carcinomas. Numerous early studies reported the usefulness of this
technique in the management of bladder cancer. It has been documented that flow
cytometric DNA ploidy results correlate well with cystoscopic and cytologic findings.
When FCM and urine cytology were used together an improved diagnostic ability was
observed. However, recent reports did not confirm these early findings. In addition, FCM
requires numerous cells, therefor only bladder washes are suitable specimens.
DNA Ploidy – Static Image Analysis
The alternative and most commonly used technology to evaluate a DNA ploidy in
urine specimens is image analysis (IA). Image analysis is a broad term, encompassing
morphometry, densitometry and even neural networks. Typically, the term is used to
describe an integrated, interactive computer-based system in which measurements of
specific cellular features, including the amount of DNA, are analyzed. In this method,
cells (100 – 200) are visually selected by operator. All urine specimens are suitable for
analysis. Nuclear DNA ploidy is evaluated on Feulgen-stained slides.
In the DNA staining method, developed by Feulgen and Rossenbeck,
hydrochloric acid is used to hydrolyze the ribose-purine bonds in the DNA to give sugar
aldehyde residues, and a dye is then coupled stoichometrically to the sugar aldehyde. The
staining intensity becomes a measure of the DNA content in the nucleus. The absorption
spectrum maximum for the Azure A stain is 620 nm. The IOD is assumed to be
equivalent to the amount of DNA present in the nuclei.
DNA Ploidy – Laser Scanning Cytometry (LSC)
The Laser Scanning Cytometer (LSC) is a newly developed instrument highly
suited for DNA ploidy analysis. The LSC combines features of both flow and image
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cytometry and is capable of measuring multicolor fluorescence, light scatter and location
of cells fixed to a microscopic slide. It is capable of rapid and automatic measurements
of a large number of cells. In addition, cell location is recorded so the cells of interest
can be relocated for a morphologic examination and classification.
For DNA analysis the cells are stained with propidium iodide (PI) and cytokeratin
conjugated with fluorescein isothiocyanate (FITC). PI stoichiometrically intercalates
with the nucleic acids on the DNA strand. The fluorescence signal from a cell is
proportional to its DNA content. PI-stained nuclei emit fluorescence light at
wavelengths between 580 and 650 nm. The emission color is red. FITC emits light at
wavelengths between 488 and 525 nm. The emission color is green.
Pitfalls in DNA Ploidy
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Superficial cells
Polyoma virus infected cells
Seminal vesicle cells
Comparison between FCM, IA and LSC
FEATURES
FCM
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IA
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LSC
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+
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+
++
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+
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+
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++
+
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+
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Applicability to routine cytology specimens
Correlation with morphology
Specimen preparation
Speed
Labor intensity
Operator dependency
Measurement of multiple parameters
DNA Ploidy – Summary
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Low grade carcinoma – diploid
High grade carcinoma – aneuploid
Rare benign conditions – aneuploid
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•
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Help distinguish urothelial atypia from carcinoma
Not a screening test
Follow up of patients with history of urothelial carcinoma
Complement routine cytology
Morphometry
Morphometry has been defined as the “quantitative description of a structure”. In
practice, this term is usually applied to quantitative techniques that measure features of
size, shape, and texture in two dimensions and/or spatial relationships from cells or other
tissue structures. The need for measurement comes from the recognition that
interobserver and intraobserver diagnostic decisions are poorly reproducible.
Morphometry has several advantages over conventional visual assessment: objectivity,
reproducibility and the ability to detect changes too subtle to be visually appreciated in
individual cells. Therefore morphologic diagnostic accuracy and precision can be
improved by applying this technique.
Morphometry – summary
• Valuable diagnostic tool
• Important prognostic information
• Potential for automation
• Mostly under investigation
Molecular Alterations in Bladder Carcinoma
A number of studies aimed at defining loss of heterozygosity have shown a
general chromosomal instability in UC with loss of parts of chromosome 9 at early stages
and of chromosomes 11, 13, 3, 4, 8, 17 and 18 during further development of the tumor.
It has been postulated that two different tumor suppressor gene loci on chromosome 9 are
involved as tumorigenic events in bladder cancer. It was also postulated that loss of
heterozygosity of 9p might be associated with the development of tumor with more
aggressive behavior.
Fluorescence in situ hybridization (FISH) has been demonstrated as a viable
method for determination of chromosome specific anomalies in cells obtained from urine
specimens for early tumor detection or recurrence. Recently, a multi-color FISH Probe
Mixture designed for interphase cell analysis for detection and quantification of
chromosome 3, 7, 17 and the 9p21 region has been made commercially available
(UroVysion  Multi-color FISH Probe Mixture, Vysis).
Tumor Markers in Urothelial Carcinoma
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Lewis X
- the only blood group antigen with potential prognostic application.
Immunocyt  -M344, 19A211, LDQ10; sensitivity – 86%, specificity – 79%
CK 20 RP-PCR; sensitivity – 91%
E-cadherin - up-regulated in papillary tumors, expression gradually lost in high grade,
invasive carcinomas
p53 sensitivity in voided urine – 23.5%, specificity – 75%
Telomerase - telomerase activity is measured using a telomeric repeat amplification
protocol (TRAP). This method requires a minimum 30 ml of urine. The
reported sensitivity ranges from 56 to 89% and specificity ranges from 70
to 96.4%.
BTA  The original BTA test is a latex agglutination assay which detects the
presence of basement membrane antigens that have been isolated and
characterized in the urine of bladder cancer patients. Reported sensitivity
of the BTA test for detection of recurrent bladder tumors ranged between
32% and 74%, and the specificity ranged between 40% and 96%.
Modification in the original BTA test resulted in the development of a
single step, five-minute, immunochromatographic assay, BTA Stat and
BTA TRAK assay. These assays detect a human complement factor H
related protein that is produced in vitro by several human bladder cancer
cell lines but not other epithelial cell lines. The BTA Stat shows an
improved sensitivity and specificity as compared to the original BTA test.
At this moment, despite numerous controversial reports, most authors
would agree that this test could be utilized only as an adjunct to cytology,
particularly for the detection of recurrent tumors.
NMP  NMP22 is an enzyme immunoassay for the quantification of nuclear
matrix proteins that comprise the internal structural framework of the
nucleus. The antibodies in this assay recognize two domains of the nuclear
mitotic apparatus protein. This is a quantitative assay with a recommended
cut off point of 10 IU/ml.
CYFRA 21-1 enzyme-linked immunoabsorbent assay kit (ELISA-CYFRA 21-1; CIS Bio
International, Gif-Sur Yvette, France. The assay uses two monoclonal
antibodies, BM 19-21 and KS19-1, to recognize cytokeratin 19 fragments.
Overall median sensitivity and specificity
(Adapted from Lotan and Roehrbon, Urology 61: 109-118, 2003)
Marker
Cytology
NMP 22
BTA test
CYFRA
Telomerase
Immunocyt
Patients
(n)
1255
834
976
225
104
79
Sensitivity
(%)
34 (20-53)
73 (47-87)
49 (24-74)
94 (74-99)
77 (53-91)
86
15
Patients
(n)
1521
1579
1398
245
168
170
Specificity
(%)
99 (83-99)
80 (58-91)
86 (66-95)
69 (57-78)
99 (46-99)
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II. FNA OF RENAL LESIONS
Fine needle aspiration (FNA) of kidney masses have been performed for the diagnosis of
mass lesions, confirmation of advanced neoplasia and metastases, staging of tumors, and
rarely as therapeutic aspiration of cystic lesions. 1 In the past the decision of whether to
perform a nephrectomy used to be based on radiographic features and size, precluding the
use of FNA. 2 Today where treatment is not limited to surgery the indications for renal
FNA have expanded.
The indications of renal FNA in solid masses include:
1.Patients with presumed malignant lesions who aren’t candidates for resection. These
include patients with unresectable primary tumors, patients with metastatic disease and
patients with another primary tumor with other comorbidities to preclude surgery.
2. Cases where partial nephrectomy or laparoscopic morcellation is preferred over radical
nephrectomy
3.Cases where non surgical treatment methods such as minimally invasive methods are
preferred.
4.Cases where preoperative/neoadjuvant chemotherapy or biological response modifiers
are preferred.
5. Cases where pretreatment molecular/ cytogenetic typing of the tumor is recommended
to individualize the treatment of choice.
The indications of renal FNA in cystic masses include:
1. Simple cysts for therapeutic aspiration (this is more of an indication of the past, today
most simple cysts are just followed up).
2.Radiologically indeterminate cystic lesions.
Prerequisites and technique for Renal FNA: A platelet count of > 70.000/ml is
required; and the patients on anticoagulants should stop taking them 2 days prior to the
biopsy. The FNA is performed under conscious sedation in addition to local anesthesia,
with 20- 23 gauge needle (spinal or Chiba) following an 18 gauge guide needle under US
(and rarely CT) image guidance.
Complications of Renal FNA are very rare and include: perirenal hemorrhage,
pneumothorax, infection, A-V fistula, urinoma. There are very few reports of needle tract
seeding. 3,4
Renal FNA Statistics: The accuracy of FNA of kidney in diagnosing tumors range from
73% to 94 %, the sensitivity 50-90%, the specificity 50-93%. The diagnostic yield quoted
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in earlier papers are as low as 40%, however with the newer imaging techniques it has
risen to up to 95%. 5,6,7 8,910,11 Nevertheless, there are several challenges in diagnoses:
differentiation of the normal renal elements, identifying well differentiated renal cell
carcinomas (RCC), differentiating between oncocytoma and chromophobe RCCs, and
differentiating between high grade papillary RCC, urothelial carcinoma, collecting duct
carcinoma and metastatic carcinomas. Another potential problem is necrotic,
hemorrhagic, or cystic tumors, which may lead to a false negative diagnosis. Currently
there is no consensus on the adequacy criteria however it has been suggested to deem soft
tissue and/or normal kidney elements only, and blood and/or necrotic tissue, and scant
cellularity (few well-preserved cells) as unsatisfactory on solid renal mass FNA. 6 In
practice a sample is deemed satisfactory if it is sufficiently cellular to conjure a
differential diagnosis and to render a specific diagnosis. Cystic lesions, on the other hand
are tricky, even though abundant fluid is aspirated the smear could be acellular; or it
could be composed of macrophages only therefore it is difficult to define adequacy in
cystic lesions.
Normal Kidney Cytology:
Glomeruli: Cellular globular/papillary structures composed of spindled and round
cells. Prominent capillary loops could be identified. Differential diagnosis (DDX):
Papillary RCC (shows atypia and true fibrovascular cores)
Proximal Convoluted Tubules: Rare cells with indistinct cytoplasmic borders,
abundant granular cytoplasm, and low N:C ratio. DDX: Oncocytoma, Chromophone
renal cell carcinoma (RCC) (both have sharply defined cell borders)
Distal Convoluted Tubules: Rare groups of small cells with clear or granular
cytoplasm with well-defined cell borders and inconspicuous nucleoli. These are smaller,
flatter epithelial cells compared to the proximal tubular cells. DDX: Clear cell RCC
(shows cytoplasmic vacuolization and nuclear atypia in higher grades), papillary RCC
(shows atypia and papillae)
Collecting Ducts: Small, tight clusters of small cells with scanty cytoplasm, high
N:C ratio, indistinct cellular borders and inconspicuous nucleoli. DDX: High grade
papillary carcinoma, collecting duct carcinoma, metastatic adenocarcinoma (all these
entities show more cellular atypia and have more conspicuous nucleoli)
Cystic Lesions: The majority of renal mass lesions (70-85%) are cysts; 12, 13 and they are
mostly benign, acquired, and solitary. Renal cysts are classified radiologically according
to the likelihood of the cyst being benign/malignant (Bosniak System) 14 Category I being
benign, IV being most likely malignant, II and III indeterminate. It is controversial
whether or not to perform FNA on simple cysts (Bosniak I), however it is becoming a
common practice to opt for FNA when there is suspicion of malignancy (Bosniak II-IV).
The incidence of a cyst harboring RCC ranges between 1-25%. 15,16,17 , and the negative
predictive value of a renal cyst FNA is low. In case of multiple cysts, the differential
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diagnosis includes cysts due to long term dialysis or transplantation (these have a 9%
chance of developing renal cell carcinoma) 18, and autosomal dominant (adult type)
polycystic disease of the kidney. FNA of most simple cysts including the cases with
multiple cysts yield clear, pale straw-colored fluid which shows a few foamy
macrophages and no epithelial elements.
Benign Lesions:
Xanthogranulomatous Pyelonephritis (XP): Inflammatory sequela of chronic
suppurative renal infection (Proteus or E.coli), often associated with an obstruction. The
peak age incidence is between 4th and 6th decades. Cytology shows a cellular aspirate
with foamy histiocytes singly and in clusters, multinucleated giant cells, and
neutrophils. 19 DDX: Clinically, radiographically and pathologically can be confused with
renal cell carcinoma (RCC has a round nucleus compared to the kidney-bean shape in
XP, the nucleoli are more prominent in RCC). A panel of immunohistochemical stains
(ipox) and histochemical stains could differentiate reliably between the two (XP: PAS,
LMWtCK, EMA (-) and CD 68 (+)).
Renal Abscess: The aspirate is cloudy, white to yellow. Cytology shows acute
inflammatory cells. Gram negative organisms are the most common agent.
Renal infarct: Radiographically, they present as a wedge-shaped lesion. Cytology shows
necrotic glomeruli and tubules. Rarely atypia, cytoplasmic vacuolization, prominent
nucleoli could be seen. 20 DDX: RCC (atypia is more pronounced)
Metanephric adenoma: Rare tumors that may arise from renal tubule epithelium. It is
most commonly seen in women in 5th decade. Cytology shows aggregates of small
tubules and glomeruloid, tight short papillae composed of bland cells with scant
cytoplasm, fine chromatin and rare nucleoli. Rare foci of necrosis may be present. DDX:
Wilms tumor (WT1 (+)), papillary RCC (usually has more cytoplasm, longer papillae;
and are pancytokeratin and EMA (+) unlike MA), metastatic papillary carcinoma of the
lung or thyroid (clinical history plus pancytokeratin, EMA TTF-1 or thyroglobulin (+))
Renal cortical (papillary) adenoma: Small papillary renal cell tumors <0.5 cm in
diameter occur commonly and rarely become malignant. In the recent WHO
classification they are classified as renal cortical adenoma. 21 Cytologically these tumors
are same as papillary RCC.
Angiomyolipoma: is composed of smooth muscle, adipose tissue and vessels. About
20% of cases are associated with tuberous sclerosis complex. Owing to high vascularity it
may be confused with renal cell carcinoma on angiogram. Cytology shows a highly
cellular aspirate with spindled to epithelioid cells singly and in clusters. Stromal cells are
round to oval nuclei with fine chromatin, and inconspicuous nucleoli. Sporadic
intranuclear inclusions could be seen. Pleomorphism, mitotic figures and necrosis are
very rare. Ipox: HMB45 (+) and CD10 (-).
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Oncocytoma: Account for 3-5% of renal masses. Cytology shows loosely cohesive small
groups and isolated cells with abundant eosinophilic, granular cytoplasm with distinct
cell borders, round nuclei with fine chromatin and occasional binucleation. However
sometimes nuclear atypia, pleomorphism and prominent nucleoli could be seen making it
difficult to differentiate from RCC. DDX: Proximal tubular cells (the granules of the
cytoplasm spill out in benign tubular cells and the cytoplasmic membranes are indistinct),
hepatocytes (hepatocytes have a polygonal cytoplasm and are heppar1 (+)), chromophobe
RCC (see below for detailed discussion), clear cell RCC (unlike clear cell RCC,
oncocytoma is pancytokeratin (+), vimentin (-), CD10 (-)). In case of scant cellular
specimen where further studies (ipox, electron microcopy) can not be done the lesion is
better classified as an ‘oncocytic neoplasm’ on cytology.
Malignant Lesions:
Renal Cell Carcinoma (RCC): This is the most common tumor of the kidney. It is most
prevalent in males in the 5th –7th decades. It is important to distinguish between types of
RCC since they have different prognostic and treatment implications.
Clear Cell RCC: Approximately 75% of RCC are clear cell type, and they are associated
with chromosome 3p deletions. The cytologic features are of a cellular aspirate composed
of large clusters and sheets of cells with abundant and vacuolated cytoplasm, low N:C
ratio and eccentric nucleus. DDX: Tubular cells, macrophages, adrenal, hepatocytes
(because of the bland nature of low grade RCC it could be mistaken for benign elements,
however benign tubular cells and macrophages are not found in large clusters,
hepatocytes have a more granular and polygonal cytoplasm and several ipox could be
used to differentiate RCC from adrenal neoplasms: EMA, vimentin, CD 10 (+) in RCC,
inhibin, melan A, synaptophysin, calretinin (+) in Adrenal cortical neoplasms)
Papillary RCC: Approximately 15% of RCC are papillary, and they are associated with
trisomy chromosome 7, 16, and 17. These tumors are usually small and peripheral; they
could be multifocal and associated with cortical adenomas. The prognosis is better than
of the clear cell type. Cytology shows a cellular aspirate with the malignant cells
arranged in a papillary configuration around fibrovascular cores. The cells could have a
granular or vacuolated cytoplasm with rare intracytoplasmic hemosiderin deposits. N:C
ratio is high, the nuclei are uniform; and rarely intranuclear grooves could be identified.
Occasional foamy macrophages and rare Psammoma bodies could also be seen. DDX:
Benign distal tubular cells, clear cell RCC, urothelial carcinoma, collecting duct
carcinoma, metastatic carcinomas (Ipox aids in the diagnosis i.e. Like other RCC: EMA,
Low molecular weight CK (+), Mucin, CEA (-); unlike other RCC CK7 (+); unlike
Collecting Duct Ca: High molecular weight CK (K903) (-))
Chromophobe RCC: Only 3-5% of RCC are of chromophobe type and are associated
with multiple chromosomal deletion. These tumors also have a better prognosis than clear
cell RCC. Cytology shows a cellular aspirate composed of broad ribbons and loosely
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cohesive groups of cells with fluffy/flocculent to granular cytoplasm with focal
vacuolization and distinct cell borders. There is frequent binucleation and nuclear size
variation. Diff-Quik stain shows a perivascular reticulated zone. DDX: Oncocytoma,
clear cell RCC (Oncocytomas could have a membraneous staining of Hale’s colloidal
iron whereas Chromophobe RCC are usually diffusely positive.
Due to morphologic, molecular, and antigenic similarities (such as c-kit (+) 22 in both
tumors) it is thought that these tumors could be of similar descent i.e. different
expressions of the same morphologic spectrum, but detailed studies are still needed to
verify this theory. A variety of ipox have been reported to have a differentiating value
between chromophobe RCC and oncocytoma ks-cadherin (+/-) 23, caveolin 1 (+/-) 24, CD 3
(-/+) 25, CD63 (diffuse+/apical or polar+) 26 although to this date the gold standard still
electron microscopy where oncocytomas show abundant cytoplasmic mitochondria and
chromophobe RCC show cytoplasmic microvesicles).3
Sarcomatoid RCC: Accounts for 3-5% of renal cell carcinomas. It is defined by the
presence of a high grade spindle cell component, with or without epithelioid
differentiation. If the epithelial component is not seen CK (+) cells are necessary for
diagnosis. It is not a subtype for RCC, it rather represents dedifferentiation of any type of
RCC. The prognosis bad with a median survival of 6 months. Cytology shows malignant
high grade spindle cell component in a background of RCC. Undersampling could fail to
detect the sarcomatoid component thus if there is a radiologic suspicion for sarcomatoid
differentiation (different echogenic areas) it is important to ask for additional samples for
an accurate diagnosis. DDX: Metastatic high grade sarcoma (sarcomatoid cells are EMA,
CK (+), sma (+/-), vimentin (+))
Collecting Duct Carcinoma: Very rare adenocarcinoma arising from the collecting
ducts epithelium. Cytology shows cells arranged in small clusters, papillary configuration
or single cells with scant dense to vacuolated cytoplasm, high N:C ratio, hyperchromatic
nuclei, and prominent nucleoli. DDX: High grade RCC, High grade UC, metastatic
carcinomas (cytology alone can not distinguish these entities, ipox is of help; i.e. CDC
ulex and mucin (+)).
Renal Medullary Carcinoma: Clinical entity seen in young black men with sickle cell
trait. Cytology reveals cohesive cellular groups with vacuolated cytoplasm, indented
nuclei, irregular membranes, coarse or vesicular chromatin. 27 DDX: High grade
urothelial carcinoma, metastatic carcinoma.
Urothelial Carcinoma (UC): This is the most common tumor of the renal pelvis,
accounting for 10% of all malignant renal tumors. It is most commonly seen in men in 7th
decade1,28. There is a significant association with synchronous or metachronous urothelial
tumors in other sites so the surgical approach is different than of RCC therefore
differentiation on cytology is important. The low grade (LG) tumors cytologically reveal
sheets and papillae composed of cells with dense, nonvacuolated cytoplasm with large
hyperchromatic nuclei. High grade (HG) tumors reveal single or small clusters of cells
with scanty dense to wispy cytoplasm, high N:C ratio, with large hyperchromatic nuclei,
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and cercariform cells. DDX of LG UC: Papillary RCC (less layers of epithelial elements
compared to UC). DDX HG UC: Collecting duct carcinomas, metastatic papillary
neoplasms (e.g. lung, thyroid) and papillary RCC (history and ipox helps in accurate
diagnosis. UC are CK 7, CK 20, uroplakin III and thrombomodulin (+))
Metastatic Carcinomas: The most common primary sources are breast, lung, intestine,
opposite kidney, and stomach. 29 Metastatic tumors of the kidney are often bilateral and
multifocal. The history of a previous primary lesion and an ipox aid in the diagnosis.
Other rare lesions: Lymphoma (secondary involvement of diffuse large B-cell
lymphoma is the most common), sarcoma (leiomyosarcoma is the most common type).
Summary of immunohistochemical profiles of common renal neoplasms
CK7 CD10 EMA LMW CK HMW CK Vimentin Ulex CEA Mucin Hale's CI
UC
+
+
+
+
+/- PRC
+
+
+
+
+
CDC
+
+
+
+
+
+
+
+
RCC
+
+
+
CRCC
+
+
Oncocytoma +
+/-
UC= Urothelial carcinoma, PRCC=Papillary renal cell carcinoma, CDC=collecting duct
carcinoma, RCC=Renal cell carcinoma, CRCC=Chromophobe renal cell carcinoma, CK
7=cytokeratin 7, LMW= low molecular weight, HMW= high molecular weight, CEA=
carcinoembryonic antigen
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