, Fan Lin2 and Haiyan Liu2
(1)
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
(2)
Department of Laboratory Medicine, Geisinger Health System, Danville, PA, USA
Keywords
AngiomyolipomaRenal cortical adenomaXanthogranulomatous pyelonephritisMetanephric adenomaRenal oncocytomaUrothelial carcinomaCystic renal cell carcinomaClear cell renal cell carcinomaChromophobe renal cell carcinomaPapillary renal cell carcinomaCollecting duct renal cell carcinomaWilms tumor (nephroblastoma)Metastatic tumorCryotherapyRadiofrequencyEthanol injectionsMucinous tubular and spindle cell carcinomaXp11 translocation renal cell carcinomaTubulocystic renal cell carcinomaMyelolipomaMalakoplakiaAdrenal cortical adenomaAdrenal cortical carcinomaPheochromocytomaCK 7CK20 EMA VimentinInhibinMelan AKIM-1pVHLSummary of Pearls and Pitfalls
Up to 30% of aspirates are nondiagnostic; a scant specimen containing only small number of atypical cells is not reliable for a positive diagnosis; even if it is called suspicious, it is likely the kidney will be resected.
The diagnosis of a cystic renal cell carcinoma (RCC) has very low sensitivity on FNA.
RCCs can be subclassified by FNA.
It may be difficult to distinguish oncocytoma from chromophobe RCC, especially for the hybrid oncocytic chromophobe tumor.
When evaluating an FNA from a radiographically visible mass, renal adenoma is not a diagnostic consideration.
It is difficult to make a diagnosis of an angiomyolipoma on FNA in practice because only the radiographically the low fat masses are selected for FNA.
Metanephric adenomas are benign and negative for EMA and may be difficult to distinguish from a Wilms tumor (nephroblastoma) but mostly in children under 6 years old.
Urothelial carcinoma (UC) cells often have hyperchromatic angulated nuclei and squamoid cytoplasm, such as cercariform cells, and are frequently immunoreactive for CEA, GATA3, and CK20 .
Metastatic tumor cells usually have different cytomorphologic features and usually have known primary elsewhere, except collecting duct RCC, which can mimic metastatic tumors.
Hepatocytes can be accidently sampled, usually have abundant granular cytoplasm with patterns in groups and singly placed cells, may have bile, or show nuclear and cellular size variation.
Adrenal cortical lesions are immunoreactive for inhibin , calretinin, and melan A .
Fine-needle aspiration (FNA) of the kidney is a useful technique for the diagnosis of selected renal lesions. Most renal lesions are not candidates for FNA.
Resected with a presumptive diagnosis based on imaging studies, without a preoperative FNA.
In adults, the great majority of renal lesions are either radiologically benign cysts requiring no treatment or radiologically suspicious masses requiring a resection regardless of the result of an FNA.
Only a small percentage of adult renal lesions, perhaps less than 10%, are candidates for FNA, but in these cases, an FNA can be very helpful.
Recently a more conservative treatment of a small renal mass (less than 7.0 cm) has been introduced:
Cryotherapy
Radiofrequency
Ethanol injections
As the result, a preoperative diagnosis is often required. So FNA or thin-needle core biopsy may gradually gain its popularity.
FNA Indications
When radical nephrectomy is contraindicated:
Unresectable renal cell carcinoma.
Possible metastasis to the kidney (e.g., history or suspicion of cancer elsewhere).
Patient has coincident medical problems and cannot tolerate the operation.
Patient desires an investigational treatment (lesion ablation in vivo); an FNA is obtained for tissue diagnosis before the ablation procedure.
When radiologic findings are equivocal:
Atypical cysts; FNA is used to triage patients for either surgery or clinical observation. Advances in radiographic assessment of cystic renal lesions have made FNA less useful in this setting.
Fat-free angiomyolipomas.
When a partial nephrectomy is considered :
Some papillary RCC and chromophobe RCC with a good prognosis.
Smaller lesions and lesions in younger patients as the incidence increases.
Patients with the von Hippel-Lindau syndrome at risk for bilateral tumors.
Patients with decreased renal function are candidates for nephron-sparing surgery.
Although the ultimate decision to treat by partial nephrectomy depends on the size and location of the lesion as well as other clinical factors, FNA is valuable because it discloses whether or not the tumor is one of the “good prognosis” neoplasms amenable to conservative treatment .
When an abscess is suspected :
Patient with a renal abscess, needle placement permits both diagnosis and therapeutic drainage.
An equivocal case is best diagnosed as “oncocytic neoplasm: oncocytoma, chromophobe RCC, and clear cell RCC with eosinophilic granular cytoplasm.” With a note, if clinically indicated, a partial nephrectomy should be considered. Finally one must consider inadvertent sampling of the liver .
Specimen Collection and Preparation
All aspirations are virtually carried out by radiologists: They rarely are performed intraoperatively by surgeons.
Complications are uncommon and include bleeding, hematuria, pneumothorax, infection, arteriovenous fistula, and urinoma.
Needle-tract seeding is extremely rare with the use of small (less than 18-gauge) needles.
Slides may be air-dried and stained with a Romanowsky stain and/or alcohol fixed and stained with the Papanicolaou or hematoxylin and eosin stains.
Cell blocks are particularly helpful for identifying architectural features such as papillae and provide an ideal platform for immunohistochemical studies (e.g., HMB-45 to confirm the diagnosis of an angiomyolipoma) .
Accuracy and Adequacy
The true accuracy of renal FNA in routine practice is uncertain. Investigators with experience find:
Renal FNA accurately distinguishes benign from malignant lesions in 73–94% of cases.
Correct subclassification of RCC is achieved in 74% of cases.
In the 1998 College of American Pathologists Non-Gynecologic Cytology Program, renal FNA had the highest false-positive rate (30.4%) of any FNA specimen and the second highest false-negative rate (13.9%).
False-positive results occur with FNA:
Xanthogranulomatous pyelonephritis
Angiomyolipoma
Benign hepatocytes
Benign tubular cells
Benign adrenal cortical cells
This disappointing accuracy is likely a reflection of the difficulty in obtaining experience in general practice, however, which better reflects the spectrum of routine practice, because so few kidney lesions are aspirated.
There is no consensus on adequacy:
Up to 30% of renal aspirates are nondiagnostic (inadequate).
A repeat aspiration is unhelpful in over 40% of cases.
It is reasonable to consider a specimen adequate if a specific (benign or malignant) diagnosis can be made or if there is sufficient cellularity to suggest a limited differential diagnosis. A specimen composed exclusively of macrophages is best reported as “nondiagnostic” rather than negative, because a cystic RCC cannot be excluded.
Table 9.1 lists the new version of the classification of renal neoplasia . This chapter will mainly focus on the common renal and adrenal tumors which often can be diagnosed on FNA specimens.
Table 9.1
ISUP Vancouver modification of WHO (2004) histologic classification of kidney tumors
Renal cell tumors |
Papillary adenoma |
Oncocytoma |
Clear cell renal cell carcinoma |
Multilocular cystic clear cell renal cell neoplasm of low malignant |
potentiala |
Papillary renal cell carcinomab |
Chromophobe renal cell carcinoma |
Hybrid oncocytic chromophobe tumora |
Carcinoma of the collecting ducts of Bellini |
Renal medullary carcinoma |
MiT family translocation renal cell carcinomaa |
Xp11 translocation renal cell carcinoma |
t(6;11) renal cell carcinomaa |
Carcinoma associated with neuroblastoma |
Mucinous tubular and spindle cell carcinoma |
Tubulocystic renal cell carcinomaa |
Acquired cystic disease associated renal cell carcinomaa |
Clear cell (tubulo) papillary renal cell carcinomaa |
Hereditary leiomyomatosis renal cell carcinoma syndrome-associated |
renal cell carcinomaa |
Renal cell carcinoma, unclassified |
Metanephric tumors |
Metanephric adenoma |
Metanephric adenofibroma |
Metanephric stromal tumor |
Nephroblastic tumors |
Nephrogenic rests |
Nephroblastoma |
Cystic partially differentiated nephroblastoma |
Mesenchymal tumors |
Occurring mainly in children |
Clear cell sarcoma |
Rhabdoid tumor |
Congenital mesoblastic nephroma |
Ossifying renal tumor of infants |
Occurring mainly in adults |
Leiomyosarcoma (including renal vein) |
Angiosarcoma |
Rhabdomyosarcoma |
Malignant fibrous histiocytoma |
Hemangiopericytoma |
Osteosarcoma |
Synovial sarcomaa |
Angiomyolipoma |
Epithelioid angiomyolipomaa |
Leiomyoma |
Hemangioma |
Lymphangioma |
Juxtaglomerular cell tumor |
Renomedullary interstitial cell tumor |
Schwannoma |
Solitary fibrous tumor |
Mixed mesenchymal and epithelial tumors |
Cystic nephroma/mixed epithelial stromal tumor |
Neuroendocrine tumors |
Carcinoid (low-grade neuroendocrine tumor) |
Neuroendocrine carcinoma (high-grade neuroendocrine tumor) |
Primitive neuroectodermal tumor |
Neuroblastoma |
Pheochromocytoma |
Hematopoietic and lymphoid tumors |
Lymphoma |
Leukemia |
Plasmacytoma |
Germ cell tumors |
Teratoma |
Choriocarcinoma |
Metastatic tumors |
Other tumors |
The Kidney
Normal cytology of the kidney:
Glomeruli
Proximal tubular cells
Distal tubular cells
Benign lesions :
Oncocytoma
Renal cortical adenoma
Angiomyolipoma
Metanephric adenoma
Cystic nephroma/mixed epithelial and stromal tumor
Xanthogranulomatous pyelonephritis
Renal abscess
Renal infarct
Renal cysts
Renal cell carcinoma :
Clear/conventional renal cell carcinoma
Papillary renal cell carcinoma
Chromophobe renal cell carcinoma
Sarcomatoid renal cell carcinoma
Mucinous tubular and spindle cell carcinoma
Xp11.2 translocation-associated renal cell carcinoma
Collecting duct carcinoma (Bellini tumor)
Urothelial carcinoma
Metastatic tumors
Normal Elements
Glomeruli
Cytological Features
Large papillary structures
Capillary loops (Fig. 9.1)
Fig. 9.1
Normal glomerulus . Dense cohesive spherical structures with small nuclei and scalloped borders, the capillary loops with spindle endothelial cells. Proximal tubular cells with abundant granular cytoplasm and ill-defined cell borders. Rare smaller distal tubular cells with scant cytoplasm (Papanicolaou stain)
Differential Diagnosis
Papillary RCC
Clear cell RCC
Proximal Tubular Cells
Cytological Features
Differential Diagnosis
Oncocytoma
Chromophobe RCC
Distal Tubular Cells
Differential Diagnosis
Low-grade clear cell or papillary RCC
Normal elements are occasionally encountered and may be misinterpreted as tumor cells. The cells in a glomerulus are not evenly distributed, but rather are much more dense in the center than at the periphery. Most importantly, endothelial cells lining capillary loops are seen at the edges. In RCCs, the nucleus is atypical, not as flat as that of an endothelial cell, and has size variations. See Fig. 9.1.
Proximal tubular cells have abundant granular cytoplasm and poorly demarcated cell membranes, and the granules often appear to be spilling out of the cells. They are similar to the cells of an oncocytoma and chromophobe RCC. Usually the cell borders of tumor cells are well defined, while those of proximal tubular cells are torn and irregular. See Figs. 9.1 and 9.2.
Distal tubular cells are smaller cells with less clear to granular cytoplasm and small round nuclei without nucleoli. The cell borders are well defined, and the cytoplasm is not vacuolated. These cells are very similar to those of a low-grade clear cell or papillary RCC. However, the tumor cells of low-grade papillary RCC form papillae and spherules . See Fig. 9.1.
Benign Lesions
Oncocytoma
Key Clinical Findings
Benign and comprise 3–5% of all renal tumors
Usually adults
Predominantly male
May be bilateral or multicentric
Key Radiologic Findings
Imaging findings substantially overlap those of common subtypes of clear cell and non-clear cell renal cell carcinomas. Multifocal renal oncocytomas are not rare, and making the diagnosis of oncocytoma with concomitant renal cell carcinoma is difficult. In addition, renal oncocytomas that demonstrate interval growth or develop in the setting of end-stage renal disease may be mistaken for malignancy.
Cytological Features
Hypercellular with mainly isolated uniform cells and cohesive nests
Abundant eosinophilic and granular cytoplasm
Well-demarcated cell borders
Frequent binucleation, round nuclei with prominent nucleoli
Figure 9.3a, b
Fig. 9.3
(a) Single uniform cells with abundant granular cytoplasm and distinctive cell borders, binucleation, and small prominent nucleoli (Papanicolaou stain). (b) Single uniform cells and small round nests with edematous stroma (cell block H&E)
Differential Diagnosis
Chromophobe RCC
Clear cell RCC with granular cytoplasm
Hepatocytes
Renal (Cortical) Adenoma
Except for their size, renal cortical adenomas are histologically, immunohistochemically, and cytogenetically indistinguishable from low-grade papillary RCCs. Renal adenomas account for 20% of adult kidneys and are by definition very small lesions, always in the cortex and less than 0.5 cm and usually less than 0.2 cm. They are too small to be aspirated, and therefore, the diagnosis “renal cell adenoma” is inappropriate for an FNA specimen .
Angiomyolipoma
Key Clinical Findings
Accounts for 0.07–2% of renal tumors.
Average is 40 years (30 years in tuberous sclerosis patients). Range is 12–72 years.
Predominantly female, up to 80% bilateral and multifocal in tuberous sclerosis (TS) patients. Usually unilateral and solitary in patients without TS.
About half occur in young patients with TS. Most are benign, large lesions, can bleed, and are often resected to prevent this from occurring. A very small proportion of the epithelioid subtype does metastasize, but predicting malignant behavior is not possible by FNA. The tumor has three neoplastic components: blood vessels, mature fat, and an atypical smooth muscle cell that can be spindled or epithelioid.
Asymptomatic lesions incidentally detected on CT scan or ultrasound. Symptomatic lesions greater than 4 cm have higher risk of spontaneous rupture and hemorrhage.
Pleomorphism and mitoses not associated with more aggressive behavior .
Key Radiologic Findings
The typical lesion with abundant adipose tissue is diagnosed confidently radiologically and as a result is rarely aspirated. Most FNAs are from radiologically atypical lesions, usually those with scant adipose tissue .
Cytomorphology
Fragments of spindle cells with vacuolated cytoplasm
Mature fat cells
Eccentrically thick-walled blood vessels
Often nuclear atypia
Most cases immunoreactive for HMB-45
Figure 9.4a-d
Fig. 9.4
(a) Cohesive tissue fragments comprised of vacuolated spindle cells and mature adipocytes (Romanowsky stain). (b) More spindle-shaped, smooth muscle cells and interspersed mature adipocytes (Papanicolaou stain). (c) Epithelioid AML with atypical nuclei and small prominent nucleoli mimics clear cell RCC (Papanicolaou stain). (d) Classic AML with vacuolated spindle cells, eccentrically thickened vessel wall, and scant mature adipose tissue (H&E)
Differential Diagnosis
Clear cell RCC when epithelioid cells predominate
Sarcomatoid RCC or sarcoma when spindle cells predominate
Metanephric Adenoma
Key Clinical Findings
A benign lesion most commonly occurs as an incidental finding predominantly in women with a mean age of 41 years.
10% of patients with polycythemia.
May have abdominal or flank pain, hematuria, fever, and hypertension.
Key Radiologic Findings
CT shows moderate enhancement of a mass with mean tumor size of 5.5 cm. Cystic areas along with hemorrhage and necrosis are common.
Cytomorphology
Cellular smear with tight, short papillae and loose sheets
Round monotonous nuclei, fine chromatin, rare small nucleoli, and scant cytoplasm
Occasional psammoma bodies
Negative for EMA and CK7 and positive for WT-1, CD56, and CD57
BRAF V600E mutations found in ~90% of tumor
Figure 9.5a–c
Fig. 9.5
(a) Loose sheets or small clusters of round cells with monotonous nuclei, fine chromatin, rare small nucleoli, and scant cytoplasm (Romanowsky stain). (b) Well-circumscribed tumor with crowded small acini of primitive blue cells in paucicellular intervening stroma. (c) Diffuse nuclear stain for WT-1
Differential Diagnosis
Wilms tumor (epithelial predominant type)
Papillary RCC (low grade)
Metastasis or small cell carcinoma
Renal Abscess
Radiologically renal abscess may appear as a mass. Aspirates contain necrotic material and numerous neutrophils with rare atypical epithelial cells, which may be confused with those of a clear cell RCC. The atypical cells are few in number, however, and such aspirates should be diagnosed as suspicious rather than positive .
Xanthogranulomatous Pyelonephritis
Key Clinical Findings
8% of kidneys removed for inflammation
Usually adults, predominantly female
UTI symptoms, almost always associated with urinary outflow obstruction
Key Radiologic Findings
Solid nodules centered upon pyramids
Cytomorphology
Single and clusters of histiocytes
No nuclear atypia
Multinucleated giant cells
CD68 positivity and negative for cytokeratin and EMA
Figure 9.6
Fig. 9.6
Single or clusters of histiocytes with uniform small nuclei and abundant foamy granular cytoplasm (Papanicolaou stain)
Differential Diagnosis
Clear cell RCC
Renal Infarct
Rarely, renal infarcts present as a mass suspicious for malignancy. Specimens are sparsely cellular and composed of necrotic material, which can contain rare atypical cells resembling those of clear cell RCC. A diagnosis of malignancy should be avoided when the atypical cells are few in numbers, which is usually the case with renal infarcts .
Renal Cysts
Cysts are common and most are benign.
Renal cell carcinomas can be cystic.
Adequate sampling difficult.
Some benign cysts are difficult to distinguish from RCC, such as cysts due to renal failure, adult polycystic kidney disease, and cystic nephroma.
The value of a negative diagnosis is limited.
If an FNA is performed and even a few atypical cells are seen, a “suspicious” diagnosis is appropriate.
If the result is nondiagnostic (macrophages only), an explanatory note can be helpful, such as “the findings are consistent with a cystic renal lesion. Because parenchymal elements have not been sampled, the possibility of a neoplasm cannot be excluded .”
Benign Entities that Sometimes Have Atypical Cells
Proximal tubular cells
Renal abscess
Xanthogranulomatous nephritis
Renal infarct
Atypical cysts
Angiomyolipoma
Best Diagnostic Clue
Hypocellular
Best Diagnostic Terminology
Suspicious rather than positive
Renal Cell Carcinoma
RCC is the most common tumor of the kidney. Patients may present with hematuria, flank pain, or a palpable mass, but the tumor is often discovered incidentally. RCCs are graded using the Fuhrman system ; because it is based on nuclear features, it is easily applied to cytologic preparations, with good cytological-histologic correlation. With heterogeneous RCCs, the highest grade is assigned. The most recent histologic classification system, strongly influenced by cytogenetic data on the various subtypes, is shown in Table 9.2. Many immunohistochemical markers are proven to be useful in distinction among the subtypes of renal cell neoplasms. Table 9.3 summarizes the frequently used markers .
Table 9.2
Cytogenetic data on subtypes of renal neoplasms
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