Section 4 -

Fine Needle Aspiration of Kidney Lesions Guliz Barkan Loyola University Medical Center Chicago

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. [1] Today where treatment is not limited to surgery the indications for renal FNA have expanded. The indications of renal FNA in solid masses include: 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. Cases where partial nephrectomy or laparoscopic morcellation is preferred over radical nephrectomy Cases where non surgical treatment methods such as minimally invasive methods are preferred. Cases where preoperative/neoadjuvant chemotherapy or biological response modifiers are preferred. 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: Simple cysts for therapeutic aspiration (this is more of an indication of the past, today most simple cysts are just followed up). 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 in earlier papers are as low as 40%, however with the newer imaging techniques it has risen to up to 95%. [5, 6] 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. [5] 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 vacuolation 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; [7] 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) [8] 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%. [9] , and the negative predictive value of a renal cyst FNA is low. In case of multiple cysts, the differential diagnosis includes cysts due to long term dialysis or transplantation (these have a 9% chance of developing renal cell carcinoma) [10], 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. 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) could differentiate reliably between the two (XP: PAS, LMWtCK, EMA (-) and CD 68 (+)). Renal Abcess: 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 vacuolation, prominent nucleoli could be seen. [11] 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 panCK and EMA (+) unlike MA), metastatic papillary carcinoma of the lung or thyroid (clinical history plus panCK, 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. [12] 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 (-). 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 theureupeutic 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 cohesive groups of cells with fluffy/flocculent to granular cytoplasm with focal vacuolation 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 ckit (+) [13] 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 (+/-) [14], caveolin 1 (+/-) [15], CD 3 (-/+) [16], CD63 (diffuse+/apical or polar+) [17] 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 entitites, ipox is of help; i.e. CDC ulex and mucin (+)). Renal Medullary Carcinoma: Clinical entity seen in young black men with sickle cell tra it. Cytology reveals cohesive cellular groups with vacuolated cytoplasm, indented nuclei, irregular membranes, coarse or vesicular chromatin. [18] 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 decade [1, 19] . 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, 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, uroplakinIII and thrombomodulin (+)) Metastatic Carcinomas: The most common primary sources are breast, lung, intestine, opposite kidney, and stomach. [20] 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 Histoand 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 References: Ruth L. Katz: Kidneys, adrenals and retroperitoneum. 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