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Intraoperative Pathology Consultation for Kidney and Urinary Bladder Specimens

Posted on: Thursday, 15 December 2005, 03:02 CST

By Truong, Luan D; Krishnan, Bhuvaneswari; Shen, Steven S

Context.-Intraoperative pathology consultation for kidney and urinary bladder specimens is relatively infrequent. Scant literature is devoted to this topic.

Objective.-The clinical indications and diagnostic usefulness and pitfalls of intraoperative pathology consultation of kidney and urinary bladder specimens will be reviewed, based on literature and personally encountered cases.

Data Sources.-The indications for intraoperative pathology consultation for renal lesions included (1) surgical margins in partial nephrectomy specimens, (2) solid renal mass in unusual clinical or radiologic settings, (3) synchronous renal and extrarenal masses, (4) cystic renal lesions, (5) ureteral surgical margin for transitional cell carcinoma, (6) multiple renal masses, (7) solid mass in a diffusely cystic kidney, and (8) evaluation of renal injury. The indications for urinary bladder included (1) status of the surgical margins, (2) diagnosis of bladder tumor biopsy, (3) diagnosis of extravesical tumors with vesical extension, (4) diagnosis of extravesical mass, including pelvic lymph nodes encountered during cystectomy, and (5) status of bladder neck margin during radical prostatectomy for cancer. The frequent problematic areas for the kidney included misdiagnosis or incorrect classification of cystic tumors or spindle cell tumors, and confusion of clear cell renal cell carcinoma with inflammatory lesions. The problematic areas for urinary bladder included the differential diagnoses of high-grade dysplasia/carcinoma in situ with reactive changes at the ureteral or urethral surgical margins.

Conclusions.-Distinctive indications and diagnostic pitfalls are recognized for intraoperative consultation of renal or urinary bladder lesions. Awareness of the pertinent problems should improve diagnostic accuracy and facilitate the proper management of these lesions.

(Arch Pathol Lab Med. 2005;129:1585-1601)

Intraoperative pathology consultation (IPC) for kidney and urinary bladder specimens is relatively infrequent.1-3 In one study, only 21 of 1000 specimens submitted for frozen section (FS) diagnosis were of genitourinary origin.4 This probably reflects both the relatively low incidences of kidney or bladder lesions that necessitate surgery requiring IPC, and the limited role of FS in the surgical management of these lesions.2 Most renal tumors are clinically assumed to be renal cell carcinoma (RCC) and are treated by radical nephrectomy without the need for an intraoperative diagnosis. Easy endoscopie accessibility enables a preoperative diagnosis for most bladder lesions. Intraoperative pathology consultation, however, remains essential for surgery in several instances. The clinical indications and diagnostic usefulness and pitfalls of IPC of kidney and urinary bladder specimens will be reviewed here.

KIDNEY

Types of Specimens

The types of renal specimens submitted for IPC are listed in Table 1.

Indications

Although the indications for IPC of renal specimens are not well defined and probably reflect personal preference, institutional tradition, and the type of hospital, those listed in the Table 2 are representative.

Gross Consultation.-Gross identification of a renal tumor is the most frequent form of IPC. Most renal tumors are treated by total nephrectomy (a decision mainly derived from clinical and imaging studies rather than a tissue diagnosis), and usually only gross consultation is requested to confirm the lesion. Diagnosis of tumor by FS is not needed because it does not alter treatment. Frozen section of vascular or ureteral surgical margin is usually not requested because involvement of these margins is rare.

Frozen section.-Frozen section is requested infrequently for the reasons listed in Table 2. It may be performed on total nephrectomy specimen to confirm the diagnosis of a clinically suspected RCC, or for an immediate diagnosis of a solid renal mass with clinical or imaging features unusual for RCC. In the latter situation, lesions other than RCC may be rather frequent and, in our experience, may include malakoplakia, xanthogranulomatous pyelonephritis, renal lymphoma, metastatic tumor, angiomyolipoma, large renal medullary fibroma, leiomyoma, perirenal mesothelial cyst, subcapsular hematoma, adrenal cortical carcinoma extending to kidney, or mixed epithelial and stromal tumor of the kidney.5

Table 1. Two Hundred Forty Consecutive Cases for Renal Intraoperative Consultation: Types of Specimens*

Table 2. Indications for 325 Consecutive Cases for Renal Intraoperative Consultation*

Partial nephrectomy is increasingly used to treat renal tumors.6 It is indicated when total nephrectomy renders the patient anephric,7 such as in solitary kidney; bilateral synchronous RCC; or genetic predisposition to multiple synchronous or sequential tumors, as in patients with von Hippel-Lindau disease (VHL). It is also indicated for small RCCs (usually <4 cm) confined to kidney,6 and more recently, for inflammatory masses or some benign renal tumors, such as multilocular cysts and angiomyolipomas.8 Partial nephrectomy specimen is routinely submitted for FS of surgical margin because complete tumor resection is essential for success.6 Frozen section is also increasingly requested for a specific diagnosis in this context, because tumor type may be one of the factors that determine whether partial nephrectomy is appropriate.6

The standard treatment for renal pelvic transitional cell carcinoma (TCC) is nephroureterectomy including a cuff of bladder wall. This type of specimen may be submitted for gross examination for demonstration of the tumor. In cases in which a renal pelvic tumor is present for which TCC is not preoperatively diagnosed but clinically suspected, nephrectomy with only a portion of the ureter is usually performed and FS is requested to confirmed TCC. Confirming TCC is important because it mandates removal of the rest of the ureter to prevent recurrence. Frozen section evaluation of the ureteral margin may also be requested because TCC is often multifocal and may involve this margin. From these considerations, it is suggested that FS be routinely performed for nephrectomy specimen with a predominantly hilar renal mass for which a preoperative tissue diagnosis is not available.

Up to 15% of renal tumors may be predominantly cystic and, on renal imaging, may appear simple (unilocular, with smooth and thin wall) or complex (multilocular, with thick, shaggy wall and solid areas).9 Simple cysts, which are usually accurately diagnosed by renal imaging with or without fine-needle aspiration, are usually not subjected to surgery. Complex cysts may histologically represent a large variety of lesions, including simple cyst with superimposing hemorrhage or infection, cystic nephroma, multilocular cystic RCC, and RCC with marked cystic changes secondary to necrosis or hemorrhage.9 The treatment for these lesions is quite different and depends on a specific diagnosis, which is usually not obtainable preoperatively, despite sophisticated renal imaging techniques or even fine-needle aspiration.9-11 Therefore, FS is usually performed. The submitted specimen may be a wedge biopsy of the cyst wall, the diagnosis of which may dictate a conservative approach versus surgical excision. It may be a partial or a total nephrectomy specimen, in which case, although FS may not alter therapy, it is requested to provide an immediate diagnosis that was unavailable preoperatively.

Medical renal biopsies are usually interpreted by specialized in- house or referral laboratories. However, initial handling of these biopsies may require the immediate attention of the pathologist. Because the majority of renal biopsies are performed for glomerular diseases, there may be a need to intraoperatively assess whether glomeruli are present in the submitted tissue cores.

Although FS of biopsy of kidneys donated for transplantation accounts for about 7% of all renal FS in our institution, this indication is not well recognized and may reflect its limitation to specialized centers. In response to an increasing demand for renal transplantation, there is an increasing willingness to use kidneys from "marginal donors" (those older than 55 years; those with diabetes, hypertension, acute tubular necrosis, or disseminated intravascular coagulation; or those without heart beat at time of renal harvesting).12 In these conditions, FS may be requested to aid in determining whether the kidneys are still suitable for transplantation.12

Frozen section is also indicated for specific diagnoses when multiple masses are identified in one or both kidneys, or when extrarenal masses, including enlarged lymph nodes, are unexpectedly encountered during surgery for renal tumors.

Gross Examination

Total Nephrectomy.-The following method for handling a total nephrectomy specimen is easy and informative. The intact, undisturbed specimen should be bivalved through the renal pelvis. To achieve this, a probe can be placed into the excretory system through the ureteral opening or through a nick made anywhere along this system. This probe guides accurate bivalving of the kidney so that the entire pyelocalyceal system is exposed. Most often, this single cut clearly reveals the renal lesion, with its cut surface, and its relationship to the adjacent renal p\arenchyma, renal pelvis, and perirenal soft tissue. In eccentric lesions, although the original cut may not suffice, additional cuts parallel to the original cut should provide gross details. This approach is particularly helpful for the differential diagnoses of rumors that predominantly involve the renal medulla/renal pelvic area. Renal cell carcinomas of large size or advanced stage, or tumors that tend to predominantly involve the renal medulla, such as collecting duct RCC, may extend to the peripelvic soft tissue and to the pelvic wall with or without extending to the pelvic lumen. Transitional cell carcinoma, on the other hand, typically appear as a shaggy thickening of the pelvic wall with involvement of pelvic lumen.

Table 3. Conventional (Clear) Renal Cell Carcinoma (RCC) Versus Xanthogranulomatous Pyelonephritis (XCP) Versus Renal Malakoplakia

Partial Nephrectomy.-Because of the complex anatomy of the kidney and the excretory system, the partial nephrectomy specimen is often disoriented or even disrupted, with the surgical margin difficult to identify. In such a case, orientation by the surgeon is essential. The margin should be inked, followed by serial sectioning perpendicular to the surgical margin to demonstrate the tumor and its relation to the margin. Although the shortest tumor to margin distance should be recorded, the minimum accepted distance has not been established.6,13 Renal cell carcinomas chosen for partial nephrectomy are usually small (<4 cm), circumscribed, and evenly encapsulated tumors of low nuclear grade, and remain confined to the kidney.13 Because of these considerations, the renal parenchymal margin is the most critical one, however, other margins (excretory system, vessels, and perirenal soft tissue) should also be evaluated.14 Satellite tumor nodules may be encountered in up to 25% of all RCCs but in approximately 7% of those suitable for partial nephrectomy.13 A recent study showed that in the latter instance, these nodules measure 0.1 to 2.8 cm and are situated 0.2 to 6.0 cm from the main RCC.13 These data suggest that satellite nodules are not usually included in the partial nephrectomy specimens and are not a problem in FS.

Biopsy.-Wedge or needle biopsy of renal lesion should be entirely submitted for FS, with the premise that the result would dictate immediate treatment decision and, in case a diagnosis is not achieved, additional tissue can be requested.

For medical renal biopsies, usually 2 or 3 tissue cores obtained by needle biopsy are submitted in saline or a preservative medium (usually tissue culture fluid). Because a spring-loaded biopsy device attached to an 18-gauge needle is currently used in most institutions, the obtained tissue cores are very thin. The division of these tissue cores for different studies is well described,15 but is beyond the scope of this section. However, requests may be made to determine whether glomeruli are sampled. Among various methods, we find the following method accurate and technically feasible, regardless of the particular laboratory setting.16 The tissue cores should be placed on a regular glass slide within a drop of preservative medium and examined under a regular light microscope. Open glomeruli are usually easily and accurately identified. Gently placing a coverslip on top of the cores will flatten the cores and facilitate glomerular visualization. Sclerotic glomeruli may not be visualized by this technique. For handling of the biopsy from donated kidney, please refer to the section "Donors' Kidneys" on p 1596.

Frozen Section Diagnoses

Although most renal tumors are treated by total nephrectomy followed by a gross examination consultation, FS is sometimes requested. In cases of total nephrectomy, an incorrect or deferred diagnosis will not alter the treatment and, therefore, does not affect patient care. However, in cases in which an intraoperative treatment decision (conservative vs partial or total nephrectomy) must be made, a correct FS diagnosis is essential.17 Selected differential diagnostic problems derived from our experience or literature are discussed next. It should be emphasized that because RCCs display a broad morphologic spectrum and because the histologic classification of RCC is still evolving, an exact FS diagnosis may not be possible in some cases. Deferment in these cases is appropriate and usually does not affect patient care.

Differential Diagnoses of Conventional (Clear) RCC Versus Xanthogranulomatous Pyelonephritis Versus Malakoplakia.- Differentiation between conventional (clear) RCC, Xanthogranulomatous pyelonephritis, and malakoplakia (Table 3) is usually difficult using imaging studies and gross examination. Frozen or permanent sections are necessary because the correct diagnosis depends on recognizing the cell type and characteristics for each entity.18-21 The clear cells in solid areas of RCC usually appear intact with a preserved cell membrane and a characteristic clear or clear/granular cytoplasm in a rich vascular network recognizable in FS (Figure 1, A). Difficulty may be encountered if the delicate cytoplasm of the tumor cells disintegrates, resulting in bare nuclei; this is especially true for low-grade tumor cells from cystic areas. Alternatively, during FS, the "clear" cytoplasm of tumor cells may display a faint eosinophilia. It was suggested that fixing the frozen tissue sections in formalin for 1 minute and hematoxylin overstain for 2 minutes may better delineate cell membranes and accentuate the clear cytoplasms.22 The features of clear cells can also be well recognized in touch preparations.

Figure 1. Differential diagnoses of clear cell renal cell carcinoma, xanthogranulomatous pyelonephritis, and malakoplakia. A, Clear carcinoma renal cell carcinoma is composed of compact cells with well-defined cell membranes and clear cytoplasm, separated by thin-walled blood vessels, without admixed inflammatory cells. B, Xanthogranulomatous pyelonephritis is characterized by accumulation of cells with abundant, granular, or vacuolated cytoplasm, admixed with inflammatory cells. C, Malakoplakia is characterized by accumulation of cells with abundant, eosinophilic cytoplasm containing diagnostic Michaelis-Cutmann bodies. They may be easily identified in the frozen sections because they are strongly basophilic and may obscure cell nuclei (arrows). D, The Michaelis- Gutmann bodies are less conspicuous in permanent sections (arrows) (hematoxylin-eosin, original magnification 400 [A-D]).

The xanthomatous cells of xanthogranulomatous pyelonephritis, instead of having a clear cytoplasm, typically display an abundant and finely vacuolated cytoplasm, which can be recognized in FS (Figure 1, B). Small clusters of xanthoma cells are frequent in papillary RCC and should not cause a diagnostic problem; however, a rare case of papillary RCC may have confluent, grossly visible sheets of xanthoma cells, which can be misleading on FS.23 In such a situation, careful evaluation of the FS for epithelial lining is necessary.

The von Hansemann histiocytes typical for malakoplakia may closely simulate RCC cells, especially the granular cells20; however, many of these cells contain pathognomonic Michaelis- Guttmann bodies. In the few cases of malakoplakia personally encountered by the authors, the Michaelis-Gutmann bodies, for unknown reason, are deeply basophilic in FS and much easier to recognize in FS than in permanent sections (Figure 1, C and D).

The Differential Diagnoses of Renal Pelvic TCC.-The diagnosis of renal pelvic TCC (Table 4) must be established before or during surgery for the choice of operation (nephrectomy vs nephroureterectomy). Frozen section may be requested if a preoperative diagnosis of TCC is not made. Transitional cell carcinoma must be differentiated from other tumors, which may involve the renal medulla predominantly or share some histologic features with TCC, that is, collecting duct RCC,21,24,25 primary renal pelvic adenocarcinoma,21,26 metastatic adenocarcinoma,21,27 and papillary RCC.21,28 Papillary RCC may be confused with either TCC or collecting duct RCC because papillary structures may predominate in all 3 of these tumor types. Primary renal pelvic adenocarcinoma or metastatic adenocarcinoma may closely simulate collecting duct RCC, but they are rarely submitted to FS, because the former is exceptional, and the latter is usually diagnosed by other means, such as fine-needle aspiration, which obviates the need for surgery.21,27 Features that may facilitate these differential diagnoses are listed in Table 4.21,29 Successful bivalving of the nephrectomy specimen through the pyelocaliceal system is very helpful, because this often clearly demonstrates (in the case of TCC) that the tumor develops from the pyelocaliceal system, with or without invasion into the kidney. Diagnosis of TCC by FS (Figure 2, A through D) is also facilitated by noting that samples taken from the portion that invades the kidney may not have typical features of TCC, but those from the pelvic portion are often readily diagnostic.21,29

Table 4. Differential Diagnoses of Renal Pelvic Transitional Cell Carcinoma (TCC)

Figure 2. Differential diagnosis of a renal pelvic tumor. A, A transitional cell carcinoma involving the renal pelvis displays typical features. B, The intrarenal component of this transitional cell carcinoma, however, appears as ill-defined glandlike structures or solid cords, separated by abundant and inflamed stroma, reminiscent of a collecting duct carcinoma. C, Collecting duct carcinoma is composed of tubulopapillary structures with high-grade nuclei, separated by desmoplastic stroma. D, This papillary renal cell carcinoma is composed of irregular, elongated tubules without obvious papillary structures, but it is typically encapsulated (arrows) and displays low-grade nuclei (hematoxylin-eosin, original magnifications 200 [A and D] and 400 [B and C]).

On\cocytoma Versus Chromophobe RCC.-Oncocytoma and chromophobe RCC need to be separated because oncocytoma is benign,30,31 whereas chromophobe RCC may behave aggressively.12,33 Intraoperative differentiation between them may be irrelevant in the case of total nephrectomy. However, partial nephrectomy for benign renal tumors (including oncocytoma, regardless of size) is being considered, and, in such a case, accurate differentiation between oncocytoma and chromophobe RCC by FS will be needed because their gross appearance may be identical. Features that help separate them are listed in Table 5. Two subtypes of chromophobe RCC are recognized, that is, typical and eosinophilic.32 Typical chromophobe RCC can often be separated from oncocytoma by the features listed in Table 5 and illustrated in Figure 3, A through D. In FS, the perinuclear halo or the well-defined cell membrane typical for chromophobe RCC may not be obvious in tissue sections, but may be better appreciated in touch preparations. The characteristic growth pattern of chromophobe RCC, that is, a closely packed broad sheet of tumor cells and abundant cytoplasm, remains helpful because it is maintained in FS and not seen in oncocytoma (Figure 3, A and B). Many of the features that are characteristic for typical chromophobe RCC and help separate it from oncocytoma are not obvious in the eosinophilic variant of chromophobe RCC.32,33 Differentiation of this variant from oncocytoma remains problematic, even in permanent sections. In fact, the eosinophilic variant of chromophobe RCC and oncocytoma may represent a spectrum of the same type of tumor.34

Table 5. Oncocytoma Versus Chromophobe Renal Cell Carcinoma (RCC)

Figure 3. Differential diagnosis of oncocytoma and chmmophobe renal cell carcinoma. A, An oncytoma composed ofacinar structures separated by edematous stroma. An area of "oncoblasts" characterized by hyperchromatic cells and scanty cytoplasm is present (upper left). These cells are seen in only approximately 4% of oncocytomas, but are typical for this neoplasm. B, Chmmophobe renal cell carcinoma composed of trabeculae of cells with well-detined cell membranes, perinuclear halos, irregular nuclear contours, and occasional binucleation. C, A chmmophobe renal cell carcinoma, eosinophilic variant, displaying a trabecular growth of tumor cells with abundant eosinophilic cytoplasm but without obvious cell membranes or perinuclear halos. D, The perinuclear halo of the tumor in (C) is obvious on permanent sections (hematoxylin-eosin, original magnification 400 [A-D]).

Figure 4. Angiomyolipoma. A, The 3 diagnostic elements, that is, smooth muscle, thick wall blood vessels (V), and adipose tissue, are present. Adipose tissue is difficult to identify in a frozen section and may appear as irregular, clear spaces (f), an artifact characteristic for angiomyolipoma. B, Thick-walled, open blood vessels characteristic of angiomyolipoma are present, even in tumor composed predominantly of smooth muscle. The smooth muscle cells that seem to involve the adventitia are closely associated with the media. C, Angiomyolipoma may be predominantly extrarenal and may be contused with well-differentiated liposarcoma. D, In the tumor in (C), microscopic collection of smooth cells with vacuolated cytoplasm and atypical nuclei interspersed with mature adipose tissue can simulate well-differentiated liposarcoma (hematoxylin- eosin, original magnifications 200 [A] and 400 [B and D]).

Angiomyolipoma.-Because angiomyolipoma (AML) is composed of adipose tissue, smooth muscle, and blood vessels in various proportions, it has been confused with many other renal tumors during FS.35,36 Accurate FS diagnosis of AML is important because AML occurs rather frequently and can attain large size, but is almost uniformly benign and is increasingly considered a good candidate for partial nephrectomy.6 The usefulness of FS in the surgical management of AML is well documented.8 Imaging study can accurately identify AML if it is composed mostly of adipose tissue, but remains problematic if the other components predominate.35 In our experience, touch preparation of AML may not facilitate the diagnosis and may even be misleading because the tumor cell clusters closely simulate those from RCC. Noting the 3 components of AML in tissue sections remains essential for diagnosis (Figure 4, A). The adipose tissue component may display severe frozen artifact and appear as variably sized and ragged clear spaces interspersed between spindled cells and vessels (Figure 4, A). This artifact, however, has a diagnostic value because, in our experience, it is regularly seen and should raise the possibility of AML. One important clue for a correct diagnosis is abnormal, thickened blood vessels with a radial array of spindled cells around them (Figure 4, B). This feature, characteristic for AML, is not seen in other renal tumors and can be readily appreciated in FS.35 Angiomyolipoma composed predominantly of smooth muscle and vascular components (especially in cases with significant nuclear atypia, noted in approximately 8% of AML35 or in the recently described epithelioid AML35) can be confused with other renal tumors, such as sarcomatoid RCC, sarcomas, inflammatory myofibroblastic tumor (inflammatory pseudotumor), RCC, or large cell lymphoma. A correct FS diagnosis should be achieved by always considering AML in the differential diagnosis of an unusual renal tumor and by recognizing the characteristic perivascular cell array. In contrast, sarcomatoid RCC is frequently associated with areas typical of other types of RCC, which can be recognized grossly and in FS.37 True renal sarcoma is very rare and practically is not a consideration.21 Other spindle cell tumors, such as leiomyoma, inflammatory myofibroblastic tumor, or solitary fibrous tumor are both exceptional and their spindle cell component displays little or no atypia.21 Mesoblastic nephroma or metanephric stromal tumor feature prominent spindled cells, but these cells are clearly benign and these 2 tumors are practically limited to the first few years of life.18 Angiomyolipoma composed predominantly of adipose tissue can be confused with well- differentiated retroperitoneal liposarcoma (Figure 4, C and D); this is especially true when AML attains a large size and contains a large extrarenal component.15 A correct FS diagnosis is aided by an awareness of this type of AML, the presence of a constant, albeit small, intrarenal component, and microscopic fields of vascular/ smooth muscle even in areas which look like adipose tissue on gross examination. Frozen section can reveal AML tissue in renal vein or in other organs, such as spleen, para-aortic lymph nodes, or liver, but these are considered multifocal disease rather than metastasis.15,36

Table 6. Differential Diagnoses of Cystic Renal Tumors

Cystic Tumors.-Up to 15% of renal tumors may be predominantly cystic tumors (Table 6; Figures 5 and 6).9 The major differential diagnoses include simple cyst, simple cyst with superimposing hemorrhage or infection, cystic nephroma, multilocular cystic RCC, RCC with marked cystic changes secondary to necrosis or hemorrhage, and renal pelvic hamartoma.'9,10,39 Some features helpful for their differentiation are listed in Table 6. This table does not include cystic partially differentiated nephroblastoma, which is also predominantly cystic, but is practically limited to the first 2 years of life.3M These cystic lesions usually have distinctive gross features, which facilitate the differential diagnoses (Table 6; Figure 5, A through C). Some practical caveats pertinent to FS are emphasized. Identifying the epithelial cells lining the cyst wall is essential for a correct diagnosis (Table 6). These cells, however, may be necrotic and replaced by inflammatory fibrous tissue, such as is often seen in cystic papillary RCC (Figure 6, B and C). Indeed, necrosis is an important clue for RCC diagnosis, and its presence should prompt an attempt to confirm this diagnosis. The presence of clear cells lining the cyst wall, usually more than 1 layer, and/or clusters of clear cells within septa is required for diagnosing multilocular cystic RCC and differentiating it from other cystic tumors, including cystic nephroma (Figure 6, D and E). During tissue preparation, these cells may be completely lost or appear only as mildly atypical bare nuclei, reminiscent of lymphocytes, an artifact probably caused by their delicate cytoplasm, which is devoid of well- developed organelles or cytoskeleton. In these situations, however, the highly vascularized and edematous stroma of the cyst wall or the septa, characteristic for clear cell RCC, is still present, and, in our experience, is an important diagnostic clue (Figure 6, F). The diagnostic pitfalls are highlighted by personally encountered cystic tumors that were diagnosed as a "benign cyst" in FS because only the fibrous wall was identified, although, on permanent sections, the rare cyst lining cells characteristic for either clear or papillary RCC were observed. These considerations imply a need for careful specimen sampling and for additional biopsies if the subtle clues for RCC, as described, are encountered in the initial biopsy.

Figure 5. Cross features of renal cystic tumors. A, A papillary carcinoma appearing as a unilocular cystic structure with necrotic, shaggy, wall lining, without mural nodules. Simple cysts with intracystic hemorrhage, infection, or bleeding may show similar gross features. B, An extensively cystic/hemorrhagic renal cell carcinoma appears as a multilocular cyst. The individual locules, probably derived from degeneration of tumor tissue, contain hemorrhagic, necrotic debris in the lumen and along the septae. The septae may have a variable thickness, and areas of solid tumor can still be seen. C, A multilocular cystic renal cell carcinoma appears as a well-circumscribed and encapsul\ated multilocular mass. The septae are thin and mould along the locules. Necrosis or solid tumor areas are not seen. Cystic nephroma and multilocular cystic renal cell carcinoma may be grossly identical.

Kidneys With Diffuse Cysts.-The 2 most common conditions that cause bilateral diffuse renal cystic changes are autosomal dominant polycystic kidney and acquired cystic kidney, a condition associated with chronic dialysis. Symptomatic mass lesion, including cyst infection, hematoma, or RCC may develop in these kidneys. Because the true nature of these masses may not be established by clinical or imaging findings, total nephrectomy may be needed and an intraoperative consultation may be requested. In this context, it should be emphasized that RCC is rare in autosomal dominant polycystic kidney and that most renal masses in this context represent intracystic hematoma (Figure 7, A) or, less frequently, infection.40 In contrast, RCC is very frequent and usually multifocal in acquired cystic kidney and, in about a third of cases, is associated with hemorrhage, which may be massive and mask the RCC.41 Indeed, the presence of renal hematoma in the context of acquired cystic kidney should prompt a thorough search for RCC (Figure 7, B).

Multiple Renal Masses.-Up to 10% of renal tumors are multiple or bilateral.13 As listed in Table 7, these tumor masses may represent the same or different histologic types.

Up to 25% of sporadic RCCs show satellite tumor nodules of the same histologic type as the main tumor, but the specific frequency depends on factors such as size, grade, or type of the index tumor.42 Because most of these satellite nodules are small and not obvious by renal imaging or during operation, they are not submitted to FS and are usually detected by permanent sections.

Renal tumors develop in up to 70% of patients with VHL during their life span. These tumors display a morphologic spectrum that includes variably sized, unilocular or multilocular cysts, cysts with solid mural nodules, and solid tumors ranging from microscopic to unequivocal RCC.43 They are almost always composed of clear cells of low-grade nuclei and simultaneously or sequentially present in the kidneys in various combinations, with RCC encountered in about 50% of patients, at an age much younger than for sporadic RCC.7 These tumors are usually treated by conservative surgery, including tumor enucleation and partial nephrectomy7 because (1) all of these tumors are now known to be precursors of RCC; (2) new lesions continue to develop in both kidneys throughout life, which may necessitate repeated surgery; and (3) this approach help delay dialysis dependency until all renal tissue is removed. Renal cysts in VHL may rarely be so extensive that they simulate polycystic kidney disease; however, the uniform presence of clear cells lining cyst walls and within septae is constant in VHL and absent in polycystic kidney disease. The renal lesions may be submitted to FS "to rule out RCC." It should be emphasized that all renal lesions in VHL patients have the same cytologie features (being composed of clear cells with a low nuclear grade) and represent a morphologic continuum, within which the demarcation of RCC from the rest may be subjective, and, indeed, has not been defined.43 Because RCC metastasizes in 30% to 50% of VHL patients and this is the cause of death in 15% to 50% of these patients, a more critical question for the relevance of FS is at what point RCC can give rise to metastasis.7,43 In this aspect, Walther et al44 noted that no patients with a solid tumor smaller than 3 cm left untreated for a median of 60 months developed metastasis. Primary tumors of organs other than kidney often develop in VHL patients and, if encountered during renal surgery, must be differentiated from metastatic RCC. The most frequent problems in this context are differentiating metastatic RCC versus pheochromocytoma of the adrenal gland, metastatic RCC versus a variety of primary cystic or solid pancreatic neoplasms, and metastatic RCC versus hemangioblastoma of the brain, all of which may feature a prominent clear-cell component.45

Figure 6. Microscopic features of renal cystic tumors. A, A simple cyst with intracystic bleeding displaying a fibrous wall lined by degenerated red blood cells and fibrin. Necrotic cells are not obvious. B, A cystic papillary renal cell carcinoma (RCC) with cyst wall composed of fibrous tissue and overlying necrotic cells. C, Additional sampling of the same tumor shows areas of papillary carcinoma within the cyst wall. D, The wall of this locule in a multilocular cystic mass is lined by clear cells, diagnostic for multilocular cystic RCC. E, The septum separating locules in a multilocular cystic mass is composed of clear cells, diagnostic for multilocular cystic RCC. F, A different locule of the RCC shown in (D) shows loss of clear cells lining its wall, but the underlying hypervascular stroma, typical for RCC, remains. G, A locule of a mixed stromal and epithelial tumor is lined by benign columnar epithelial cells with typically hypercellular stroma that often contain smooth muscle cells and open blood vessels. H, A cyst wall of a cystic nephroma is composed of 1 layer of epithelial cells with eosinophilic cytoplasm, without nuclear atypia, and underlying poorly cellular stroma (hematoxylin-eosin, original magnification 400 [A-H]).

Figure 7. Kidney with diffuse cyst. A, A kidney with adult polycystic kidney disease displays 2 hematomas, which simulate renal neoplasms on renal imaging. B, A kidney with acquired cystic kidney disease with a massive perirenal hematoma (H), associated with a renal cell carcinoma (arrows). The renal parenchyma is atrophic and shows diffuse small cysts.

Table 7. Types of Multiple Renal Masses*

Primary renal lymphoma, defined as isolated renal involvement without systemic disease, is not rare. It was shown that 3 of 48 renal lymphomas were primary and 6 of 200 renal tumors initially thought to be RCC were primary renal lymphoma.46 Primary renal lymphoma may be identical to RCC on imaging studies, but up to one third of them may have unusual features, including multiple masses, predominantly perirenal plaque, or unilateral or bilateral diffuse renal enlargement without masses. Alternatively, a renal mass in patients with systemic lymphoma may be RCC, because a 10-fold increase in the incidence of RCC is noted in these patients.47 Fine- needle aspiration or FS is usually performed to establish the diagnosis because the treatment of choice for renal lymphoma is radiation/chemotherapy, whereas the treatment of choice for RCC is nephrectomy. The FS diagnosis of renal lymphoma is usually not problematic, even in a small biopsy, if the clinical context is kept in mind. The lesion is composed of compact lymphoid cells, which "crowd out" renal tissue and form nodules, or insinuate between intact renal tubules at the periphery of the nodules. The vast majority of primary renal lymphoma is large B-cell type.46

Multiple renal masses of the same histologic type may also be encountered in the following situations: (1) multiple or bilateral AML seen in up to 70% to 85% of tuberous sclerosis patients35; (2) papillary RCC, which may be multifocal in up to 39% of cases28; and (3) oncocytoma, which may be multifocal in up to approximately 13% of cases.31 Another condition that features multifocal oncocytoma is renal oncocytosis, a recently described condition in which multiple oncocytomas, chromophobe RCCs, and tumors with hybrid features are found in the same kidney.48 Frozen section may be requested for these situations and awareness of these conditions is the key to a correct diagnosis.

Multiple lesions of different histological types can be rarely seen in the same kidney, as listed in Table 7.49,50 The gross and histologic features of these lesions are similar to those of their respective isolated counterparts.

Extrarenal Masses.-These masses may be encountered during surgery for a primary renal tumor and are often submitted for FS. These include enlarged lymph nodes, adrenal masses, or masses of other organs, including the peritoneum.

The enlarged lymph nodes may be caused by metastatic RCC, reactive lymphoid hyperplasia, or lymphoma. Metastatic RCC displays the same histologic spectrum as the primary tumor; however, the primary tumor may not be available for comparison because nodal FS is usually performed before nephrectomy. Technical manipulation during FS preparation to enhance the clear cytoplasm as well as touch preparation may facilitate the diagnosis.22 Micrometastasis may coexist with reactive lymphoid hyperplasia. Because a 10-fold increase in the incidence of RCC was recently reported in patients with lymphoma,47 enlarged lymph nodes in the context of nephrectomy for RCC may be caused by associated lymphoma. Awareness of this association aids in the differential diagnoses and ensures proper tissue triage for special studies, including flow cytometry and gene rearrangement. As mentioned, AML tissue may be encountered in lymph nodes, but this represents multifocal tumor rather than metastasis.35

Table 8. Donors' Kidneys: Indications for Frozen Section Consultation

Table 9. Grading of Chronic Renal Injury for Donors' Kidneys

Masses of other organs may be metastatic RCC or incidental lesions unrelated to RCC. In our experience, adrenal involvement is most frequent, and may include RCC extending to or metastatic to the adrenal gland, adrenal cortical adenoma, or nodule; adrenal cortical carcinoma extending to the kidney; and pheochromocytoma.

Donors' Kidneys.-Clinical criteria (no history of renal disease or hypertension, normal renal function, and normal urinalysis results) are traditionally used to determine whether a donated kidney is accepted for transplantation.12 However, there are situations, as listed in Table 8, in which FS is indicated and may play a pivotal rolein the clinical decision to accept or reject a donor's kidney. Morphologic changes can be more sensitive than clinical parameters in predicting parenchymal injury and they may be pronounced even when renal function is normal.12 This discrepancy, usually encountered in donors with conditions that may promote renal scarring, is best demonstrated by FS.12 Because there is increasing willingness to consider the kidneys from these "marginal" donors in response to an organ shortage, more of this type of FS is expected, and it represents the most frequent indication for FS in the context of renal transplantation.

Either wedge or needle biopsy may be submitted. Wedge biopsy provides more tissue but may sample cortical scars in which globally sclerotic glomeruli are overrepresented, a fact that should be taken in consideration during FS.12 Needle biopsy may be more representative, but may not provide enough tissue. In our practice, up to 4 pieces (<1 mm each) are obtained from the biopsies and saved for possible electron microscopy. The remaining tissue is divided into 2 portions and entirely submitted for FS. At the completion of FS, 1 block will be submitted for light microscopy and the other for immunofluorescent study. Permanent sections of the previously frozen tissue may show arcts, which hamper precise interpretation. However, we think that this limitation is well compensated for by the more accurate and timely available information if the entire specimen is submitted to FS.

An adequate specimen requires cortical tissue with at least 25 glomeruli.12 Additional tissue should be requested if this criteria is not met. The following types of lesions should be sought: chronic parenchymal injury, intravascular coagulation, cortical necrosis, and glomerulonephritis. Evaluating chronic parenchymal injury should include separate evaluation of glomerular, tubulointerstitial, and vascular injury, as listed in Table 9. Although these parameters are separately evaluated, their severity roughly correlates with one another.12 In FS, normal renal tissue may show tubular retraction associated with apparent expanded and edematous interstitium, which may be confused with chronic injury (Figure 8, A). Chronic injury, however, should also include tubular atrophy, fibrous stroma, and increased stromal cellularity, including inflammatory cells (Figure 8, B). Sclerotic glomeruli may be difficult to identify in FS and a longer exposure to eosin may be helpful (Figure 8, A and B). The threshold of chronic injury for accepting or rejecting a donor's kidney has not been established.12 In general, rejection is recommended when significant injury is noted in any compartment (more than 20% of glomeruli with global sclerosis or more than mild tubulointerstitial or vascular injury).

Intravascular coagulation may be seen in up to 10% of unselected donor renal biopsies, and this incidence may be as high as 30% in those who died of brain trauma (probably caused by sudden release of brain thromboplastin, a potent procoagulant, into the circulation).51 This is a frequent cause of petechial hemorrhage intraoperatively observed on the renal surface. It is characterized by the presence of fibrin thrombi in rare or many glomerular capillaries, and in other blood vessels much less frequently. Once one is aware of these thrombi, they should be easily detectable in FS (Figure 8, C). Intravascular coagulation should not, by itself, be a contraindication for transplantation, even when severe, because the long-term outcome of the transplanted kidneys with this lesion is comparable with controls.51 However, severe and prolonged intravascular coagulation may induce cortical necrosis, which renders the kidney unacceptable.

Figure 8. Donor kidney for transplantation. A, This normal kidney shows unremarkable glomeruli. The tubules are of normal size but are separated by expanded "edematous" stroma. The stromal changes are artifactual and should not be interpreted as chronic tubulointerstitial injury. Sclerotic glomeruli (S) may be seen in normal kidney; they are inconspicuous and may be missed in frozen section. B, Chronic tubulointerstitial injury characterized by tubular atrophy, thickening of the tubular basement membrane, interstitial fibrosis, and interstitial inflammation. Chronic tubulointerstitial injury is frequently associated with sclerotic glomeruli (S). C, Kidney with disseminated intravascular coagulation, characterized by glomerular capillary thrombosis. D, Disseminated intravascular coagulation is associated with cortical necrosis characterized by necrosis of all renal elements, including frank necrosis of the tubular epithelial cells. E, Degenerated changes of tubular epithelial cells including flattening, detachment, and necrosis are frequently seen. The changes tend to involve the proximal tubules and spare other tubular segments (arrows). They may represent acute tubular necrosis or frozen section artifacts but do not seem to have any long-term adverse effects on the graft (hematoxylin-eosin, original magnifications 200 [A] and 400 [B-E]).

Cortical necrosis is characterized by necrosis of all cortical elements including tubules and glomeruli and the injury is irreversible. Cortical necrosis in donor kidney is very rare and almost always caused by massive intravascular coagulation.51 Cortical necrosis must be differentiated from acute tubular necrosis, in which acute injury, including necrosis, is limited to the tubular cells and the injury is potentially reversible. Recognizing cortical necrosis in FS may not be difficult, especially in cases of frank coagulative necrosis or infarct (Figure 8, D), but acute tubular necrosis may be very difficult to diagnose because many changes characteristic for acute tubular necrosis are either masked by FS or confused with FS artifacts (Figure 8, E). Fortunately, acute tubular necrosis is not a reason for rejecting a kidney, because, although such a kidney may have delayed graft function when transplanted, it has a normal long-term outcome.12

Table 10. One Hundred Consecutive Bladder Specimens for Intraoperative Consultation*: Types of Specimens and Indications

Donors with a significant glomerulonephritis are often recognized and eliminated by clinical criteria. Mild glomerulonephritis, which is often asymptomatic, may escape FS detection only to be diagnosed on permanent studies. This sequence is probably most frequent for immunoglobulin A nephropathy, a disease with very high prevalence in some ethnic groups. Fortunately, these mild forms of donor- transmitted glomerulonephritis have not been shown to adversely affect the graft and may even regress.12

Grossly visible nodules may be identified during renal harvesting and require FS for diagnosis. If a benign tumor such as cyst, leiomyoma, AML, or papillary adenoma (papillary growth, low nuclear grade, less than 0.5 cm) is identified, it should be removed and, by itself, should not be a cause for rejecting the kidney.12 True RCCs that escape clinical screening are, however, identified in up to 0.3% of donated kidneys.52 Whether benign tumors preclude transplantation has not been determined but probably depends on many features, including tumor size, histologie type, and nuclear grade.

URINARY BLADDER

Types of Specimens

The type of specimens submitted for IPC may include ureteral, urethral, and soft tissue margins during radical cystectomy; bladder neck margin during radical prostatectomy for prostate adenocarcinoma; radical or partial cystectomy specimen; extravesical masses, including enlarged lymph nodes identified during surgery; biopsy of bladder lesion; or biopsies of bladder peritoneal nodules during pelvic or abdominal surgery (Table 10).

Indications

Gross Consultation.-In contrast to the kidney, in which gross demonstration of tumor is frequent, similar request is rare for radical cystectomy specimens, probably because these tumors are already visualized by endoscopy before surgery.

Frozen Section.-Checking the ureteral margins is the most frequent indication for FS because it is routinely requested before radical cystectomy performed for a previously diagnosed invasive TCC; TCC is usually multifocal and may involve these margins.53 Other surgical margins, such as those from soft tissue or urethra, are not routinely evaluated by FS. Other surgical margins for FS are limited to special situations dictated by intraoperative observations of soft tissue extension or a clinical impression of widespread in situ tumor, which may involve the urethra and, therefore, affect the decision for the type of urinary diversion. Bladder neck tissue is sometimes submitted to FS to check for involvement by prostatic adenocarcinoma during radical prostatectomy. Although most bladder tumors are biopsied preoperatively for a specific diagnosis, FS of biopsies is sometimes requested to provide an immediate diagnosis. This usually involves evaluating the depth of invasion of a TCC, typing of an unusual primary bladder tumor, or differentiating TCC from prostatic or colonie adenocarcinoma extending to bladder. Occasionally, the urologist will request FS of lymph node for metastatic disease to guide the extent of lymphadenectomy.

Frozen Section Diagnoses

The FS diagnosis of the bladder specimen is usually straightforward and is mostly related to recognizing TCC at surgical margins or unusual locations. Some practical caveats are discussed here.

Ureteral margin specimen is often composed of a less than 3-mm- thick cross section of the ureter and the true surgical margin may or may not be marked by the surgeon. The entire specimen should be submitted for cross sectioning and tumor identified at any level would reflect a positive margin. In our experience, high-grade dysplasia/carcinoma in situ is frequent in these margins and is found in 7 (16%) of 43 radical cystectomy specimens personally encountered; however, this diagnosis is usuall\y straightforward (Figure 9). Urothelium at the surgical margin usually shows reactive changes or low-grade dysplasia. In addition, urothelial cell nuclei in FS are often artifactually enlarged and hyperchromatic, that is, they seem more atypical than their counterparts in permanent sections (Figure 9, A). The changes can be differentiated from carcinoma in situ, which display irregular nuclear contours, as well as nuclear crowding, overlapping, loss of polarity, and mitosis (Figure 9, B and C). These features are not seen in reactive conditions. According to the most recent classification of urothelial neoplasms by the World Health Organization/International Society of Urologic Pathology, only partial involvement of the urothelium by carcinoma cells, that is, those with hyperchromatic, enlarged, and irregular nuclei,54 is required for diagnosing high- grade dysplasia/carcinoma in situ. In our experience, a margin positive for tumor always shows diffuse involvement of the urothelium by neoplastic cells. Sometimes, the segment of the ureter with in situ carcinoma shows dilation, chronic inflammation, and complete or partial sloughing of the neoplastic urothelial cells (Figure 9, D). Recognizing these changes in FS should raise the possibility of carcinoma in situ and prompt examination of deeper tissue levels, or recommendation for margin reexcision. In more aggressive types of urothelial tumors, such as micropapillary or signet ring cell carcinoma, isolated or small clusters of tumor cells can rarely be seen in the periureteral soft tissue at the surgical margin, without involvement of the urothelium (Figure 9, E). The urethra is partially lined by stratified columnar epithelium, which on FS, may simulate urothelial carcinoma in situ (Figure 9, F), but may be differentiated from it by the features described above in this section.

Figure 9. Transitional cell carcinoma in situ at margin. A, Reactive urothelium at the ureteral margin may look more atypical in frozen section than in permanent section. The nuclei may seem hyperchromatic and enlarged, but there is no nuclear crowding, overlapping, or loss of polarity. B, Transitional cell carcinoma in situ with hyperchromatic spindle cells with nuclear pleomorphism, crowding, and overlapping. C, Transitional cell carcinoma in situ composed of highly atypical, pleomorphic, and disorganized cells. D, The urothelium is completed denuded or only a few cell layers are maintained. The subepithelial tissue shows edema and chronic inflammation. Although no obvious malignant cells are seen, these features are suggestive of carcinoma in situ, and additional tissue sections or a biopsy should be generated. E, Isolated carcinoma cells (arrows) are seen at the periureteral soft tissue at the surgical margin (m, muscularis). F, The urethra is partially lined by stratified columnar epithelium, which, on FS, may simulate urothelial carcinoma in situ (hematoxylin-eosin, original magnification 400 [A-F]).

The depth of TCC invasion is most often provided by preoperative endoscopic biopsy; however, tumor tissue is rarely submitted to FS for this purpose. Because invasion into muscularis propria is a major indication for radical cystectomy, its diagnosis must be accurate and must be differentiated from a tumor-induced desmoplastic reaction or invasion into muscularis mucosae.54 It should be emphasized, however, that the differentiation may be impossible in small tissue samples, even in permanent sections.54,55 In case of doubt, a conservative diagnosis should be made. Muscularis propria invasion is recognized by tumor cells surrounded by large bundles of unequivocal smooth muscle fibers, which appear as closely packed arrangements of spindled cells with cigar-shaped nuclei and abundant eosinophilic cytoplasm (Figure 10, A). It is differentiated from tumor-induced desmoplastic reaction, which may include abundant myofibroblasts, by noting that the myofibroblasts usually have pointed nuclei, less eosinophilic cytoplasm than smooth muscle cells, and are usually separated by fibrous stroma (Figure 10, B). Invasion to muscularis mucosa is usually suggested by the association of tumor cells with unequivocal but small and discontinuous smooth muscle bundles, which are close to large blood vessels.

Figure 10. Muscularis versus desmoplastic reaction. A, Muscularis propria tissue characterized by large smooth muscle bundles. The smooth muscle cells are closely packed and have cigar-shaped nuclei and abundant cytoplasm. B, Desmoplastic reaction characterized by myofibroblasts with scanty cytoplasm, pointed nuclei, separated by abundant stroma (hematoxylin-eosin, original magnification 200 [A and B]).

Biopsy of tumor from bladder may be submitted to FS for a specific diagnosis. The diagnosis of TCC is usually straightforward. Glandular or squamous differentiation may be encountered in up to 6% of TCC, but this should not be misinterpreted as adenocarcinoma or squamous cell carcinoma because typical TCC should be encountered elsewhere.53 In case of a pure adenocarcinoma, the differential diagnoses should include colonic adenocarcinoma invading the bladder, prostatic adenocarcinoma extending into the bladder, or a primary bladder adenocarcinoma, in order of incidence.56 Because primary adenocarcinomas of bladder and colon are often histologically identical, their differentiation depends on clinical information, imaging studies, and intraoperative examination.56 Prostatic adenocarcinoma may extend to the bladder neck and base.56 These tumors, usually of a high Gleason's score, may or may not display obvious glandular formation, but are composed of relatively uniform cells with round to oval nuclei, fine nuclear chromatin, prominent nucleoli, and relatively few mitoses. In contrast, irregular nuclei with coarse chromatin and numerous mitoses are usual features of TCC.57 Comparison with the previous biopsy of the primary tumor, if available, is always helpful. Rare primary bladder adenocarcinomas are composed of signet ring cells and can be a diagnostic challenge at FS, because this type of tumor may not form a mass, but tends to diffusely infiltrate the bladder wall as individual cells.54 Diagnosing nodal metastasis, which often occurs with this tumor type, may also be difficult by FS because the tumor cells may closely simulate sinusoidal histiocytes.

Frozen section diagnosis of TCC that occurs outside of the bladder, such as soft tissue margin, lymph nodes, or distant metastasis, is usually straightforward, not only because metastatic TCC often closely simulates its primary tumor, but also because biopsies of the primary tumor are usually available for comparison. Histiocytic reaction characterized by sheet of histiocytes with abundant, granular cytoplasm replacing large portions of the pelvic lymph nodes is frequently seen in patients with joint prosthesis of the lower extremities, and should be differentiated from metastatic carcinoma.58 Frozen section diagnosis of bladder peritoneal nodule is not an infrequent request during abdominal or pelvic surgery. The most frequent diagnostic entities include: mesothelial hyperplasia, fibrosis, chronic inflammation, calcification, endometriosis, endosalpingiosis, and, rarely, metastatic carcinoma. In these situations, awareness of the clinical history and histologic features of these common entities will provide an accurate diagnosis.

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Source: Archives of Pathology & Laboratory Medicine

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