Table 1. Types of Ancillary Studies for Diagnosis of Urologic Pseudoneoplasms

Morphometry Histochemistry Immunohistochemistry Molecular biologic : DNA genetic lesions Molecular biologic : RNA expression profiling Molecular biologic : Proteomics

Selected examples of application of these studies to the diagnosis of urologic tumor-like conditions will be provided.

Morphometry
Morphometry means measurement of form (Greek morphos = form) but a more practical definition might be "the quantitative description of geometric features of structures in any dimension" [15] or "quantitative techniques that measure features of size, shape, and texture in two dimensions and/or spatial relationships from cells or other tissue structures" [16]. Such quantitation is desirable as a methodology to increase the precision and reproducibility of diagnoses in anatomic pathology [16, 17] , but currently morphometric studies are not in routine use in the diagnosis of urologic pseudoneoplasms. Some of the potential limitations of morphometric analyses include its time-consuming and labor-intensive nature, the operator-dependant selection of cells for characterization, the expense (for image analyzers), and the dependence of the results on tissue processing and fixation.

An example of the potential diagnostic utility of morphometric quantitation is the assessment of nuclear features in flat urothelial lesions [18], which can be notoriously difficult to diagnose because of lack of objective criteria and uniformity in terminology [18, 19] . For flat urothelial lesions, distinction of a true neoplasm, that is, carcinoma-in-situ (CIS) from dysplasia, and benign urothelium can occasionally be arduous, based on light microscopic examination of H&E-stained sections alone. The separation of CIS from benign urothelium may pose particular difficulties when there is denudation of normal urothelial cells [20] and when there are reactive urothelial changes, such as those seen secondary to inflammation. In a recent study [18], an image analysis system was used to measure several nuclear features, including area, diameter, roundness, ellipticity, and optical density in normal urothelium, urothelial dysplasia, and CIS. The mean nuclear area and mean nuclear area of the 25% largest nuclei were useful discriminators: The mean upper quartile nuclear area relative to lymphocytes was 2.2 times (range 1.4 – 2.8) in normal urothelium, 2.9 times (range 1.8 – 3.6) in urothelial dysplasia, and 4.9 times (range 4.0 to 7.6) in CIS. Validation of this approach in a large, separate patient population and extension to inflammatory and/or treatment-related atypia would be necessary steps for quantitative image analysis-based diagnosis of CIS vs. pseudoneoplasms to move beyond the experimental stage.

Histochemistry
Histochemical reactions play a limited role in the diagnostic evaluation of urologic pseudoneoplasms. One setting where histochemical staining can provide important confirmation of a diagnosis suspected on the basis of examination of H&E-stained sections is in malakoplakia. Malakoplakia can involve any anatomic site in the genito-urinary system, but is most common in the urinary bladder [5]. It has long been recognized that malakoplakia can be confused for carcinoma [20]. Tumefactive nodules or plaques can be seen grossly in the kidney and bladder, and sometimes papillary or polypoid tumor-like lesions are seen in the bladder [3]. Histologically, most cases are typified by sheets of histiocytes (von Hansemann cells). Older lesions may exhibit a fibrosing and spindle cell pattern, which could prompt concern for a spindle cell neoplasm [21]. Confirmation of the diagnosis of malakoplakia is established by identification of Michaelis-Gutmann bodies, which may be found in intracytoplasmic and/or extracellular locations. Typical Michaelis-Gutmann bodies appear on H&E-stained sections as rounded, basophilic structures, imparting a "targetoid" appearance. These calcospherites are highlighted particularly well by the von Kossa histochemical stain for calcium [2, 5, 22] . Iron and PAS stains also mark the Michaelis-Gutmann bodies, but since the von Hansemann histiocytes are also PAS-positive, the PAS stain is less useful [2]. Detection of these Michaelis-Gutmann bodies by histochemical means is of greatest benefit when they are difficult to find in routine sections, or when they are scarce, as in the fibrosing phase of malakoplakia.

Immunohistochemistry
Currently, immunohistochemical stains are the most widely-used and valuable adjunctive studies for the diagnosis of pseudoneoplasms in urologic pathology. Specific examples are given in Table 2.

Table 2. Immunohistochemical Reactions in the Differential Diagnosis of Urologic Pseudoneoplasms: Selected Examples

Anatomic Site	Pseudoneoplasm	Immunostains
Kidney	Xanthogranulomatous pyelonephritis	Epithelial membrane antigen to rule out renal cell carcinoma
Testis	Granulomatous orchitis	Placental alkaline phosphatase and pan-cytokeratin to rule out neoplastic germ cells obscured by inflammation
Prostate	Atrophy Atypical adeneomatous hyperplasia Basal cell hyperplasia Granulomatous prostatitis	34ßE12, p63, AMACR 34ßE12, p63, AMACR 34ßE12, p63, AMACR Pan-cytokeratin, PSA, PSAP, CD68, lysozyme
Bladder or prostate	Nephrogenic adenoma	Pitfalls : can be AMACR positive, weakly PSA and/or PSAP positive, 34ßE12 -

The antibodies most frequently employed in immunohistochemical studies are those used to address the differential diagnosis of minimal adenocarcinoma vs. a benign mimicker in the prostate. The benign lesions most often misdiagnosed as adenocarcinoma are atypical adenomatous hyperplasia (AAH) or adenosis, atrophy, and basal cell hyperplasia (BCH) [3, 10, 12, 13, 23] . Immunohistochemical markers for basal cells (Table 3) are helpful in certain cases to substantiate a diagnosis of AAH (adenosis), atrophy, or BCH.

Table 3. Basal Cell Markers in the Prostate

Antibody	Antigen	References
34ßE12 *	High-molecular weight cytokeratins (CK1,5,10,14) in cytoplasm	[24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]
CK 5/6	Cytokeratins 5 and 6 : cytoplasmic	[35, 36]
p63	Nuclear p63 protein	[37, 38, 39]

* Sometimes called CK903

All these antibodies in Table 3 work well on formalin-fixed, paraffin-embedded tissue sections. It is vital to note that a minority of benign glands in prostatic pseudoneoplasms can lack a basal cell layer: Atrophy can reveal scattered negative glands in 11% to 23% of cases [28, 40] . Up to 12% of BCH glands fail to stain [28] and 10-90% (average = 50%) of AAH glands do not stain [41, 42] . In contrast, prostatic adenocarcinoma glands are, by definition, completely and diffusely negative for basal markers.

A monoclonal antibody reactive against α -methylacyl CoA racemase (AMACR), also known as P504S, can also be helpful since it is highly sensitive and selective for neoplastic prostatic epithelial cells in high-grade prostatic intraepithelial neoplasia and carcinoma and is negative in the large majority of pseudoneoplastic prostatic proliferations [43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53] (Table 4). AMACR immunohistochemical staining in benign prostatic luminal epithelium is almost always focal, weak, and noncircumferential. The main pitfall in the utilization of the AMACR immunostain to assess prostatic pseudoneoplasms is that a small minority (about 8%] of AAH cases exhibit diffuse positivity [49]. Also, scant individual AMACR-positive cells can be found in a small percentage (13%) of florid BCH cases [51]. Finally, nephrogenic adenoma can be strongly AMACR positive [54, 55] . As always, these immunohistochemical stains should be interpreted in the histological context.

Table 4. Immunophenotype of Prostatic Pseudoneoplasms * : Basal Cell Markers and AMACR

Pseudoneoplasm	Basal Cell Markers **	AMACR
AAH (adenosis)	Fragmented, discontinuous; 50% glands stain on average (range 10-90%)	Most negative; 10% focally positive 8% diffusely positive
Atrophy	Mainly positive; a few negative glands in 11-23% of cases	Negative
Basal cell hyperplasia	Mainly positive; up to 12% of cases negative	2/15 cases with scant positive cells
Nephrogenic adenoma	Negative in up to 44% of cases	4/4 cases positive

* vs. prostatic adenocarcinoma : basal cell markers negative; AMACR positive in 80-90% of usual acinar adenocarcinomas (with lower positivity for these variants : 68% of atrophic adenocarcinomas, 77-83% of pseudohyperplastic adenocarcinomas, and 68% of foamy gland adenocarcinomas) ** Basal cells detected by immunostaining for 34ßE12

Molecular Biologic: DNA Genetic Lesions
Structural abnormalities in DNA are currently not routinely utilized in the diagnosis of pseudoneoplasms of the genitourinary system, although there is substantial promise in emerging techniques. For example, quantitative analysis of glutathione S-transferase (GSTPI) gene methylation has revealed GSTPI methylation in prostate cancer but not a limited number of benign cases with potential pseudoneoplastic states, such as atrophy, glands with inflammation, and seminal vesicle tissue [56, 57] .

Hypermethylation of GSTPI is the most common (greater than 90%) epigenetic alteration in prostate cancer and so is an attractive DNA genetic lesion for diagnosis. Additionally, this fluorogenic real-time methylation specific polymerase chain reaction is quantitative and is applicable to formalin-fixed, paraffin-embedded tissues, with sufficient sensitivity to allow use of prostate needle core tissue [57]. One caveat is that this hypermethylation of GSTPI is also seen in high-grade prostatic intraepithelial neoplasia [56]. In the future, additional studies should focus on expansion on the number and type of prostatic pseudoneoplasms examined by the technique. Prospective testing and validation of diagnostic utility in a large number of cases difficult to diagnose by standard light microscopy and/or immunohistochemistry would be desirable. Assessment of quantitative GSTPI methylation in basal cell hyperplasia, and atypical adenomatous hyperplasia (AAH; adenosis), two prominent carcinoma mimics, would be important.

Examination of DNA genetic loss in AAH thus far is not proven to be useful in the differential diagnosis vs. adenocarcinoma since genetic chromosomal DNA loss, as detected by allelic imbalance, has been found in 12% [58] to 47% [59] of AAH cases, where sites of loss were those also lost in adenocarcinoma, such as 8p11-12. Potential future methodologies for differential diagnosis of pseudoneoplasms vs. neoplasms, based on genome-wide analysis of DNA structural abnormalities, include array comparative genomic hybridization to assess DNA copy number [60] and oligonucleotide array analysis of single nucleotide polymorphisms (SNPs) to detect genome-wide loss of heterozygosity [61].

Molecular Biologic: RNA Expression Profiling
DNA microarrays can be utilized for large-scale monitoring of gene expression in cancer [62, 63] . cDNA clones (with relatively large DNA molecules) or oligonucleotides corresponding to thousands of individual genes are arrayed on microscope glass slides. The DNA microarrays are then probed with one or more differentially labeled cDNA pools derived from mRNA of test and reference cells, such as cancer and corresponding normal tissues [62]. The hybridization signal produced on each probe is the mRNA expression level of the corresponding gene in the sample. The signals are detected, quantified, integrated and normalized with dedicated software and reflect the "gene expression profile" or "molecular portrait" for each biological sample [63].

As an example, expression profiling of prostate cancer vs. benign prostatic tissue has yielded, in a number of studies, hundreds of genes with expression level differences between benign and malignant prostate tissue [64, 65, 66, 67, 68, 69, 70, 71, 72] . Gene sets have been developed that are grade, stage, and outcome related, but only recently has emphasis been placed on development of diagnostic models. In one 4 gene model, classification of 20 cases as benign or malignant was 90% accurate, with 2 benign prostate tissues diagnosed as cancer [72]. This model has not been proven to provide added value beyond standard histological diagnosis. No investigation has yet profiled prostatic pseudoneoplasms such as atrophy, AAH (adenosis), or basal cell hyperplasia vs. prostatic carcinoma. Such a study could provide valuable markers that could be employed in immunohistochemistry to aid in differential diagnosis. Another advance will be the ability to use formalin-fixed, paraffin-embedded tissue samples to perform gene expression profiling (Affymetrix news release; 12/4/03), which was until now restricted to non-fixed tissue samples.

Molecular Biologic: Proteomics
The term "proteome" may be defined as the entire protein complement in a given cell, tissue or organism. In a broad sense, proteomics is the assessment of protein activities, modifications and localization, and interactions of proteins in complexes [73]. Clinical proteomics often entails studying global patterns of protein content and activity in disease states. Such assays could be useful for identification of new drug targets and new diagnostic markers. Currently, proteomics are not applied to diagnose urologic pseudoneoplasms, but feasibility studies have shown its capability to identify new markers for urologic malignancies such as prostate cancer. One could envision that there will be markers discovered by proteomics that could be used in the differential diagnosis of urologic pseudoneoplasms vs. true neoplasms. Proteomic technologies have been used to assess sera and prostate tissues from prostate cancer patients [77, 78, 79, 80, 81, 82, 83, 84] . In serum, mass spectrometry, utilizing matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) or surface enhanced laser desorption ionization time-of-flight (SELDI-TOF} techniques, has been used to distinguish benign prostatic hyperplasia and cancer [77, 78] . For prostatic tissues, SELDI-TOF mass spectrometry and two-dimensional (2-D) gel electrophoresis have been used to discover prostate cancer-associated proteins [77-84]. Proteomics technologies will continue to expand and would benefit from increased sensitivity, a reduction in sample size requirement, increased throughput, reproducibility, more rapid identification of specific proteins corresponding to proteomic patterns, and the ability to more effectively uncover various types of protein alterations such as post-translational modifications [74]. Biomarker discovery in the proteomics field could rapidly translate into diagnostic tools to distinguish true urologic neoplasms from urologic pseudoneoplasms.

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