NKX3.1 as a marker of prostatic origin in metastatic tumors.

NKX3.1 is a prostatic tumor suppressor gene located on chromosome 8p. Although most studies have shown that staining for NKX3.1 protein is positive in the majority of primary prostatic adenocarcinomas, it has been shown to be downregulated in many high-grade prostate cancers, and completely lost in the majority of metastatic prostate cancers (eg, in 65% to 78% of lesions). A recent study showed that NKX3.1 staining with a novel antibody was highly sensitive and specific for high-grade prostatic adenocarcinoma when compared with high-grade urothelial carcinoma. This raised the question that this antibody may perform better than earlier used antibodies in metastatic prostate tumors. However, the sensitivity and specificity for prostate carcinomas for this antibody in metastatic lesions was not determined. Although prostate-specific antigen (PSA) and prostatic-specific acid phosphatase (PSAP) are excellent tissue markers of prostate cancer, at times they may be expressed at low levels, focally, or not at all in poorly differentiated primary and metastatic prostatic adenocarcinomas. The purpose of this study was to determine the performance of NKX3.1 as a marker of metastatic adenocarcinoma of prostatic origin. Immunohistochemical staining against NKX3.1, PSA, and PSAP was carried out on a tissue microarray (TMA) (0.6-mm tissue cores) of hormone naïve metastatic prostate adenocarcinoma specimens from lymph nodes, bone, and soft tissue. To determine the specificity of NKX3.1 for prostatic adenocarcinoma, we used TMAs that contained cancers from various sites including the urinary bladder, breast, colon, salivary gland, stomach, pancreas, thyroid, and central nervous system, and standard paraffin sections of cancers from other sites including the adrenal cortex, kidney, liver, lung, and testis. Overall 349 nonprostatic tumors were evaluated. Any nuclear staining for NKX3.1 was considered positive and the percentage of cells with nuclear staining and their mean intensity level were assessed visually. Sensitivity was calculated by considering a case positive if any TMA core was positive. The sensitivity for identifying metastatic prostatic adenocarcinomas overall was 98.6% (68/69 cases positive) for NKX3.1, 94.2% (65/69 cores positive) for PSA, and 98.6% (68/69 cores positive) for PSAP. The specificity of NKX3.1 was 99.7% (1/349 nonprostatic tumors positive). The sole positive nonprostatic cancer case was an invasive lobular carcinoma of the breast. NKX3.1 seems to be a highly sensitive and specific tissue marker of metastatic prostatic adenocarcinoma. In the appropriate clinical setting, the addition of IHC staining for NKX3.1, along with other prostate-restricted markers, may prove to be a valuable adjunct to definitively determine prostatic origin in poorly differentiated metastatic carcinomas.

ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer.

Dysregulation of the developmental gene anterior gradient protein 2 (AGR2) has been associated with a metastatic phenotype, but its mechanism of action and control in prostate cancers is unknown. In this study, we show that overexpression of AGR2 promotes the motility and invasiveness of nonmetastatic LNCaP tumor cells, whereas silencing of AGR2 in the metastatic derivative C4-2B blocks invasive behavior. ErbB3 binding protein 1 (EBP1), a putative repressor of AGR2, is attenuated in prostate cancer. We show that the anti-invasive effect of EBP1 occurs, at least in part, through its ability to inhibit AGR2 expression. Mechanistic investigations indicate that EBP1 downregulates Foxa1- and Foxa2-stimulated AGR2 transcription and decreases metastatic behavior. In contrast, EBP1 ablation upregulates AGR2 via Foxa1- and Foxa2-stimulated AGR2 promoter activity and increases metastatic behavior. In both prostate cell lines and primary tumors, we documented an inverse correlation between EBP1 and AGR2 levels. Collectively, our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer.

Benign and Malignant Neoplasms of the Testis and Paratesticular Tissue.

Benign and malignant tumors of the testes and paratesticular tissues present an interesting spectrum of diagnostic entities often encountered in routine surgical pathology practice. Germ cell tumors are the most common tumors of the testes and, despite a rising incidence, have excellent prognosis because of their radiosensitivity and/or effective chemotherapeutic agents. The proper classification of these tumors aids in the choice of appropriate treatment options. This article reviews benign and malignant neoplastic entities of the testes and paratesticular tissues and illustrates the classic pathologic characteristics. The differential diagnosis, along with ancillary studies, clinical significance, and presentation are discussed also.

A comparison of the diffusion of two innovations -- a pilot study: telemicroscopy versus teleradiology.

Despite speculation that Telemicroscopy and Digital Microscopy will follow the same diffusion curves as their counterparts in the world of Radiology - Teleradiology and Filmless Radiology, no study has offered definitive evidence in support of this hypothesis. To address this gap in the informatics knowledge base, dual survey instruments were created to measure current opinions on both technologies among Pathologists and Radiologists and disseminated to Pathologists and Radiologists at two major academic medical centers.

False positive labeling of prostate cancer with high molecular weight cytokeratin: p63 a more specific immunomarker for basal cells.

Occasional nonspecific staining of prostate cancer cells with high molecular weight cytokeratin (HMWCK) can lead to false-negative diagnoses. We compared p63 and HMWCK immunostaining to check their specificity for basal cell identification. Out of 6887 prostate cancer cases sent in consultation to one of the authors over 1.5 years, we identified 22 (0.3%) cases with HMWCK labeling of cancer cells, including 20 needle biopsies and 2 transurethral resections of prostate (TURP). Cases were sent in consultation because of the confusing immunostaining pattern, where prostate cancer cells labeled with HMWCK at the outside institutions. In 6 cases, p63 immunostains were also received from the outside institution, whereas in the remaining 16 cases p63 immunohistochemistry was performed at our institution. In 14 cases, we used either an extra destained hematoxylin and eosin slide or a negative control slide for immunohistochemistry with antibodies to p63, and in the 2 remaining cases submitted unstained slides were used. The Gleason scores were 3+3=6 in 20 cases and 4+4=8 in 2 cases. The size of the tumor on needle biopsy ranged from 0.5 to 6.0 mm (mean 1 mm) and on the 2 TURP cases consisted of 44 and 68 cancer glands, respectively. The number of tumor cells positive for HMWCK in each of the needle biopsy cases ranged from 3 to 48 (mean 13 cells), whereas on the 2 TURP cases 26 and 10 cells were labeled with HMWCK. Corresponding stains for p63 on the same cases were negative in 18 cases. In 3 of 4 cases, p63 labeled 1, 1, and 2 tumor cells, respectively. The fourth case had 5 positive cells on p63 staining with 4 positive for HMWCK. To assess whether overstaining was a factor, we evaluated the intensity of HMWCK staining in the basal cells of the benign glands, which was moderate in 6 and strong in 16 cases. The cytoplasm of benign secretory cells showed focal weak (n=3), diffuse weak (n=1), and focal moderate (n=2) staining for HMWCK. HMWCK labeling of prostate cancer cells is uncommon and does not seem to be solely attributable to overstaining. p63 is a more specific marker for basal cells than HMWCK, with less labeling of tumor cells. Recognition of this phenomenon and performing stains for p63 when it occurs can help prevent underdiagnosing prostatic carcinoma.

The Symphony protocol for H&E staining of prostatic adenocarcinoma on needle biopsy: a multicentre analysis of 120 cases.

AIMS: The diagnosis of prostate carcinoma is based on a constellation of architectural, nuclear, cytoplasmic, and ancillary features. The aim of this study was to determine if the Ventana Symphony H&E protocol can improve on the detection of prominent nucleoli in foci of prostate cancer. METHODS: One hundred and twenty cases of Gleason score 3 + 3 = 6 cancers involving 10-30% of one core were retrieved from four academic institutions and two large laboratories (20 cases per institution). The routine H&E and Symphony H&E protocol stained slides from the same case were reviewed centrally in a blinded fashion at the Johns Hopkins Hospital. The mean percentages of prominent nucleoli in malignant and benign glands by visual estimation were recorded for each case. After unblinding, the routine H&E slides were compared in a pair-wise t-test with the corresponding Symphony stained slide. RESULTS: Within all sites, the Symphony slides showed statistically significantly more prominent nucleoli in the malignant glands than the routine slides. CONCLUSIONS: The Symphony H&E staining protocol consistently highlights nucleoli in cancer to a greater extent than routine H&E stains and may increase the likelihood of making a diagnosis of limited adenocarcinoma of the prostate in challenging cases.

Basal cell carcinoma of the prostate: a clinicopathologic study of 29 cases.

We studied 29 cases of basal cell carcinoma of the prostate including what others call adenoid cystic carcinoma of the prostate. Patients' age ranged from 42 to 89 (mean 69) years. The most common methods of diagnosis was transurethral resection (TURP) (n=29) and needle biopsy (n=9). In 28/29 cases, slides were reviewed and 24 (86%) cases showed more than 1 pattern: adenoid cysticlike (AC-P) pattern and small solid nests with peripheral palisading were the most predominant patterns, each seen in 18 cases (64%). Other patterns included: basal cell hyperplasialike in 9 cases (32%); small tubules occasionally lined by a hyaline rim in 9 cases (32%), with 4 of these cases also demonstrating intermingling cords of cells; and large solid nests in 8 cases (28.5%), 5 of which had central necrosis. Fourteen cases of small nests and tubules were centrally lined by eosinophilic cells. Desmoplasia was noted in 20 (71%) cases. Infiltration around benign glands was seen in 10 (36%) cases, with predominantly small nests and AC-P. Invasion of thick muscle bundles of the bladder neck was seen in 10 of 21 TURP cases. Perineural invasion was noted in 3 cases with AC-P and 1 case of small basaloid nests. Perineural and vascular invasion was seen in 2 basal cell carcinomas with large basaloid nests. Mitoses ranged from 0 to 60/10 hpf (mean=4). bcl2 was diffusely positive in 22/24 (92%) cases. Ki67 ranged from 2% to 80% (mean=23%). Ki67 > or =20% was seen in 13 (56.5%) cases, including all patterns except small solid nests. Basal cell markers (HMWCK, p63) either: (1) highlighted multiple layers of cells in 15/25 (60%) cases with sparing of the inner most luminal layer; (2) labeled just the outermost layers in 6/25 (24%) cases; or (3) reacted with only a few scattered cells in 4/25 (16%) cases (3 with large solid nests with central necrosis, 1 with tubules and cords). Seven patients had RP with: 5/7 showing extraprostatic extension with 1/5 also showing seminal vesicle involvement and 2/5 also with a positive margin; 1/7 having organ confined disease; and 1/7 showing no residual disease. An additional 11 cases showed extraprostatic extension on TURP with bladder neck invasion (n=10) or periprostatic adipose tissue invasion (n=1). Of 29 (65.5%) cases, 19 had follow-up > 1 year with a mean of 4.3 years (1 to 19 y). Of 19 (77%) cases, 14 had no evidence of disease after 1 to 19 (mean 5.8) years. Of 19 patients, 4 locally recurred with 2 after TURP, 1 after enucleation, and 1 after RP. Metastases developed in 4/29 patients: 1 in lung, 1 in lung and liver, 1 in lung, bone and liver, 1 in penile urethra. Basal cell carcinomas are rare tumors with a broad morphologic spectrum. These tumors predominantly show an indolent course with local infiltrative behavior. A small subset behaves aggressively with local recurrences and distant metastases. The most common morphology among those with an aggressive behavior is large solid nests more often with central necrosis, high Ki67%, and less staining with basal cell markers.

Perineural involvement by benign prostatic glands on needle biopsy.

Uncommonly, benign prostatic glands can be seen in the perineural space, known as "benign perineural involvement." This phenomenon has not been specifically studied on needle biopsies; 27 needle biopsy cases with perineural involvement were evaluated; 22 (81.4%) were received in consultation, while 5 (18.5%) were in-house cases. In 15 of 22 (68.2%) consult cases, a question was raised by the submitting pathologist regarding the focus. The following patterns of perineural involvement were observed: indentation 14 (51.8%) cases, by up to 3 glands; tracking 8 (29.6%) cases, by up to 6 glands; wrapping 7 (25.9%) from one half to three fourths around the nerve, by up to 3 glands, 1 case showed 95% wrapping; intraneural 4 (14.8%) cases by up to 3 glands; adjacent 2 (7.4%) cases by up to 2 glands. Partial atrophy in the involved glands was seen in 10 (38.4%) cases and complete atrophy in 6 (23%). Of 8 cases with the lesion still present on slides for immunohistochemistry, high molecular weight cytokeratin (HMWCK) and p63 were positive in 6 (75%) and negative in the 2 (25%) cases with partial atrophy. A total of 6 (27%) cases had more than one pattern of perineural involvement. On hematoxylin and eosin sections, basal cells were not identified in 12 (46%) cases, including 2 negative and 1 positive cases stained for HMWCK. Patterns most closely mimicking cancer included intraneural and incomplete perineural encirclement. Perineural invasion by benign atrophic glands cause diagnostic difficulty, especially with negative HMWCK. Careful attention to hematoxylin and eosin morphology and comparison of perineural involvement to adjacent and distant benign glands are necessary.

Exfoliative sputum cytology of cancers metastatic to the lung.

Although largely replaced by fine-needle aspiration (FNA) and bronchoscopy, cytological examination of sputum for exfoliated malignant cells still is considered a valuable initial diagnostic test in patients presenting with a lung mass. Thirty-five cases of secondary/metastatic tumors involving the lung and diagnosed on sputum were retrospectively reviewed from our cytopathology files for a period of 22 yr (1980-2001). Clinical history and the relevant histopathological material were examined and correlated with the cytological findings. In all cases, a history of malignancy was known. Cytological diagnoses included colonic adenocarcinoma (7 cases); non-Hodgkin's lymphoma (NHL; 5 cases); malignant melanoma (MM; 5 cases); breast carcinoma (5 cases); Hodgkin's lymphoma (HL; 3 cases); pancreatic adenocarcinoma (2 cases); prostatic adenocarcinoma (2 cases); and 1 case each of urothelial carcinoma, endometrial carcinoma, renal cell carcinoma, hepatic small-cell carcinoma, squamous-cell carcinoma (cervix), and leiomyosarcoma (LMS). Cellular preservation was optimal in all cases. The smear background was relatively clean in 25 (71%) cases and predominantly inflamed and/or necrotic in 10 (29%) cases. In non-lymphoid tumors (27 cases), isolated single malignant cells were seen in 7 (26%) cases (all cases of MM and prostatic adenocarcinoma), whereas 20 (74%) cases displayed fragments with intact tumor architecture. Overall, only 10/35 (29%) cases showed noticeable tumor-cell necrosis. In one case (LMS), cell block sections were used for immunoperoxidase (IPOX) studies with positive staining for desmin and actin. Exfoliation of cancer cells in sputum from secondary tumors in the lung is a rare phenomenon in current-day practice, with metastatic colonic adenocarcinoma seen most commonly. Intact tumor architecture was observed in exfoliated cells in 75% of the cases.

Splenic hamartoma: immunohistochemical and ultrastructural profile of two cases.

Splenic hamartoma (SH) is a rare, benign lesion. We present 2 cases, both in females (2 and 30 years, respectively) with multiple urinary tract infections, and left upper quadrant abdominal pain. Immunohistochemical staining with factor VIII displayed intense diffuse staining in the SH with corresponding weak staining in the adjacent spleen. CD31 showed a reverse pattern from that of factor VIII. CD34 staining pattern was identical in both the spleen and the SH. Ultrastructurally, the SH showed endothelial cells with relatively empty cytoplasm, scattered Weibel Palade bodies, and lining by basement membrane surrounded by fibrous long-spacing collagen. Our study highlights the unique immunohistochemical profile of SH. The ultrastructural features are interesting, although their diagnostic significance remains to be confirmed in future studies.