Higher Expression of miR-182 in Cytology Specimens of High-Grade Urothelial Cell Carcinoma: A Potential Diagnostic Marker.

OBJECTIVE: MicroRNAs (miRs) are short noncoding RNA molecules that posttranscriptionally modulate protein expression. There are distinct miR alterations characterizing urothelial cell carcinoma (UCC) of the urinary bladder. STUDY DESIGN: In this study, we investigate the possibility of using miR as a noninvasive marker in the screening of UCC. The total RNA was extracted from 75 cytology specimens including bladder or renal washings and voided urines. Cases comprise UCC (21 high grade and 6 low grade), 25 normal controls and 23 cases with a history of UCC but negative at the time of testing (negative with a positive history). The expressions of miR-96, miR-182, miR-183, miR-200c, miR-21, miR-141 and miR-30b were determined using quantitative TaqMan real-time PCR. RESULTS AND CONCLUSION: This study shows that the level of miR-182 is higher in cytology specimens from high-grade UCC patients as compared to normal controls. Measuring miR-182 may provide a potential alternative or adjunct approach for screening high-grade UCC.

Expression of SALL4 and SF-1 in gonadoblastoma: useful markers in the identification of the invasive germ cell component.

Gonadoblastoma is a rare gonadal neoplasm composed of primordial germ cells and sex cord-stromal cells and usually occurs in patients with dysgenetic gonads. When patients with gonadoblastoma develop an invasive germ cell tumor, the invasive germ cell component can take the form of dysgerminoma/seminoma, embryonal carcinoma, or yolk sac tumor. In this study, we performed immunohistochemical analysis for SALL4 and steroidogenic factor-1 (SF-1) on 4 cases of gonadoblastoma to examine the expression patterns of these proteins. All of the patients were phenotypically female. One patient had Swyer syndrome, the rest had Turner syndrome. The primordial germ cell component was histologically similar to cells in dysgerminoma/seminoma in these 4 cases. Two patients showed the invasive component-dysgerminoma. As expected, SALL4 stained the germ cells and SF-1 stained the sex cord-stromal cells. There was a clear distinction between the staining patterns of these 2 cell populations. This study demonstrates the utility of SALL4 and SF-1 in determining whether or not there is an invasion in the primordial germ cell component.

Useful immunohistochemical panel for differentiating clear cell papillary renal cell carcinoma from its mimics.

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described low-grade renal cell tumor. In this study, we investigated the expression of paired box 8 (PAX-8), carbonic anhydrase IX (CA IX), CK7, and α-methylacyl-CoA-racemase (AMACR) in this tumor by immunohistochemistry in a group of 20 cases of CCPRCC. Clear cell papillary renal cell carcinoma showed diffuse (70%) or intermediate (30%) nuclear positivity for PAX-8 in each case, with predominantly moderate intensity (50%). Ninety percent of the cases showed some degree of cytoplasmic staining for CA IX, predominantly with moderate intensity (50%). In addition, each case of CCPRCC also showed diffuse membranous staining for CK7. Most CCPRCCs (95%) were negative for AMACR. PAX-8, CA IX, CK7, and AMACR comprise a concise panel for distinguishing CCPRCC from its mimics. PAX-8 positivity helps to confirm the renal origin of this tumor. Positivity for CA IX and CK7 differentiate CCPRCC from conventional clear cell renal cell carcinoma, which is usually CA IX positive while CK7 negative. The CK7-positive and AMACR-negative pattern seen in CCPRCC differentiates it from papillary renal cell carcinoma, which is usually positive for both AMACR and CK7.

Immunohistochemical markers for the differential diagnosis of nephrogenic adenomas.

Nephrogenic adenoma (NA) is a rare benign lesion commonly occurring in the urinary bladder that poses challenges to devising a diagnosis. In this study, 21 cases of NAs were studied by performing immunohistochemistry for PAX8, p63, CK903, PSA, S100A1, BerEP4, and CEA on routine tissue sections. PAX8 showed diffuse moderate to strong (2+ and 3+) nuclear staining in all of NAs (n = 6 and 15, respectively) and negative in the normal urothelium (n = 15). Nuclear staining for p63 was not seen in any case of NAs examined (n = 19) and was diffuse and strong (3+) in the normal urothelium (n = 14). High-molecular-weight keratin CK903 showed weak (1+) diffuse staining in all of the NAs examined (n = 19) and diffuse and moderate to strong positivity in the normal urothelium (n = 16). PSA staining was negative in both of the NAs (n = 21) and normal urothelium (n = 16). S100A1 showed strong (3+) diffuse staining in 19 of 20 of the NAs examined (n = 19) and diffuse weak (1+) (n = 14) to moderate (n = 3) staining in the normal urothelium. BerEP4 showed focal to diffuse, mild to moderate (1+ and 2+) cytoplasmic staining in all of NAs (n = 2 and 19) and negative in the normal urothelium (n = 19). CEA staining was negative in both of the NAs (n = 21) and normal urothelium (n = 17). A panel composed of PAX8, p63, PSA, S100A1, and CEA appears to be sensitive and specific in differentiating NA from its mimics of urothelial and prostatic origins.

Malignant tumors with clear cell morphology: a comparative immunohistochemical study with renal cell carcinoma antibody, Pax8, steroidogenic factor 1, and brachyury.

This study aimed to identify an immunohistochemical panel to aid in the differential diagnosis for tumors with clear cell morphology. Twenty-five clear cell renal cell carcinomas (CCRCCs), 19 clear cell ovarian carcinoma (CCOCs), 20 cases of adrenal cortical carcinomas(ACCs), and 10 chordomas were stained for renal cell carcinoma marker (RCC Ma), Pax8, brachyury, and steroidogenic factor 1 (SF-1). The extent of stains was scored as focal (<25%), nonfocal (25%-50%), and diffuse (>50%). The intensity was scored as weak, moderate, and strong. Twenty-two CCRCCs were positive for RCC Ma (88%) and Pax8 (88%), respectively. The RCC Ma cytoplasmic staining was largely diffuse (76%) and strong (76%). The nuclear Pax8 staining was usually diffuse (76%) and moderate (64%) to strong (8%). All of CCRCCs were negative for brachyury and SF-1. All of 19 CCOCs were positive for Pax8 nuclear staining. The staining was diffuse, moderate (21%) to strong (79%). All of CCOCs were negative for RCC Ma, brachyury, and SF-1. All of 20 ACCs were positive for SF-1 nuclear staining. The staining was largely diffuse (95%), moderate (55%) to strong (15%). All of ACC were negative for RCC Ma, Pax8, and brachyury. All of 10 chordomas were positive for brachyury nuclear staining. The staining was diffuse and strong. All of chordomas were negative for RCC Ma, Pax8, and SF-1. In summary, the panel of RCC Ma, Pax8, brachyury, and SF-1 is useful in the differential diagnosis of tumors with clear morphology.

The expression of heterochromatin protein 1α/ß in the kidney tumors: a microarray immunohistochemical study.

Kidney tumors of various types may behave differently and have different prognosis. Due to some overlapping morphological features and immunohistochemical staining pattern, they may pose diagnostic challenge. Therefore, it is necessary to explore additional immunohistochemical stains to help in subclassifying these epithelial neoplasms. Tissue microarrays of 20 cases each of renal cell carcinomas (RCC) of clear cell, chromophobe, and papillary variants and oncocytoma were constructed and used to test the heterochromatin-associated protein (HP) 1α/ß expression. HP-1α/ß showed strong nuclear staining. Expression of HP-1α/ß was found mostly in papillary RCC (79%) and oncocytoma (75%) but less in chromophobe (30%) and clear cell RCCs (35%). HP-1α/ß may be useful in the differential diagnosis of renal tumors, especially in the differentiation of chromophobe RCC and oncocytoma.

Role of carbonic anhydrase IX, α-methylacyl coenzyme a racemase, cytokeratin 7, and galectin-3 in the evaluation of renal neoplasms: a tissue microarray immunohistochemical study.

Kidney tumors of various types may behave differently and have different prognosis. Because of some overlapping morphological features and immunohistochemical staining pattern, they may pose diagnostic challenge. Therefore, it is necessary to explore additional immunohistochemical stains to help classifying these epithelial neoplasms. Tissue microarrays of 20 cases each of renal cell carcinomas of clear cell, chromophobe, and papillary variants and oncocytoma were constructed and used to test a panel of immunohistochemical markers including carbonic anhydrase IX, galectin-3, cytokeratin 7 (CK7), and α-methylacyl coenzyme a racemase. Carbonic anhydrase IX was highly sensitive for clear cell renal cell carcinoma (90% positivity) and was negative in all other renal epithelial tumors except for 1 chromophobe renal cell carcinoma (chRCC). Expression of galectin-3 was found mostly in renal tumors with oncocytic features, including oncocytomas (100%) and chRCCs (89%). α-Methylacyl coenzyme a racemase was positive in papillary renal cell carcinoma (100%). CK7 was positive in papillary renal cell carcinoma (90%), chRCC (89%), and oncocytoma (90%). Although both chRCC and oncocytoma were positive for CK7, but with a different patterns, CK7 staining in chRCC was diffuse, whereas it was sporadic in oncocytoma. Panel of carbonic anhydrase IX, galectin-3, CK7, and α-methylacyl coenzyme a racemase is sensitive and specific for the differential diagnosis of the renal epithelial tumors.

CDX2 expression in yolk sac component of testicular germ cell tumors.

CDX2 has been detected in the majority of colorectal adenocarcinoma cases and may be useful in determining the sites of origin of tumors. In this study, the authors evaluated CDX2 expression in germ cell tumors (GCTs) by immunohistochemistry. Forty cases of testicular GCTs and 8 cases of metastatic GCTs were retrieved for study. In the 40 cases of testicular GCTs, 13 were pure seminomas and 27 mixed GCTs. Yolk sac tumor (YST) was identified by morphology and glypican 3 staining in 20 testicular mixed GCTs. Of these 20 cases, 8 cases showed 1+ positivity for CDX2. Other primitive components of GCTs were negative. For the 6 cases of metastatic mixed GCT with YST, 4 cases were positive, 2+ in 2 cases and 1+ in 2 cases. The positivity of CDX2 in GCTs warrants including YST in the differential diagnosis of adenocarcinoma of unknown origin.

Metastasis of small cell carcinoma of lung into an ovarian mucinous neoplasm: immunohistochemistry as a useful ancillary technique for diagnosis and classification of rare tumors.

The authors report the first case of ovarian mucinous adenocarcinoma with metastasis from a synchronous small cell neuroendocrine carcinoma of the lung. A 62-year-old white woman presented with weight loss and increased abdominal girth. She was found to have a large, complex cystic mass in the pelvis, and during the staging evaluation, a large, right pulmonary hilar mass was detected. Bronchial brushing as well as transbronchial fine-needle aspiration was diagnostic of small cell carcinoma. The patient received 3 cycles of chemotherapy with carboplatin and subsequently underwent a supracervical hysterectomy and bilateral salpingo-oophorectomy. A large, multiloculated cystic mass was found arising from the right ovary. Microscopic examination disclosed a mucinous neoplasm with both mucinous cystadenoma and mucinous papillary adenocarcinoma components. A microscopic focus of cells with "atypical" cytomorphologic features was detected within the mucinous neoplasm. Immunohistochemistry showed that group of cells to be positive for thyroid transcription factor 1 and chromogranin, confirming them to be metastasis from the pulmonary small cell neuroendocrine carcinoma. This case, in addition to being the first reported case of such metastasis, also highlights the diagnostic utility of immunohistochemistry as a reliable and very useful ancillary technique for the diagnosis of neoplasms with unusual clinical and/or histomorphologic presentations. The clinical and prognostic implications are also discussed.

The clinical presentation and outcome of urothelial atypia on biopsy of the bladder.

OBJECTIVES: To examine the presentation and clinical outcome of patients diagnosed with reactive urothelial atypia (RUA) or urothelial atypia of unknown significance (AUS) on tissue biopsy of the bladder. METHODS AND MATERIALS: We performed a retrospective cohort study of all patients who were diagnosed with either RUA or AUS on biopsy of the bladder at our institution from November 2000 to May 2008. Excluded from the analysis were patients with a history of or a concurrent diagnosis of urothelial carcinoma. A total of 66 patients were available for final analysis. RESULTS: The mean patient age at diagnosis was 63 years (range: 18-89 years). There were 46 men (70%) and 20 women (30%). The indication for cystoscopic examination included lower urinary tract symptoms in 29 (44%), gross hematuria in 17 (26%), microscopic hematuria in 12 (18%), urolithiasis in 2 (3%), and hydronephrosis in 6 (9%) patients. On biopsy, 54 (82%) had RUA and 12 (18%) had AUS. The mean follow-up was 36 months (range: 0-271 months). During this period, 37 (56%) patients underwent at least 1 additional cystoscopy with negative result. None of the 66 (0%) patients developed biopsy-proven urothelial carcinoma. CONCLUSION: Urothelial atypia is common in men older than 60 years and often presents with either hematuria or lower urinary tract symptoms. Both RUA and AUS have a similar benign clinical course. Therefore, after diagnosis, further intervention or surveillance is unnecessary.

Expression of parafibromin in clear cell papillary renal cell carcinoma.

Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal cell neoplasm. In this study, we investigated the expression of parafibromin, CK7, and RCC marker (RCC-Ma) in this tumor by immunohistochemistry in a group of CCPRCC. Twenty cases of CCPRCC were stained for parafibromin and showed diffuse and strong nuclear positivity for this marker. In addition the cases of CCPRCC were stained for CK7 and RCC-Ma, respectively, and the majority of tumors were positive for cytoplasmic staining of CK7 and negative for RCC-Ma. This unique staining pattern can be useful in the differential diagnosis from conventional clear cell renal cell carcinomas, which have a higher positivity rate for RCC-Ma, but largely negative for CK7 and parafibromin, and papillary renal cell carcinomas, which are usually positive for CK7 and RCC-Ma but are largely negative for parafibromin.

Malignant mesotheliomas in spermatic cords: reports of two cases and a brief review of literature.

Primary malignant mesothelioma (MM) of spermatic cord is extremely rare. We presented two malignant mesotheliomas involving the spermatic cords; one was primary, one secondary. The secondary one represented the direct involvement by a peritoneal MM. No occupational exposure to asbestos was identified in either patient. Both of them presented with a painless inguinal mass. Microscopically the primary MM was epithelioid type with tumor nests infiltrating adjacent adipose tissue, while the secondary MM grew in mixed type. No tumor necrosis was seen in the primary MM, while extensive necrosis was seen in the secondary one. Rare mitotic figure was seen in the primary MM while the mitosis in the secondary tumor was brisk, and with atypical mitosis. Immunohistochemically the tumor cells were positive for calretinin and CK5/6 and negative for BER-EP4 and BRST3 in both cases. The reported cases of primary MM from spermatic cord in English literature were briefly reviewed.

SALL4 and SF-1 are sensitive and specific markers for distinguishing granulosa cell tumors from yolk sac tumors.

Granulosa cell tumors are classified as juvenile and adult types. They may be misinterpreted as a yolk sac tumor when they exhibit a "reticular" growth pattern and contain prominent mitotic activity. In this study, the authors performed immunohistochemical stains for SALL4 and steroidogenic factor-1 (SF-1) on 27 cases of yolk sac tumors and 24 granulosa cell tumors. Nuclear stains for both antibodies were considered as positive and the intensity of staining was graded as negative, weak, moderate, and strong. All the yolk sac tumors were positive for SALL4 (100%) with moderate to strong grade staining and negative for SF-1 (100%). In contrast, all the granulosa cell tumors were positive for SF-1 (85% moderate to strong grade staining and 15% weak staining) and negative for SALL4 (100%). The difference was significant (P < .01, Student's t test). This result indicates that these 2 markers could be used to distinguish these 2 tumors in a difficult situation.

Primary retroperitoneal mature cystic teratoma with focal enteric type adenocarcinoma in a post-partum woman: report of a case with literature review.

Teratomas are characterized by containing tissue from all three germinal cell layers. Occasionally, somatic type malignancies develop within a mature cystic teratoma. We reported here a rare case of enteric type adenocarcinoma, with associated dysplastic epithelial precursor lesion, arising within a mature cystic teratoma in the retroperitoneum of a 30-year-old woman status post vaginal delivery 11 weeks earlier. The mass is 17.5 cm and cystic. A polypoid mass component measuring 4.7×4.2×2.5 cm was located inside the cystic component. Microscopically, the majority of the specimen was a mature cystic teratoma with all three germinal cell layers. The polypoid mass component was an adenocarcinoma with an adjacent dysplastic epithelial precursor lesion. The adenocarcinoma was diffusely positive for CK20 and CDX-2, and focally positive for CD7, indicating enteric differentiation. A brief review of retroperitoneal mature cystic teratomas with associated somatic type malignancy was performed.

Immunohistochemical studies of metastatic germ-cell tumors in retroperitoneal dissection specimens: a sensitive and specific panel.

Germ-cell tumors (GCTs) are the most common malignancies in adolescent and young men. These tumors are highly treatable, even at an advanced stage; therefore, accurate diagnosis is imperative. In this study, we evaluated immunohistochemical stains for SALL4, NANOG, glypican-3 (GPC3), D2-40, and CD30 with adequate control in retroperitoneal dissection specimens under the same laboratory conditions. The study groups included 31 cases of metastatic testicular GCTs with the following components: 11 seminomas, 14 embryonal carcinoma (ECs), 12 yolk sac tumor (YSTs), 8 teratomas, 10 cases of metastatic melanomas, 14 cases of malignant lymphomas, and 11 cases of metastatic, poorly differentiated carcinoma. SALL4 showed diffuse nuclear labeling for all seminomas, ECs, and YSTs. NANOG showed diffuse nuclear positivity in all seminomas and ECs. Metastatic carcinomas, melanomas, and malignant lymphomas were negative for these 2 markers. Gypican-3, D2-40, and CD30 showed sensitive staining for YSTs, seminomas, and ECs, respectively. In conclusion, SALL4 and NANOG are sensitive and specific markers for GCTs. GPC3, D2-40, and CD30 are sensitive but not specific for individual components of GCTs and may be useful in aiding in the differential diagnosis for the individual component of GCTs when the identity of GCT is established.

Microsatellite instability and TARBP2 mutation study in upper urinary tract urothelial carcinoma.

Microsatellite instability (MSI) contributes to the tumorigenesis of upper urinary tract urothelial carcinomas (UUT-UCs). In this study, we first used MLH1 and MSH2 immunohistochemistry to identify patients with loss of expression of either or both of these proteins in 132 UUT-UCs. We found a total loss of MSH2 expression in 4 patients. MSI was evaluated using 5 markers in these 4 cases. All of the tumors had high MSI (MSI-H) status. Trans-activation responsive RNA-binding protein 2, an integral component of DICER1-containing complex, was a putative target of DNA mismatch repair deficiency. Truncating mutation has been identified in gastrointestinal cancers with MSI. No previous study has evaluated the mutation status of this gene in MSI UUT-UCs. In this study, we analyze the mutation of TARBP2 in MSI-H UUT-UCs with reverse transcription polymerase chain reaction. No truncating mutations were identified in the MSI-H UUT-UCs.

Localized candidiasis in kidney presented as a mass mimicking renal cell carcinoma.

Candida albicans is a ubiquitous fungus and infection of urinary tract by C. albicans can be originated from blood or retrograde infection. We reported a case of localized candidiasis in the kidney presenting as a mass. The patient was a 61-year-old male with a history of type 2 diabetes mellitus and urinary bladder urothelial carcinoma status post radical cystoprostatectomy with a neobladder three years ago. Pathology at that time also showed a prostatic adenocarcinoma (Gleason score 3 + 4) in addition to the high-grade urothelial carcinoma. Three month ago the patient presented with flank pain, chill, and increased white cell counts. Imaging study showed a large renal mass suspicious for a renal cell carcinoma. Radical nephrectomy was performed and found that there was a large pocket of pus in the retroperitoneum around the right kidney during the surgery. Intraoperative abscess cultures were positive for C. albicans. Pathology showed a 13.5 cm necrotic renal mass extending to the perinephric fat. Histologically the tumor showed necrotic granulomatous inflammation. Grocott stain in the surgical specimen was positive for pseudohyphae and yeast forms. The patient was initiated a course of fluconazole postoperatively and was feeling well.