Ali Amin

Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity.

CONTEXT Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron. OBJECTIVE To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes. EVIDENCE ACQUISITION A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. EVIDENCE SYNTHESIS The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies. CONCLUSIONS Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space. PATIENT SUMMARY Kidney cancer can be subdivided into related but different cancers that arise from the kidneys tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtypes clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies.

UTILITY OF GATA3 IMMUNOHISTOCHEMISTRY IN DIFFERENTIATING UROTHELIAL CARCINOMA FROM PROSTATE ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMAS OF THE UTERINE CERVIX, ANUS, AND LUNG

Distinguishing invasive high-grade urothelial carcinoma (UC) from other carcinomas occurring in the genitourinary tract may be difficult. The differential diagnosis includes high-grade prostatic adenocarcinoma, spread from an anal squamous cell carcinoma (SCC), or spread from a uterine cervical SCC. In terms of metastatic UC, the most common problem is differentiating spread of UC to the lung from a primary pulmonary SCC. Immunohistochemical analysis (IHC) for GATA binding protein 3 (GATA3), thrombomodulin (THROMBO), and uroplakin III was performed on a tissue microarray (TMA) containing 35 cases of invasive high-grade UC. GATA3 IHC was also performed on TMAs containing 38 high-grade (Gleason score ≥8) prostatic adenocarcinomas, representative tissue sections from 15 invasive anal SCCs, representative tissue sections from 19 invasive cervical SCCs, and TMAs with 12 invasive cervical carcinomas of the cervix [SCC (n=10), SCC with neuroendocrine features (n=1), and adenosquamous carcinoma (n=1)]. In addition, GATA3 IHC was performed on representative tissue sections from 15 pulmonary UC metastases and a TMA with 25 SCCs of the lung and 5 pulmonary non–small cell carcinomas with squamous features. GATA3, THROMBO, and uroplakin III were positive in 28 (80%), 22 (63%), and 21 (60%) cases of high-grade UC, respectively. All cases of GATA3-positive staining were nonfocal; 25 (89%) cases demonstrated moderate to strong staining, and 3 (11%) demonstrated weak staining. Of the 7 cases that failed to express GATA3, 5 were positive for THROMBO and/or uroplakin III, whereas 2 were negative for all 3 markers. None of the 38 high-grade prostatic adenocarcinomas was positive for GATA3. Weak GATA3 staining was present in occasional basal cells of benign prostate glands, in a few benign atrophic glands, and in urothelial metaplasia. Of the 15 cases of anal SCCs, 2 (7%) cases showed focal weak staining, and 1 (3%) showed focal moderate staining. Weak staining was also rarely observed in the benign anal squamous epithelium. Of the 31 uterine cervical carcinomas, 6 (19%) showed weak GATA3 staining (3 nonfocal and 3 focal), and 2 (6%) demonstrated focal moderate staining. Twelve (80%) of the metastatic UCs to the lung were positive for GATA3, with 11 cases showing diffuse moderate or strong staining and 1 case showing focal moderate staining. None of the pulmonary SCCs or non–small cell carcinomas with squamous features was GATA3 positive. GATA3 IHC is a sensitive marker for UC, and positive staining in UC is typically nonfocal and moderate or strong in intensity. GATA3 is also highly specific in excluding high-grade prostate adenocarcinoma. Although some cervical and anal SCCs can be GATA3 positive, unlike in UC, staining is more commonly focal and weak. GATA3 is also a useful maker when diagnosing metastatic UC to the lung.

Gleason Score 7 Adenocarcinoma of the Prostate With Lymph Node Metastases: Analysis of 184 Radical Prostatectomy Specimens

CONTEXT Prostate cancer (PC) with lymph node metastases (LN(+)) is relatively rare, whereas it is relatively common in disease with a Gleason score (GS) 8 to 10 and virtually never seen in PC with GS 6 or less. It is most variable in GS 7 PC. OBJECTIVE To determine clinicopathologic features associated with GS 7 PC with LN(+) compared with a control group without lymph node metastases (LN(-)). DESIGN We analyzed 184 GS 7 radical prostatectomies with LN(+) and the same number of LN(-) Gleason-matched controls. The LN(+) cases were GS 3 + 4 = 7 (n = 64; 34.8%), GS 4 + 3 = 7 (n = 66; 35.9%), GS 3 + 4 = 7 with tertiary 5 (n = 10; 5.4%), and GS 4 + 3 = 7 with tertiary 5 (n = 44; 23.9%). RESULTS The LN(+) cases demonstrated higher average values in preoperative prostate-specific antigen (12.2 versus 8.1 ng/mL), percentage of positive biopsy cores (59.1% versus 42.9%), prostate weight (54.4 versus 49.4 g), number of LNs submitted (12.7 versus 9.4), incidence of nonfocal extraprostatic extension (82.6% versus 63.6%), tumor volume (28.9% versus 14.8%), frequency of lymphovascular invasion (78.3% versus 38.6%), intraductal spread of carcinoma (42.4% versus 20.7%), incidence of satellite tumor foci (16.4% versus 4.3%), incidence of pT3b disease (49.5% versus 14.7%), and lymphovascular invasion in the seminal vesicles (52% versus 30%). There were differences in GS 4 patterns and cytology between LN(+) and LN(-) cases, with the former having higher volumes of cribriform and poorly formed patterns, larger nuclei and nucleoli, and more-frequent macronucleoli. All P ≤ .05. CONCLUSION Gleason score 7 PC with LN(+) has features highlighting a more-aggressive phenotype. These features can be assessed as prognostic markers in GS 7 disease on biopsy (eg, GS 4 pattern, intraductal spread, cytology) or at radical prostatectomies (all variables), even in men without LN dissection or LN(-) disease.

Gleason Score 7 Prostate Cancer on Needle Biopsy: Relation of Primary Pattern 3 or 4 to Pathological Stage and Progression After Radical Prostatectomy

PURPOSE There have been only a few contradictory publications assessing whether Gleason score 4 + 3 = 7 has a worse prognosis than 3 + 4 = 7 on biopsy material in predicting pathological stage and biochemical recurrence. Older studies predated the use of the modified Gleason grading system established in 2005. MATERIALS AND METHODS We retrospectively studied 1,791 cases of Gleason score 7 on prostatic biopsy to determine whether the breakdown of Gleason score 7 into 3 + 4 vs 4 + 3 has prognostic significance in the modern era. RESULTS There was no difference in patient age, preoperative serum prostate specific antigen, maximum tumor percent per core or the number of positive cores between Gleason score 3 + 4 = 7 and Gleason score 4 + 3 = 7. Gleason score 4 + 3 = 7 showed an overall correlation with pathological stage (organ confined, focal extraprostatic extension, nonfocal extraprostatic extension, seminal vesicle invasion/lymph node metastases, p = 0.005). On multivariate analysis Gleason score 4 + 3 = 7 (p = 0.03), number of positive cores (p = 0.002), maximum percent of cancer per core (p = 0.006) and preoperative serum prostate specific antigen (p = 0.03) all correlated with pathological stage. Gleason score 4 + 3 = 7 on biopsy was also associated with an increased risk of biochemical progression after radical prostatectomy (p = 0.0001). On multivariate analysis Gleason score 4 + 3 = 7 (p = 0.001), maximum percent of cancer per core (p <0.0001) and preoperative serum prostate specific antigen (p <0.0001) but not number of positive cores correlated with the risk of biochemical progression after radical prostatectomy. CONCLUSIONS Our study further demonstrates that Gleason score 7 should not be considered a homogenous group for the purposes of disease management and prognosis.

Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients

We are presenting the morphological features of 121 cases of atypical penile intraepithelial lesions. The term penile intraepithelial neoplasia (PeIN) was used to encompass all of them, and lesions were classified into 2 major groups, differentiated and undifferentiated. The latter was further divided in warty, basaloid, and warty-basaloid subtypes. Ninety-five cases were associated with invasive squamous cell carcinomas. Differentiated lesions predominated (68%), followed by warty-basaloid (14%), basaloid (11%), and warty (7%) subtypes. Multifocality was found in 15% of the cases. Differentiated lesions were preferentially located in foreskin, whereas warty and/or basaloid subtypes were more prevalent in the glans. The former lesions were preferentially seen in association with keratinizing variants of squamous carcinoma, whereas the latter subtypes were found mostly in conjunction with invasive warty, basaloid, and warty-basaloid carcinomas. Lichen sclerosus was present in 51% of cases of differentiated lesions and absent in warty and/or basaloid subtypes. In summary, PeIN can be classified into 4 distinctive morphological subtypes. The proper pathological characterization of these lesions may provide important clues to the understanding of the pathogenesis and natural history of penile cancer.

Pathologic stage of prostatic ductal adenocarcinoma at radical prostatectomy: effect of percentage of the ductal component and associated grade of acinar adenocarcinoma.

It is unknown whether ductal adenocarcinomas are more aggressive when matched for Gleason score (assigning the ductal component as Gleason pattern 4). Moreover, little is known whether a certain percentage of the ductal component is needed to account for its more aggressive behavior. Of 18,552 radical prostatectomies performed from 1995 to 2008, 93 cases with a ductal adenocarcinoma component were identified. Cases were classified based on their ductal/acinar ratio (<10%; ≥10% and <50%; ≥50%). There was no difference in the distribution of Gleason score 3+4=7 versus 4+3=7 between ductal and nonductal tumors, such that cases were combined as Gleason score 7. There was no age, race, and serum prostate-specific antigen difference between patients with and without ductal adenocarcinoma. Cases with ductal adenocarcinoma were less likely to be organ confined (36.6% vs 65.6%) and more likely to show seminal vesicle invasion (SVI) (19.3% vs 5.3%), P<0.0001. There was no difference in lymph node metastases or positive margins between cases with and without ductal features. An increasing percentage of the ductal component correlated with an increased risk of extraprostatic extension (P=0.04) and SVI (P<0.0001). To account for overall different Gleason scores between ductal and nonductal cases, and the effect of differing percentages of ductal features as well, the following analysis was carried out. For Gleason score 7 cases and ≥10% ductal differentiation, cases with ductal features were more likely to have nonfocal extraprostatic extension (64.0%) versus cases without ductal features (34.7%), P=0.002. In this group, there was no statistically significant difference in SVI or lymph node involvement between Gleason score 7 ductal and nonductal tumors. For Gleason score 7 cases with <10% ductal features, there was no difference in pathologic stage versus nonductal cases. There was no difference in pathologic stage between ductal and nonductal cases for Gleason score 8 to 10 cases, regardless of the percentage of the ductal component. This study shows that ductal adenocarcinoma admixed with Gleason pattern 3 is more aggressive than Gleason score 7 acinar cancer, as long as the ductal component is ≥10%. In cases with a very minor ductal component, these differences are lost. In addition, Gleason score 8 to 10 tumors with ductal features are not significantly more aggressive that acinar Gleason score 8 to 10 cancers in which the pure high-grade tumor, regardless of ductal features, determines the behavior.

Noninvasive micropapillary urothelial carcinoma: a clinicopathologic study of 18 cases

Noninvasive micropapillary urothelial carcinoma consists of slender tufts of urothelial carcinoma lacking fibrovascular cores analogous to ovarian papillary serous tumors of borderline malignancy. Eighteen noninvasive micropapillary urothelial carcinoma cases were identified from the Pathology Department of The Johns Hopkins Hospital (2000-2011). Patients lacked history of invasive urothelial carcinoma. Two patterns of noninvasive micropapillary urothelial carcinoma were identified: (1) as a variant of noninvasive high-grade papillary urothelial carcinoma (high-grade papillary urothelial carcinoma/micropapillary urothelial carcinoma) (n = 13 cases) and (2) as a variant of urothelial carcinoma in situ (carcinoma in situ/micropapillary urothelial carcinoma) (n = 5 cases with 2 of these patients also having high-grade papillary urothelial carcinoma/micropapillary urothelial carcinoma). Of 18 patients, 16 (88%) were male with a mean age of 71.8 years (range, 54-87 years). Of the 12 patients initially treated with surveillance, Bacillus-Calmette Guérin, or intravesical chemotherapy, 4 did not recur and were without evidence of disease at 6, 21, 24, and 39 months. Four patients experienced recurrences with 3 of them without evidence of disease at 36, 52, and 72 months and with the fourth whose last follow-up was at 84 months when recurrence occurred. One patient is alive at 11 months with disease, and 1 died of other causes at 1 month. Two patients progressed to pT2 and pT3 disease at 5 and 21 months, respectively. It is critical to differentiate and clearly specify in pathology reports whether micropapillary urothelial carcinoma is invasive or noninvasive because invasive micropapillary urothelial carcinoma is an aggressive disease with a high degree of understaging, whereas some cases of noninvasive micropapillary urothelial carcinoma are not necessarily associated with an adverse outcome.

Primary Central Nervous System Mucosa-Associated Lymphoid Tissue Lymphoma: Case Report and Literature Review

Primary presentation of intradural non-Hodgkin lymphoma is rare. Recently, B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) have been recognized as an important pathologic subtype. When MALT lymphomas present in the central nervous system (CNS), they are distinguishable from primary high-grade CNS lymphomas. We present the clinicopathologic features of 5 patients with primary CNS MALT lymphoma treated at our institution from 1999 to 2006. Four out of 5 patients were women, and all patients presented with headaches, focal motor deficits, or cranial nerve palsy. Radiologic studies demonstrated ill-defined dural masses in 3 and well-defined masses in 2 patients. Pathology revealed small to medium-sized cells with a moderate amount of cytoplasm and irregular nuclear borders, expressing pan B-cell markers (CD19, CD20, and CD79a) but lacking CD10, CD23, and cyclin D1, confirming low-grade MALT lymphoma. Plasma cells were encountered in all the biopsies with variable reactive T-cell infiltration. wedge chain restriction was seen in 3 patients. Therapy consisted of either surgical resection, whole-brain radiation, or systemic or intrathecal chemotherapy. There was no evidence of recurrence or systemic relapse in 4 patients at 4 years of follow-up. One patient died in 2 months, unrelated to CNS lymphoma. This case series illustrates the rare occurrence of low-grade dural B-cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions.

Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model.

Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure.

Targeted Imaging of Urothelium Carcinoma in Human Bladders by an ICG pHLIP Peptide Ex vivo

Significance Bladder cancer is the fifth most common cancer. Timely diagnosis and appropriate early management protocols are of paramount significance for improving patient outcomes. This study shows efficient pH-dependent near-infrared imaging of bladder malignant tumors without targeting of normal tissue. Our results demonstrate that the indocyanine green pH low insertion peptide (pHLIP) construct is suitable for use as a predictive clinical marker, specifically staining human bladder tumors after intravesical administration ex vivo. The targeting allows delivery of various imaging probes, which may offer early diagnosis and improve the outcomes of endoscopic and radical surgical resection of urothelial carcinomas. In addition, delivery of therapeutic molecules to cancer cells by pHLIP might open an opportunity for novel targeted treatment of bladder cancers. Bladder cancer is the fifth most common in incidence and one of the most expensive cancers to treat. Early detection greatly improves the chances of survival and bladder preservation. The pH low insertion peptide (pHLIP) conjugated with a near-infrared fluorescent dye [indocyanine green (ICG)] targets low extracellular pH, allowing visualization of malignant lesions in human bladder carcinoma ex vivo. Cystectomy specimens obtained after radical surgery were immediately irrigated with nonbuffered saline and instilled with a solution of the ICG pHLIP construct, incubated, and rinsed. Bladders were subsequently opened and imaged, the fluorescent spots were marked, and a standard pathological analysis was carried out to establish the correlation between ICG pHLIP imaging and white light pathological assessment. Accurate targeting of bladder lesions was achieved with a sensitivity of 97%. Specificity is 100%, but reduced to 80% if targeting of necrotic tissue from previous transurethral resections or chemotherapy are considered as false positives. The ICG pHLIP imaging agent marked high-grade urothelial carcinomas, both muscle invasive and nonmuscle invasive. Carcinoma in situ was accurately diagnosed in 11 cases, whereas only four cases were seen using white light, so imaging with the ICG pHLIP peptide offers improved early diagnosis of bladder cancers and may also enable new treatment alternatives.