Sarah Karram

Should intervening benign tissue be included in the measurement of discontinuous foci of cancer on prostate needle biopsy? Correlation with radical prostatectomy findings.

Currently, there is no consensus as to the optimal method for measuring tumor length or percentage of cancer on a core when there are 2 or more foci of prostate cancer in a single core separated by benign intervening stroma. One option is to measure discontinuous foci of cancer as if they were 1 single continuous focus. The other option is to add the measurements of the individual separate foci of cancer, ignoring the extent of the intervening benign prostate tissue. The surgical pathology database at The Johns Hopkins Hospital was searched for outside consult cases of prostate needle biopsies reviewed between 2005 and 2010 when the patient came to our institution for radical prostatectomy (RP). Cases were restricted to those with biopsy Gleason score 6 in which there was at least 15% discordance between the outside and our institution in terms of the reported highest percentage of cancer per core per case. One hundred and nine patients were identified fulfiling our inclusion criteria. Seventy-nine showed the same Gleason score in the RP, and 30 had an upgrade to Gleason ≥7. Including all cases (scores 6, 7, and 8 at RP), there was no significant association between the maximum percentage of cancer per core with organ-confined disease or risk of positive surgical margins, regardless if the cores were measured at Hopkins or at the outside institutions. For cases with no upgrade at RP, the differences between the maximum percentage of cancer per core per case recorded at Hopkins and the outside institutions ranged from 15% to 80%, in which the mean and median differences were 35% and 30%, respectively. The maximum percentages of tumor involvement on a core per case given at our institution more strongly correlated with the presence of organ-confined disease (P=0.004) compared with the percentages given at the outside institutions (P=0.027). Surgical margin positivity was also associated with the maximum percentages of tumor involvement per core given at our institution (P=0.004), whereas the outside percentages were not significant predictors of margin status (P=0.2). In a multivariable analysis, maximum percentage of cancer per core per case measured at Hopkins which includes intervening benign prostate tissue in the measurement was also more predictive of stage and margins than ignoring intervening benign tissue. In summary, our study demonstrated that for prostate cancer in which the needle biopsy grade is representative of the entire tumor, quantifying cancer extent on biopsy by measuring discontinuous cancer on biopsy from one end to the other as opposed to “collapsing” the cancer by subtracting out the intervening benign prostate tissue correlates better with organ-confined disease and risk of positive margins.

Iatrogenic Exserohilum infection of the central nervous system: Mycological identification and histopathological findings

An outbreak of fungal infections has been identified in patients who received epidural injections of methylprednisolone acetate that was contaminated with environmental molds. In this report, we present the mycological and histopathological findings in an index case of Exserohilum meningitis and vasculitis in an immunocompetent patient, who received a cervical spine epidural steroid injection for chronic neck pain 1 week before the onset of fulminant meningitis with subsequent multiple brain and spinal cord infarcts. The fungus was recovered from two separate cerebrospinal fluid specimens collected before initiation of antifungal therapy and at autopsy on standard bacterial and fungal culture media. The mold was identified phenotypically as Exserohilum species. DNA sequencing targeting the internal transcribed spacer region and D1/D2 region of 28S ribosomal DNA enabled further speciation as E. rostratum. Gross examination at autopsy revealed moderate brain edema with bilateral uncal herniation and a ventriculostomy tract to the third ventricle. The brainstem, cerebellum, and right orbitofrontal cortex were soft and friable, along with hemorrhages in the cerebellar vermis and thalamus. Microscopic examination demonstrated numerous fungi with septate hyphae invading blood vessel walls and inducing acute necrotizing inflammation. The leptomeninges were diffusely infiltrated by mixed inflammatory cells along with scattered foci of fungal elements. This is the first report of iatrogenic E. rostratum meningitis in humans. This report describes the microbiological procedures and histopathological features for the identification of E. rostratum (a pigmented vascularly invasive fungi), the cause of a current nationwide outbreak of fatal fungal meningitis.

Fatal exserohilum meningitis and central nervous system vasculitis after cervical epidural methylprednisolone injection.

TO THE EDITOR: We commend Thompson and colleagues (1) for the development and publication of their recent guidelines for improving entry into and retention in care for persons with HIV. These guidelines are important for consolidating best practices in the approach to this multidimensional and complex issue. However, although we understand the gaps in science that the authors present, we disagree with the III C recommendations for the use of peer navigators and intensive individual outreach. Based on our experiences in Washington, DC, these strategies should be considered vital to engaging clients from impoverished and disadvantaged communities. Both peer navigation and intensive individual outreach have become anchors for successfully engaging and retaining new and lost clients into HIV care, often in minutes rather than weeks or months. Therefore, for us, these guidelines will serve as a minimum effort required to achieve and maintain entry into and retention in care. In 2011, of 210 lost-to-care clients targeted by our outreach efforts, most of whom had detectable viral loads at their last visit, more than 50% required unorthodox approaches that exceeded the measures outlined or not mentioned in these guidelines, such as 17 telephone calls to a single client, an impromptu meeting on a street corner between a physician and client, and twice-weekly telephone calls and monthly written notes for 11 months to a single client. In an era of shrinking health care resources, we do not believe that additional research on entry into care, particularly via randomized trials, should be prioritized over implementation of effective strategies highlighted in federally funded observational studies (2, 3). In addition, a wealth of data exists on barriers to engagement in care (4, 5). Similarly, among our clients, the most common explanations and barriers to care include depression and denial associated with a new diagnosis, noninjection drug use, and delays in securing health insurance. Given this, we believe that the solutions to improving engagement in HIV care largely involve shifting resources to develop targeted policy and implementing structural interventions, such as improving access to integrated mental health and substance use treatment, expanding clinic hours, improving community health literacy, and discussing HIV and alleviating bureaucratic delays in securing health insurance. Finally, the guidelines do not specifically address the integration of pharmacists into health care teams. Inclusion of a doctor of pharmacy on our team for counseling about treatment adherence has been invaluable for client retention. If more research is funded, we agree with the recommendation to conduct operational research to demonstrate the impact of interventions like this, because it will provide evidence to justify funding for this model of service delivery.

Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies

Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment.

Papillary urothelial neoplasm of low malignant potential of the urinary bladder: clinicopathologic and outcome analysis from a single academic center

Few long-term single-center studies have addressed the outcome of patients with papillary urothelial neoplasms of low malignant potential. Our study evaluates the behavior of these tumors occurring as primary urinary bladder lesions. For this purpose, 34 primary in-house cases diagnosed and treated between 1998 and 2008 were identified from our medical records. Upon review, 3 cases were upgraded to noninvasive low-grade urothelial carcinomas and excluded from further evaluation. During follow-up (range, 3-108 months; mean, 42 months), 13 patients developed recurrences; and 9 patients progressed to a noninvasive higher grade lesion (8 to low-grade and 1 to high-grade urothelial carcinomas). None of our patients developed stage progression (>pTa) or died of bladder cancer. Size of the primary tumor was associated with the risk of recurrence (P = .043), whereas the number of episodes of recurrence was associated with the likelihood of grade progression (P = .034). In conclusion, recurrences were observed in 42% of all our patients, with a grade progression rate of 29%. None of our patients developed invasive carcinoma or died as a consequence of their disease. Considering the low but definitive risk of recurrence and grade progression, appropriate clinical follow-up of patients with primary papillary urothelial neoplasm of low malignant potential is warranted.

High-grade papillary urothelial carcinoma of the urinary tract: a clinicopathologic analysis of a post–World Health Organization/International Society of Urological Pathology classification cohort from a single academic center ☆ ☆☆

About one half of all bladder neoplasms are noninvasive, and in those, the histologic grade is a crucial prognosticator. Few single-center studies have assessed the recurrence, progression, and cancer-related mortality rates of noninvasive high-grade papillary urothelial carcinomas. With this aim, we evaluated the clinicopathologic and outcome features of 85 patients with high-grade papillary urothelial carcinoma. Median age was 68 years, and 80.5% were men. Tumor size ranged from 0.3 to 13.0 cm (median, 1.6 cm). Recurrence was found in 36.5% of the patients, whereas tumor progression, defined as invasion of lamina propria or beyond, was identified in 40% of all cases. When present, lesion reappearance involved mostly 1 to 2 episodes. Metastasis appeared in 20% of the patients, and 15% died of disseminated bladder cancer. All cancer-related deaths occurred in the group of patients with progression, whereas patients with recurrence showed similar outcomes to those with no recurrence. For patients with tumor progression, clinical stage was significantly associated with outcome (P = .002). As for prognosis, tumor size was strongly associated with progression (P < .01). In conclusion, recurrence, progression, and cancer-specific mortality rates were 36.5%, 40%, and 15%, respectively. All the patients who died of cancer had a history of tumor progression. Patients with recurrences showed similar outcomes to those with no recurrence. Tumor size was strongly associated with tumor progression and cancer-specific survival, whereas clinical stage was significantly associated with outcome in the progression group. In light of the high recurrence and progression rates of high-grade papillary urothelial carcinoma, strict clinical surveillance aimed to detect early recurrent lesions, especially in patients with larger tumors, is warranted.

Focal positive prostate-specific membrane antigen (PSMA) expression in ganglionic tissues associated with prostate neurovascular bundle: Implications for novel intraoperative PSMA-based fluorescent imaging techniques

OBJECTIVE Prostate specific membrane antigen (PSMA) is primarily expressed in glandular prostatic tissue and is frequently utilized to detect primary or metastatic prostatic adenocarcinoma (CaP). A purported novel application of PSMA detection is the intraoperative real-time identification of CaP using radioimmunoscintigraphy to define the extension of the surgical resection. Considering that PSMA expression has been reported in other tissues, we evaluated its immunoexpression in prostatic neurovascular bundle elements to assess the convenience and safety of the aforementioned procedure. MATERIALS AND METHODS Twenty consecutive specimens of radical prostatectomy (RP) were retrieved from our surgical pathology archives. PSMA immunoexpression (Clone 3E6, DAKO) was assessed in a representative section from each specimen containing neurovascular bundle elements. RESULTS PSMA expression was documented in 20/20 of examined CaP slides. Most cases exhibited an apical/cytoplasmic or cytoplasmic with membranous accentuation pattern of staining. Focal weak to moderate cytoplasmic staining was detected in associated ganglionic tissue in 3/15 of the examined RP. In all cases, staining was cytoplasmic, less extensive, and weaker than the pattern observed in CaP. None of the peripheral nerve sheath cells or lymphovascular components of the examined neurovascular bundles were positive for PSMA. CONCLUSIONS We found focal positive PSMA expression in the ganglionic cells of the prostatic neurovascular bundle. Our results suggest that the radioimmunoscintigraphic detection of radiolabeled PSMA antibodies might not be entirely specific for prostatic cells; this observation must be taken into account should an intraoperative PSMA-based fluorescent imaging technique be used to define the extension of the surgical procedure.

GATA3 expression in small cell carcinoma of bladder and prostate and its potential role in determining primary tumor origin

GATA3 is a sensitive marker for urothelial carcinoma. We here evaluate, for the first time, GATA3 expression in small cell carcinoma of bladder and prostate and assess its utility in the differential diagnosis with small cell carcinoma of lung primary. Archival tissues from 60 small cell carcinomas (12 bladder, 15 lung, and 33 prostate primary cases) were used to build 2 tissue microarrays. We also assessed whole slide sections from 10 additional primary small cell carcinomas of bladder. GATA3 nuclear expression was evaluated using standard immunohistochemistry. Intensity (weak, moderate, and strong) and extent of expression were assessed in each tissue microarray spot. Extent positivity was categorized as focal (1%-25%), multifocal (>25%), and diffuse (>75%). Nuclear GATA3 expression was encountered in 7 bladder (7/22, 32%) and 2 lung (2/15, 13%) small cell carcinomas. All 33 primary prostate small cell carcinomas were negative. Among bladder tumors, strong and diffuse (>75%) GATA3 labeling was seen in 3 cases (3/22, 14%); focal positivity was observed in the 4 remaining cases (4/22, 18%). Both positive lung cases had only focal positivity. Our study is the first to reveal GATA3 expression in the small subset of lung small cell carcinoma that should be taken into consideration in assigning site of origin in advanced small cell carcinoma cases. Our novel finding of GATA3 positivity in one-third of bladder small cell carcinoma is of potential value in differentiating small cell carcinomas of prostate origin from those of bladder origin.

Idiopathic granulomatous orchitis: morphology and evaluation of its relationship to IgG4 related disease

Idiopathic granulomatous orchitis (IGO) is rare, thought to result from an autoimmune reaction to spermatogenic elements. Its relationship to IgG4-related disease (IgG4-RD) has not been evaluated. Sixteen orchiectomy specimens (1984-2012) with a prominent intratubular granulomatous reaction were reviewed: IGO (n = 6); intratubular germ cell neoplasia unclassified (IGCNU) with a granulomatous reaction and associated seminoma (GS, n = 6); and unclassified intratubular granulomatous orchitis not fitting into a specific entity (UGO, n = 4). Men with IGO were 32 to 86 years old, presenting with a mass suspicious for malignancy. Only one patient had a history of an inflammatory disease. Clinical follow-up was available for 2 patients with IGO, and both had no evidence of systemic IgG4-RD. All IGO cases had an epithelioid granulomatous reaction confined to seminiferous tubules, an extensive interstitial lymphoplasmacytic inflammation, 3 of 6 had prominent interstitial fibrosis, and 3 of 6 cases had plasma cells with an IgG4+/IgG+ ratio >40%. In GS, 10% to 100% of tubules with IGCNU had a granulomatous reaction, which in 3 cases replaced IGCNU cells. In contrast to IGO, GS had more intratubular multinucleated giant cells, more peritubular sclerosis, fewer interstitial plasma cells, and no interstitial fibrosis. Of the 4 UGO cases, most had predominantly interstitial with less intratubular granulomatous inflammation. Only 1 non-IGO case had elevated tissue IgG4 (GS case). It is critical and sometimes difficult to distinguish GS from IGO. IGO shares some features with IgG4-RD, yet current evidence does not support its classification as a localized manifestation of IgG4-RD occurring in the testis.

MP28-08 DPC4 LOSS OF EXPRESSION IN INVASIVE UROTHELIAL CARCINOMAS: AN IMMUNOHISTOCHEMICAL STUDY

INTRODUCTION AND OBJECTIVES: DPC4 (SMAD4) is a tumor suppressor gene that encodes for a critical transcription factor involved in the TGF-beta signal pathway. Genetic inactivation of the DPC4 gene has been described in pancreatic and extrahepatic biliary adenocarcinomas, and loss of DPC4 expression by immunohistochemistry is considered a relatively specific marker of tumors originating from those sites. However, the status of DPC4 has not been previously studied in urothelial carcinomas (UC). We evaluated DPC4 expression in a set of invasive UC of the bladder and the upper urinary tract (UT). METHODS: Formalin-fixed paraffin-embedded tissues from 13 invasive UC of the upper UT (12 high grade and 1 low grade) and 18 invasive high grade UC of the bladder were retrieved from our surgical pathology archives and used to build 2 tissue microarrays. Paired tumor and non-neoplastic tissue were spotted 4 times each. DPC4 expression was evaluated using standard immunohistochemistry (DPC4: clone B8, Santa Cruz, CA). DPC4 expression in each case was categorized as intact (positive DPC4) or lost (at least focal negative DPC4). Only spots with positive internal control were considered. Intact labeling was defined as uniform expression of DPC4 in the cytoplasm of tumor cells per spot, with at least focal nuclear expression of DPC4. DPC4 loss was defined as lack of both cytoplasmic and nuclear expression in any subset of tumor cells in the presence of positive internal control staining. Several cut off values were used to reflect the extent of DPC4 loss ( 75% of the tumor cells). RESULTS: We found varying extent of DPC4 loss in 14 cases of invasive UC. Among the bladder carcinomas, 7/18 (39%) cases had some extent of DPC4 loss. Among the upper UT carcinomas, 7/13 (54%) cases had some extent of DPC4 loss, as detailed in table 1. Intact DPC4 staining was observed in 11/18 cases (61%) of invasive UC of the bladder and in 6/13 cases (46%) of invasive UC of upper UT. CONCLUSIONS: Our findings reveal that loss of DPC4 expression can be observed in UC. The current TMA based findings merrit further evaluation in whole sections of UC using immunohistochemistry. If confirmed, our findings suggest that urothelial carcinoma should be considered in the differential diagnosis of a metastatic carcinoma of unknown primary, when loss of DPC4 is seen. Sequencing analysis to assess DPC4 gene status in UC is also warranted.