Keith E. Volmar

Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma.

Florid von Brunn nests may mimic the nested variant of urothelial carcinoma. We examined formalin-fixed, paraffin-embedded tissue from 21 cases of florid von Brunn nests and 11 cases of nested variant of urothelial carcinoma. Morphologic features were recorded in detail. Also, cases were stained with monoclonal antibodies against MIB-1, p53, p27, and cytokeratin 20. Percentage positivity was calculated by counting 300 to 500 cells from each case. Clinical follow-up information was also obtained. Florid von Brunn nests from the bladder were comprised of large nests with regular spacing, and all the nests extended to the same horizontal level at the base of the proliferation. Central lumen formation was often seen within florid von Brunn nests, at times with cystic dilatation, such that there was a spectrum from proliferating von Brunn nests to cystitis glandularis to cystitis cystica. Small, crowded nests with variable spacing and an infiltrative base characterized nested variant of urothelial carcinoma. Four cases showed detrusor muscle invasion on biopsy with an additional case showing detrusor muscle invasion at cystectomy. One additional patient with nested variant of urothelial carcinoma had distant metastases and another had prostatic invasion. Nine of 21 florid von Brunn nests cases were from either the ureter or renal pelvis, whereas all cases of nested variant of urothelial carcinoma arose in the bladder. The ureteral and pelvic florid von Brunn nest cases showed smaller, more variable nests with irregular spacing closely mimicking nested variant of urothelial carcinoma but had a noninfiltrative base and often areas with either a lobular or linear array. Immunohistochemical studies showed nested variant of urothelial carcinoma to have higher MIB-1 expression (8.8% vs. 2.8%, P = 0.01). Nested variant of urothelial carcinoma had nonsignificantly higher p53 positivity (4.2% vs. 1.5%, P = 0.06) and lower p27 positivity (4.7% vs. 7.8%, P = 0.22). Cytokeratin 20 staining was not discriminatory. However, staining with each antibody was widely variable. Wide variation in staining for MIB-1, p53, p27, and cytokeratin 20 was seen in both florid von Brunn nests and nested variant of urothelial carcinoma, such that except for a few cases, a specific cutoff value could not be determined for diagnostic purposes. The findings underscore the importance of morphologic assessment in the distinction of florid von Brunn nests and nested variant of urothelial carcinoma.

Isoform-Specific Upregulation of Palladin in Human and Murine Pancreas Tumors

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a characteristic pattern of early metastasis, which is driving a search for biomarkers that can be used to detect the cancer at an early stage. Recently, the actin-associated protein palladin was identified as a candidate biomarker when it was shown that palladin is mutated in a rare inherited form of PDA, and overexpressed in many sporadic pancreas tumors and premalignant precursors. In this study, we analyzed the expression of palladin isoforms in murine and human PDA and explored palladins potential use in diagnosing PDA. We performed immunohistochemistry and immunoblot analyses on patient samples and tumor-derived cells using an isoform-selective monoclonal antibody and a pan-palladin polyclonal antibody. Immunoblot and real-time quantitative reverse transcription-PCR were used to quantify palladin mRNA levels in human samples. We show that there are two major palladin isoforms expressed in pancreas: 65 and 85–90 kDa. The 65 kDa isoform is expressed in both normal and neoplastic ductal epithelial cells. The 85–90 kDa palladin isoform is highly overexpressed in tumor-associated fibroblasts (TAFs) in both primary and metastatic tumors compared to normal pancreas, in samples obtained from either human patients or genetically engineered mice. In tumor-derived cultured cells, expression of palladin isoforms follows cell-type specific patterns, with the 85–90 kDa isoform in TAFs, and the 65 kDa isoform predominating in normal and neoplastic epithelial cells. These results suggest that upregulation of 85–90 kDa palladin isoform may play a role in the establishment of the TAF phenotype, and thus in the formation of a desmoplastic tumor microenvironment. Thus, palladin may have a potential use in the early diagnosis of PDA and may have much broader significance in understanding metastatic behavior.

Fine needle aspiration of pancreatic cysts : Use of ancillary studies and difficulty in identifying surgical candidates

OBJECTIVE To evaluate ancillary biochemical testing after pancreatic cyst fine needle aspiration (FNA) in the clinical setting. STUDY DESIGN Findings from 110 pancreatic guided FNA were reviewed cysts evaluated by image- and correlated with histology, clinical follow-up and biochemical analysis of cyst fluid and serum. Adequate followup was available for 95. RESULTS In terms of identifying cysts requiring surgery, FNA showed 55.3% sensitivity, 95% specificity, 92.9% positive predictive value (PPV) and 64.4% negative predictive value (NPV). FNA showed only nonspecific cyst contents in 51% of cases, but 40% of those patients proved to be surgical candidates at follow-up. Overall, patients with lesions requiring surgery were younger (p = 0.14), more often presented with pain (p = 0.006), had larger cysts (p = 0.05) and less often had a history of chronic pancreatitis (p = 0.12). Among cases in which FNA showed only nonspecific cyst contents, patients with lesions requiring surgery were more often female (p = 0.08), were younger (p = 0.10), had larger cysts (p = 0.06) and had pain at presentation (p = 0.02). Differences in fluid and serum analytes were not statistically significant. CONCLUSION FNA of pancreatic cysts shows high specificity but poor sensitivity, even with cyst fluid and serum biochemical analysis. FNA of cysts requiring surgery often yielded nonspecific cyst cytology and causing a misinterpretation as pseudocysts. Ancillary biochemical analysis of cyst fluid remains problematic in the clinical setting.

Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor

Cushing syndrome is rare in infancy and usually due to an adrenocortical tumor (ACT). We report an infant with Cushing syndrome due to adrenocortical carcinoma. The patient presented at six months of age with a three-month history of growth failure, rapid weight gain, acne, and irritability. Physical examination showed obesity, hypertension, and Cushingoid features. Biochemical evaluation showed very high serum cortisol, mildly elevated testosterone, and suppressed ACTH. Abdominal MRI revealed a heterogeneous right adrenal mass extending into the inferior vena cava. Evaluation for metastases was negative. The tumor was removed surgically en bloc. Pathologic examination demonstrated low mitotic rate, but capsular and vascular invasion. She received no adjuvant therapy. Her linear growth has improved and Cushingoid features resolved. Hormonal markers and quarterly PET scans have been negative for recurrence 24 months postoperatively. In conclusion, adrenocortical neoplasms in children are rare, but should be considered in the differential diagnosis of Cushing syndrome.

The Diagnostic Utility of Fine-needle Aspiration Biopsy of Soft-tissue Sarcomas in the Core Needle Biopsy Era

Fine-needle aspiration biopsy (FNAB) is a widely accepted and established diagnostic technique in diagnosing the presence of primary malignancies, metastatic disease, and benign nonneoplastic lesions. However, its role in the evaluation of soft-tissue sarcomas has remained controversial, especially as the primary modality for establishing an initial diagnosis. Arguments in favor of using core needle biopsies (CNB) relate to the fact that such samples provide ample “tissue” for evaluating architectural patterns, as well as a source for performing ancillary studies. However, in the hands of experienced cytopathologists, FNAB in conjunction with ancillary studies (performed on tissue obtained in the form of cell blocks) has been shown to have a diagnostic yield nearly identical to CNB, with an accuracy rate approaching 95% for the diagnosis of malignancy. Additionally, as therapy and prognosis are heavily dependent on the grade and stage of the tumor, it has been shown that approximately 90% of soft-tissue sarcomas can be successfully subtyped and even graded by FNAB. There are, however, certain limitations of FNAB, especially in the workup of low-grade myxoid and spindle cell sarcomas and in their separation from borderline and benign lesions. In these select subgroups, CNB may be more advantageous. Also, in the absence of an on-site cytopathologist for immediate evaluation of the sample and triage of materials for ancillary studies, CNB is preferred, although FNAB can still identify benign soft-tissue lesions and malignancies of nonmesenchymal origin not requiring ancillary studies. This review will focus on the more commonly encountered soft-tissue sarcomas and highlight the advantages and limitations of FNAB in establishing their diagnosis.

Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma

Purpose Desmoplastic stroma is a cardinal feature of primary pancreatic ductal adenocarcinoma (PDAC), but its effects on the biology, prognosis and therapeutic outcomes are not known. We developed an automated method to assess tumor stroma density (TSD) and investigated computed tomography (CT)-correlates of stroma in PDAC. Patients and Methods We collected PDAC samples from rapid autopsy and resection series and digitally annotated samples to quantify TSD. A series of resected patients also underwent preoperative multiphasic CT. Results Automated and manual assessments of TSD were highly correlated (ρ= 0.65, P < 0.001). Solid organ metastases had a lower median TSD than primary tumors (P < 0.001). Patients with high TSD enjoyed prolonged recurrence free survival (RFS) (P = 0.003; HR = 0.51) and overall survival (P = 0.008, HR = 0.57). In another independent dataset, patients with high TSD had decreased risk for recurrence (P = 0.003, HR = 0.03) and death (P = 0.003, HR = 0.03) at time of resection, however the protective effect diminished over time. Patients with normalized portovenous phase CT tumor enhancement ratio ≥0.40 had a longer RFS following resection (P = 0.020). Normalized portovenous phase CT tumor enhancement ratio was significantly correlated with TSD (P = 0.003). Conclusions Objective quantitative assessment of stroma in PDAC revealed several clinically relevant observations. Firstly, stroma was less abundant in metastatic PDAC, the cause of most PDAC mortality. Secondly, high stromal content correlates with favorable outcome in resected cases, implying a protective effect of stroma and suggesting careful consideration of active stromal depletion therapies. Finally, standard multiphase CT imaging correlates with stroma content as well as clinical outcome, indicating that non-invasive assessment of stroma is a feasible sensitivity enrichment approach in PDAC.