Sclerosing epithelioid fibrosarcoma: cytologic characterization with histologic, immunohistologic, molecular, and clinical correlation of 8 cases.

INTRODUCTION: Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon malignant fibroblastic neoplasm. The diagnosis is typically made on core needle biopsy or resection specimens. Cytomorphologic characterization of SEF has been limited to rare case reports in the literature. The goal of this study was to review a series of cases of SEF and to determine the feasibility of cytologic diagnosis of this rare tumor. MATERIAL AND METHODS: Eight SEF cases from 2009 to 2019 were identified in a retrospective review of 3 participating institutions. Cytomorphologic and corresponding histologic, immunophenotypic, molecular, and clinical data were examined and described. RESULTS: Patients were of median age 41 years old at diagnosis with a median follow-up of 35.5 months. These tumors, with a median greatest dimension of 13.4 cm, were located in the lower extremities, abdomen, retroperitoneum, head, groin, sacrum, and lung. The tumor cells ranged from small round, medium-sized ovoid/short spindle, to epithelioid/plasmacytoid cells. A sclerotic, fibrous to myxoid stroma was seen. Most samples revealed low-grade cytology. Two cases showed tumor necrosis. Only 3 cases with cell block/positive MUC4 immunostain were diagnostic. Corresponding molecular testing for EWSR1 gene rearrangement and/or EWSR1-CREB3L1 fusion were positive in 5 of 8 cases on biopsy or surgical samples. An additional case was positive for FUS-CREB3L2 fusion. CONCLUSIONS: Diagnosis of SEF based solely upon cytologic features remains challenging. Epithelioid or plasmacytoid morphology mimics common malignancies. A supportive clinical history, MUC4 immunohistochemistry, and characteristic molecular result should be used to aid the diagnosis.

Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells.

Signal transducers and activators of transcription (STATs) were identified originally as key components of cytokine signaling pathways. More recently, constitutive activation of STAT proteins has been detected in a wide variety of human tumor specimens and tumor cell lines. Here, we examined the activation of one STAT family member, Stat3, in human prostate cancer cell lines and primary prostate tumors. An analysis of 45 adenocarcinomas obtained at radical prostatectomy revealed elevated levels of constitutive Stat3 activation in 37 (82%) of 45 of the tumors compared with matched adjacent nontumor prostate tissues. A highly specific immunohistochemical assay for detection of phospho-Stat3 revealed that elevated Stat3 activity was localized primarily in the tumor cells of prostate carcinoma specimens. Furthermore, higher levels of Stat3 activation in patient specimens were correlated significantly with more malignant tumors exhibiting higher Gleason scores. In addition, all of the three human prostate cancer cell lines examined (DU145, PC3, and LNCaP) displayed constitutive activation of Stat3. Substantially lower levels of Stat3 activation were detected in LNCaP cells; however, stimulation with interleukin 6 induced a significant increase in Stat3 DNA-binding activity in these cells. Moreover, the direct inhibition of constitutive Stat3 signaling in DU145 cells using antisense Stat3 oligonucleotides induced growth inhibition and apoptosis. Our findings demonstrate that constitutive activation of Stat3 occurs frequently in primary prostate adenocarcinomas and is critical for the growth and survival of prostate cancer cells. These studies further suggest that Stat3 signaling represents a potentially novel molecular target for prostate cancer therapy.

The expression of insulin-like growth factor-I receptor correlates with Fuhrman grading of renal cell carcinomas.

Recent reports have shown significant correlation between Fuhrman nuclear grade of renal cell carcinoma (RCC) and patient survival. However, no one specific gene alteration has yet been described to account for this correlation. This study investigated the expression of the insulin-like growth factor-I receptor (IGF-IR) in RCC and correlated the results to the tumor Fuhrman nuclear grade. Formalin-fixed, paraffin-embedded sections from 68 cases of RCC were stained using the immunohistochemical avidin-biotin-peroxidase method. An anti-human IGF-IR rabbit polyclonal antibody was used. The stains were semiquantitatively evaluated using the Allred score system, assessing intensity of stain and percentage of positive tumor cells. Statistical analysis was performed using the Kruskal-Wallis test. Strong and diffuse cytoplasmic IGF-IR stain (Allred score 7 to 8) was identified in 25 of 25 (100%) of grade 3 and 4 RCCs. Grade 2 RCCs had a median IGF-IR Allred score of 4. Ten of 10 (100%) grade 1 RCCs were negative. Even in the positive high-nuclear-grade tumors, areas of low nuclear grade, when present, were IGF-IR negative. Statistical analysis using the Kruskal-Wallis test demonstrated significant correlation between increasing Fuhrman nuclear grade and increasing IGF-IR Allred score (P <0.0001). Thus we report the novel finding of significant statistical correlation between IGF-IR protein expression and Fuhrman nuclear grade of RCC, and consequentially with patient survival.

Cytokeratin staining for intraoperative evaluation of sentinel lymph nodes in patients with invasive lobular carcinoma.

BACKGROUND: Frozen section and intraoperative imprint cytology (IIC(N)) are 2 methods used for intraoperative pathologic assessment of sentinel lymph nodes (SLNs). The SLN evaluation of patients with invasive lobular carcinoma (ILC) results in a relatively high number of false-negative results using either of these methods. The purpose of this study was to evaluate the added benefits that intraoperative immunohistochemical-cytokeratin staining (I(CK-IHC)) can bring to IIC(N) in the evaluation of SLN in patients with ILC. METHODS: A total of 59 breast cancer patients with ILC underwent an SLN biopsy evaluated by our standard IIC(N) assessment in addition to I(CK-IHC). The results of IIC(N) with I(CK-IHC) were compared with the final histopathologic assessment consisting of standard hematoxylin and eosin staining and additional cytokeratin staining of nodes. RESULTS: Intraoperative evaluation of SLN using IIC(N) and I(CK-IHC) correctly diagnosed the nodal status in 45 of 59 (76.3%) patients. On final histopathologic assessment, 31 of 59 (52.5%) patients were found to have positive nodes. Using I(CK-IHC), 17 of these 31 positive cases (54.8%) were detected. Using IIC(N) alone, without the benefit of I(CK-IHC), only 13 of 31 (41.9%) positive cases were detected intraoperatively. CONCLUSIONS: For patients with ILC, I(CK-IHC) staining in addition to IIC(N) improves accuracy over using IIC(N) alone. In this study, I(CK-IHC) staining demonstrated a 12.9% improvement in the detection of SLN metastases in patients with ILC. Cytopathologists should consider employing I(CK-IHC) staining to evaluate the touch-imprint slides of SLN in ILC patients.

Case report: PET scan detects prostate cancer in a patient with Hodgkins lymphoma.

Positron emission tomography (PET) is routinely used in the management of cancers such as lung, colorectal, esophageal, breast, lymphoma, and melanoma. In urologic oncology, the role of PET has been less well defined and is currently under investigation. We report the first case of PET scan detection of prostate cancer in a patient with Hodgkins lymphoma.

Diagnostic digital cytopathology: Are we ready yet?

BACKGROUND: The cytology literature relating to diagnostic accuracy using whole slide imaging is scarce. We studied the diagnostic concordance between glass and digital slides among diagnosticians with different profiles to assess the readiness of adopting digital cytology in routine practice. MATERIALS AND METHODS: This cohort consisted of 22 de-identified previously screened and diagnosed cases, including non-gynecological and gynecological slides using standard preparations. Glass slides were digitalized using Aperio ScanScope XT (×20 and ×40). Cytopathologists with (3) and without (3) digital experience, cytotechnologists (4) and senior pathology residents (2) diagnosed the digital slides independently first and recorded the results. Glass slides were read and recorded separately 1-3 days later. Accuracy of diagnosis, time to diagnosis and diagnostician's profile were analyzed. RESULTS: Among 22 case pairs and four study groups, correct diagnosis (93% vs. 86%) was established using glass versus digital slides. Both methods more (>95%) accurately diagnosed positive cases than negatives. Cytopathologists with no digital experience were the most accurate in digital diagnosis, even the senior members. Cytotechnologists had the fastest diagnosis time (3 min/digital vs. 1.7 min/glass), but not the best accuracy. Digital time was 1.5 min longer than glass-slide time/per case for cytopathologists and cytotechnologists. Senior pathology residents were slower and less accurate with both methods. Cytopathologists with digital experience ranked 2(nd) fastest in time, yet last in accuracy for digital slides. CONCLUSIONS: There was good overall diagnostic agreement between the digital whole-slide images and glass slides. Although glass slide diagnosis was more accurate and faster, the results of technologists and pathologists with no digital cytology experience suggest that solid diagnostic ability is a strong indicator for readiness of digital adoption.

Multimodality management of a polyfunctional pancreatic endocrine carcinoma with markedly elevated serum vasoactive intestinal polypeptide and calcitonin levels.

We present an unusual case of a 52-year-old woman with severe, uncontrollable, refractory diarrhea attributable to pancreatic endocrine carcinoma (ECA) with markedly elevated serum vasoactive intestinal polypeptide (VIP) and calcitonin levels. After initial correction of fluid and electrolyte abnormalities, the patient was treated with high-dose octreotide. Shortly thereafter, due to the intractable nature of her diarrhea, she underwent cytoreductive hepatic surgery. The pancreatosplenectomy specimen showed a poorly differentiated ECA of the distal pancreas, immunoreactive for synaptophysin, CD56, and S100 protein, with morphologically similar hepatic and lymph node metastases. Postoperatively, her diarrhea improved, along with decline in serum VIP and calcitonin levels. Systemic chemotherapy with etoposide and cisplatin did not result in any radiographic and biochemical improvement. Having radiologically stable disease with depot-octreotide and short-acting octreotide (Sandostatin), she was subjected to peptide receptor radiotherapy with [177Lu-DOTA0,Tyr]octreotate (LuTate) that resulted in marked clinical and biochemical improvement, along with dramatic reduction in the number and size of hepatic metastases. In summary, this is a unique case of metastatic VIP- and calcitonin-secreting pancreatic ECA with dramatic sustained clinical, biochemical, and objective tumor response to peptide receptor radionuclide therapy.

Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor.

BACKGROUND: The prostate gland is the most common site of cancer and the third leading cause of cancer mortality in men. Solute carrier family 5 (iodide transporter), member 8 (SLC5A8) was proposed as a potential tumor suppressor gene which is silenced by epigenetic changes in various tumors. The aim of this study was to investigate the significance of DNA methylation in SLC5A8 expression in prostate tumors. METHODS: DNA methylation status of the promoter region and expression of SLC5A8 were evaluated in prostate cancer cell lines, tumor and adjacent non-tumor prostate tissues from same prostate cancer patients, by using bisulphite-modified sequencing, RT-PCR and quantitative methylation-specific PCR (QMSP) analysis. RESULTS: The reduced or lost expression of SLC5A8 was observed in 70% of the tumor tissues. The bisulphite-modified sequencing analysis on the prostate cancer cell lines which do not express SLC5A8 detected the densely methylated SLC5A8 promoter region. SLC5A8 was reactivated by treatment with DNA methyl transferase inhibitor, 5-azacytidine but not by trichostatin A (TSA). Higher methylation at the promoter region of SLC5A8 in primary prostate tumor tissues was detected as compared with those in adjacent non-tumor tissues (7/10, 70%). CONCLUSIONS: These data suggested that DNA methylation in the SLC5A8 promoter region suppressed the expression of SLC5A8 in prostate tumor.

Activated STAT3 as a correlate of distant metastasis in prostate cancer: a secondary analysis of Radiation Therapy Oncology Group 86-10.

OBJECTIVE: STAT3 participates in the regulation of cellular growth, survival, and oncogenesis. We evaluated the association between activated STAT3 expression and overall survival, disease-specific survival, distant metastasis, and local progression in a cohort of patients treated with either radiotherapy alone or radiotherapy plus short-term androgen blockade. METHODS: A total of 456 assessable patients were included in the Radiation Therapy Oncology Group 86-10 trial. Of these, 62 patients had sufficient tissue for the analysis of STAT3 expression by immunohistochemistry. Nuclear staining was quantified by an image analysis system. RESULTS: No significant difference was found in the distribution of clinical characteristics and assigned treatment between the patients available for STAT3 analysis (STAT3 cohort) and the others in the Radiation Therapy Oncology Group 86-10 trial (n = 394). Activated STAT3 correlated inversely with the development of distant metastasis (risk ratio [RR] = 0.81, P = 0.04) but not with overall survival, cause-specific survival, or local progression. Similar results were obtained when the data were dichotomized (ACIS index greater than 29%, RR = 0.41, P = 0.07). On multivariate analysis, activated STAT3 (continuous variable) was an independent predictor of distant metastasis (RR = 0.79, P = 0.04). CONCLUSIONS: Activated STAT3 was inversely related to the development of distant metastasis in prostate cancer. This marker should be evaluated further in a larger cohort of patients.

Urothelial carcinoma in a child.

OBJECTIVES: Urothelial carcinoma of the bladder occurs rarely in the first 2 decades of life. We report a case of a 12 year-old child that presented with a Ta grade II/III urothelial carcinoma of the bladder. METHODS: We describe its clinical presentation and diagnostic procedures as well as treatment and follow-up. Finally, we review the literature to analyze the etiology, treatment, and surveillance of urothelial carcinoma in the pediatric population. RESULTS: Since 1950, there are less than 100 cases of urothelial carcinoma reported in patients less than 30 years, and even less in children and adolescents. Most of the small series describe these tumors as being characteristically superficial and low grade (I-ll). This child presented with silent macroscopic hematuria and an MRI revealed a solid and papillary mass measuring 2.7 cm. A cystoscopy and resection of the tumor confirmed the diagnosis. A re-resection at two months confirmed no residual tumor in the bladder. CONCLUSIONS: There is no established criteria for the etiology, treatment, and surveillance of urothelial carcinoma in the pediatric population. Children with gross hematuria as the presenting complaint should undergo a complete evaluation to rule out the presence of urothelial carcinoma.

Accuracy of intraoperative imprint cytology for sentinel lymph node evaluation in the treatment of breast carcinoma.

BACKGROUND: The current report provides results from a large retrospective analysis of intraoperative imprint cytology performed on axillary sentinel lymph nodes (IIC(N)) removed over the course of 2137 breast surgeries (4905 lymph nodes). It is hoped that these results may serve as benchmarks for those interested in using this technique. METHODS: The current study included 2078 patients with T1-2 invasive breast carcinoma who underwent sentinel lymph node biopsy (SLNB) and IIC(N). Lymph nodes were bivalved, imprinted, stained with Diff-Quik (Baxter Diagnostics, McGaw Park, IL), and reviewed by a cytopathologist. A positive intraoperative diagnosis led to immediate complete axillary lymph node dissection (CALND). On final pathology, lymph nodes found to be negative on hematoxylin and eosin staining were submitted for cytokeratin staining. RESULTS: Of the 2137 cases for which SLNB was performed, 673 were found to have positive lymph node status on final pathology. Of these 673 cases, 359 were identified by IIC(N), resulting in a sensitivity rate of 53.3%. The specificity and overall accuracy rates for this technique were 99.5% and 85.0%, respectively. In IDC cases, IIC(N) had a sensitivity rate of 55.5%, compared with 38.7% in ILC cases. Based on these results, the reoperative CALND rate was calculated to be approximately 14.7%, with 54.5% of these reoperative procedures being performed for cases in which lymph nodes positive only for micrometastases were found. Macrometastasis-positive lymph nodes that went undetected by IIC(N) were present in only 154 of the 2137 cases examined (7.2%). CONCLUSIONS: IIC(N) accurately predicts final lymph node status in 85.0% of patients. Although the accuracy of this technique varies with tumor size and type, IIC(N) remains a time-efficient and cost-effective adjunct to SLNB.

Investigation of the safety and accuracy of intraoperative gamma probe directed biopsy of bone scan detected rib abnormalities in prostatic adenocarcinoma.

PURPOSE: We evaluated the technique of intraoperative gamma probe directed rib biopsy in patients with suspected metastatic prostate adenocarcinoma. This technique can be used to identify accurately the rib in question, reliably obtain sufficient tissue for diagnosis, be performed with minimal patient morbidity and potentially alter the course of therapy. MATERIALS AND METHODS: From 1996 to 2001, 8 patients with biopsy proved adenocarcinoma of the prostate and suspicious rib lesions on radionuclide bone scanning underwent open rib biopsy as part of the evaluation for metastatic disease. Mean prostate specific antigen in the patient population was 17.1 ng/ml (range 6.1 to 36.5) and clinical stage was T1c to T3c. A new technique of intraoperative gamma probe directed biopsy was used to localize and resect the rib in question. At 6 to 12 hours before the operation each patient received an intravenous injection of 28 mCi. (99m)technetium-oxidronate. The hand held, pencil sized gamma probe in a sterile sleeve was used to localize the area of greatest activity in the target bone and 3 cm. of bone were resected. RESULTS: Of the 8 patients who underwent the procedure 2 had metastatic prostate cancer on final rib pathological findings. Four of the remaining 5 patients had benign rib lesions (an old rib fracture) and 1 had metastatic lung cancer. The hot spot on bone scan was localized with 100% accuracy using our technique and a pathological diagnosis was made in all cases. Mean operative time was 61 minutes and estimated blood loss was less than 20 ml. in all cases. Seven of the 8 patients were discharged home the same day, while 1 required overnight hospitalization. There was 1 intraoperative complication of inadvertent entry into the pleural cavity, resulting in a small pneumothorax, which was treated with small chest catheter drainage and observation. CONCLUSIONS: Intraoperative gamma probe directed rib biopsy of suspected metastatic lesions in patients with prostate cancer can be safely and accurately performed with minimal patient morbidity. The information obtained using this technique can be used to tailor treatment decisions for this subset of patients with prostate cancer.