Thrombocytopenia with multiple splenic lesions - histiocytic sarcoma of the spleen without splenomegaly: A case report.

BACKGROUND: Histiocytic sarcoma (HS) of the spleen is reported to be a rare and lethal disease. The clinicopathological features of splenic HS have not been well described. The objective of this paper is to describe the diagnosis and treatment of a case of this rare disease and provide a review of the literature. CASE SUMMARY: In this article, we discuss the case of a 40-year-old Hispanic female who presented with progressive thrombocytopenia and multiple hypoechoic lesions in the spleen without splenomegaly. Positron emission tomography-computed tomography showed increased activity in cervical lymph nodes, as well as multiple bone and splenic lesions with positive uptake. Two bone marrow biopsies and fine-needle aspiration of the cervical lymph node were inconclusive. Laparoscopic splenectomy was performed, and gross examination showed a 110.1 g spleen with multiple rubbery, nodular lesions within the subcapsular sinus and splenic parenchyma. The microscopic findings showed multinodular histiocyte proliferation with atypia and multilobulated nuclei, which were positive for CD163, CD4, and CD68 by immunohistochemical analysis. The final pathologic diagnosis was difficult and was found to be low-grade HS of the spleen, after consultations with two renowned hematopathology institutions. At the patient's five-month follow-up visit, her bone marrow metastasis had progressed. She is waiting to be enrolled in a clinical trial. CONCLUSION: Pathologic diagnosis of splenic HS can be challenging. Low-grade differentiation may be associated with a slow progressive disease.

NUT (Nuclear Protein in Testis) Carcinoma: A Report of Two Cases With Different Histopathologic Features.

NUT (nuclear protein in testis) carcinoma (NC) is an aggressive carcinoma characterized by rearrangements of the NUT gene on chromosome 15q14. Histologically, it is a poorly differentiated carcinoma composed of monotonous, medium-sized, round cells with scant amphophilic or eosinophilic cytoplasm. Foci of abrupt keratinization are often seen. In this report, we compare the morphology of 2 cases of NC. The first case shows characteristic features of uniform, round epithelioid cells admixed with foci of abrupt keratinization. The second case demonstrates nests of epithelioid-polygonal cells that appear to be loosely cribriform within a mucoid stroma. Although considered rare, the actual incidence of NC may be underestimated, as it is likely that many go undiagnosed because the morphology deviates from what is typical. Our report demonstrates that NC should always be considered in any case of an undifferentiated carcinoma and should not be excluded if typical histologic and immunohistochemical features of squamous differentiation are lacking.

NK cell enteropathy: a case report with 10 years of indolent clinical behaviour.

AIMS: Natural killer (NK) cell enteropathy is a recently described clinically indolent condition characterised by atypical NK cell infiltrates in the gastrointestinal mucosa that mimics malignant lymphoma. We report a case that highlights the indolent clinical behaviour by documenting absence of clinical progression over 10 years. METHODS AND RESULTS: We report the case of a 69-year old female who had clinically long-standing abdominal pain and recurrent mucosal ulcerations associated with atypical NK cell infiltrates. The clinical, morphologic and immunophenotypical findings in this case were diagnostic of NK cell enteropathy. Review of the patient's prior biopsies demonstrated that this persisted without clinical progression for 10 years, confirming the clinical indolent course. CONCLUSION: Recognition of NK cell enteropathy is important to avoid over-diagnosing this benign condition as an aggressive lymphoma.

Fiber-Optic Confocal Laser Endomicroscopy of Small Renal Masses: Toward Real-Time Optical Diagnostic Biopsy.

PURPOSE: The incidental detection of small renal masses is increasing. However, not all require aggressive treatments as up to 20% are benign and the majority of malignant tumors harbor indolent features. Improved preoperative diagnostics are needed to differentiate tumors requiring aggressive treatment from those more suitable for surveillance. We evaluated and compared confocal laser endomicroscopy with standard histopathology in ex vivo human kidney tumors as proof of principle towards diagnostic optical biopsy. MATERIALS AND METHODS: Patients with a solitary small renal mass scheduled for partial or radical nephrectomy were enrolled in study. Two kidneys were infused with fluorescein via intraoperative intravenous injection and 18 tumors were bathed ex vivo in dilute fluorescein prior to confocal imaging. A 2.6 mm confocal laser endomicroscopy probe was used to image tumors and surrounding parenchyma from external and en face surfaces after specimen bisection. Confocal laser endomicroscopy images were compared to standard hematoxylin and eosin analysis of corresponding areas. RESULTS: Ex vivo confocal laser endomicroscopy imaging revealed normal renal structures that correlated well with histology findings. Tumor tissue was readily distinguishable from normal parenchyma, demonstrating features unique to benign and malignant tumor subtypes. Topical fluorescein administration provided more consistent confocal laser endomicroscopy imaging than the intravenous route. Additionally, en face tumor imaging was superior to external imaging. CONCLUSIONS: We report what is to our knowledge the first feasibility study using confocal laser endomicroscopy to evaluate small renal masses ex vivo and provide a preliminary atlas of images from various renal neoplasms with corresponding histology. These findings serve as an initial and promising step toward real-time diagnostic optical biopsy of small renal masses.

Primary Pulmonary Synovial Sarcoma during Pregnancy: A Diagnostic and Therapeutic Dilemma.

Synovial sarcoma is a rare soft tissue sarcoma that typically arises in the extremities of young adults. We report a case of a 26-year-old pregnant woman with biopsy-proven primary synovial sarcoma of the lung that was treated with chemotherapy with radiographic response. This is only the third documented case of primary pulmonary synovial sarcoma occurring during pregnancy and the first case where chemotherapy was given.

Clinical pharmacogenetics implementation: approaches, successes, and challenges.

Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine.

Trifecta nerve complex: potential anatomical basis for microsurgical denervation of the spermatic cord for chronic orchialgia.

PURPOSE: We identified structural abnormalities in the spermatic cord nerves that may explain how microsurgical denervation of the spermatic cord provides pain relief in patients with chronic orchialgia. MATERIALS AND METHODS: We retrospectively reviewed a prospective database to compare spermatic cord biopsy specimens from 56 men treated with a total of 57 procedures for microsurgical denervation of the spermatic cord for chronic orchialgia vs a control group of men without pain treated with cord surgery, including varicocelectomy in 4 and radical orchiectomy in 6. Tissue biopsies were obtained from mapped regions of the spermatic cord in all cases. Biopsies stained with hematoxylin and eosin were examined by an independent pathologist. Three human cadaveric spermatic cords were dissected to confirm localization of the nerve distribution identified on pathological mapping. RESULTS: We identified a median of 25 small diameter (less than 1 mm) nerve fibers in the spermatic cord. Of the 57 procedures for orchialgia 48 (84%) showed wallerian degeneration in 1 or more of these nerves but only 2 of 10 controls (20%) had such degeneration (p = 0.0008). In decreasing order of nerve density the 3 primary sites (trifecta nerve complex) of these changes were the cremasteric muscle fibers (19 nerves per patient), perivasal tissues and vasal sheath (9 nerves per patient), and posterior cord lipomatous/perivessel tissues (3 nerves per patient). Cord nerve distribution mapped by the biopsies was confirmed by cadaveric dissection. CONCLUSIONS: In men with chronic orchialgia there appears to be wallerian degeneration in reproducible patterns in the spermatic cord nerve fibers. Transection of these nerves may explain the effect of the denervation procedure.

The Role of KRAS Mutational Analysis to Determine the Site of Origin of Metastatic Carcinoma to the Lung: A Case Report.

Metastatic carcinomas involving the lung are a common specimen encountered in surgical pathology. These metastases may have different morphologic, and architectural patterns and may mimic primary pulmonary adenocarcinoma, especially the intra-alveolar (lepidic) pattern of spread which may simulate a primary pulmonary bronchioloalveolar carcinoma (adenocarcinoma in situ). We present the case of a metastatic pancreatic adenocarcinoma that morphologically mimicked bronchioloalveolar carcinoma of the lung in that the tumor had an exclusive intra-alveolar pattern of spread and had an immunophenotype that was noninformative as to the site of origin (cytokeratin 7+, cytokeratin 20-, TTF-1-). In this case, we used KRAS gene mutation analysis to support that the lung carcinoma represented a metastatic pancreatic carcinoma as they both possessed identical codon 12 KRAS mutations. We show that this method may be a useful way to prove site of origin of metastatic carcinoma-particularly if standard morphologic or immunohistochemical analysis is not definitive.

IgG4 Inflammatory Pseudotumor of the Kidney.

Hyper-IgG4 disease is a rare systemic disorder that usually affects middle age males. It is characterized by elevated serum IgG4 levels and infiltration of organs by IgG4 positive plasma cells associated with fibrosis. Patients usually present with mass or masses in the involved organ that mimic neoplasia. While initially described in the pancreas, IgG4-related inflammatory tumors have been now described in many organs. We describe an unusual case of an IgG4-related pseudotumor of the kidney.

Locally destructive skull base lesion: IgG4-related sclerosing disease.

A unique case of IgG4(+) sclerosing disease was diagnosed in the sphenoid sinus, a previously unreported location, and was treated in a novel manner. This study describes the clinical presentation and management of IgG4 sclerosing disease in the paranasal sinuses. A retrospective case review and review of the medical literature were performed. A 38-year-old woman with a 2-year history of constant frontal headaches presented to our clinic. Imaging showed bony destruction of the sphenoid sinus and sellar floor. The patient underwent a right-sided sphenoidotomy with debridement and biopsy. Pathological evaluation showed a dense plasmacytic infiltrate with >150 IgG4(+) cells/high-power field. She was subsequently started on a nasal corticosteroid with improved patency of the sphenoid antrostomy. We report an unusual case of a middle-aged woman who presented with IgG4-sclerosing disease (IGSD) isolated to the sphenoid sinus. Although our knowledge concerning treatment in extrapancreatic organs is lacking, there is evidence that glucocorticoid treatment improves nasal sinus opacification on CT findings (Sato Y, Ohshima K, Ichimura K, et al., Ocular adnexal IgG4-related disease has uniform clinicopathology, Pathol Int 58:465-470, 2008). This case study and literature review adds to the growing literature describing IGSD in the head and neck and more specifically isolated to the sphenoid sinus with preliminary data concerning local control with topical steroids.

Juvenile myelomonocytic leukemia in a 16-year-old with Noonan syndrome: case report.

A 16-year-old man with splenomegaly presented with ascites and bilateral leg eschars. Although he had intermittently elevated absolute monocyte counts, a diagnosis of juvenile myelomonocytic leukemia (JMML) was discounted because of his age and lack of persistent leukocytosis. Detailed examination demonstrated features consistent with Noonan syndrome (NS), including typical facies, growth retardation, a cardiac defect, and a history of a coagulopathy. He underwent a splenectomy where the surgeons encountered a rind of tissue composed of monocytes encasing the abdominal organs. After splenectomy, his leukocytes rose to over 100×10(9)/L with a monocytosis, suggesting JMML. On the basis of the clinical suspicion of NS, mutation analysis revealed a KRAS mutation, which is known to be common to both NS and JMML. Clinicians should have high index of suspicion for JMML in patients with Noonan features, regardless of a patient's age.

A46, a benzothiophene-derived compound, suppresses Jak2-mediated pathologic cell growth.

Hyperkinetic Jak2 tyrosine kinase signaling has been implicated in several hematological disorders, including myeloproliferative neoplasms. Effective Jak2 inhibitors can have significant therapeutic potential. Here, using structure-based virtual screening, we identified a benzothiophene-derived Jak2 inhibitor named A46. We hypothesized that this compound would inhibit Jak2-V617F-mediated pathologic cell growth. To test this, A46 was analyzed for its ability to inhibit recombinant Jak2 protein catalysis; suppress Jak2-mediated pathogenic cell growth in vitro; inhibit the aberrant ex vivo growth of Jak2-V617F-expressing primary human bone marrow cells; and inhibit Jak2-mediated pathogenesis in vivo. To this end, we found that A46 selectively inhibited Jak2-V617F protein when compared to wild-type Jak2 protein. The drug also selectively inhibited the proliferation of Jak2-V617F-expressing cells in both a time- and dose-dependent manner, and this correlated with decreased Jak2 and signal transducers and activators of transcription 5 phosphorylation within treated cells. The Jak2-V617F cell growth inhibition correlated with an induction of cell cycle arrest and promotion of apoptosis. A46 also inhibited the pathologic growth of primary Jak2-V617F-expressing bone marrow cells ex vivo. Lastly, using a mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. A46 significantly reduced the splenomegaly and megakaryocytic hyperplasia in the spleens of treated mice and the levels of interleukin-6 in the plasma. Collectively, our data demonstrate that the benzothiophene-based compound, A46, suppresses Jak2-mediated pathogenesis, thereby making it a potential candidate drug against Jak2-mediated disorders.

RNA-binding protein LIN28 is a sensitive marker of ovarian primitive germ cell tumours.

AIMS: LIN28 is an RNA-binding protein that has been detected in testicular germ cell tumours (GCTs), but its status in ovarian GCTs is unknown. The aim was to determine the immunohistochemical profile of LIN28 in ovarian GCTs. METHODS AND RESULTS: Immunohistochemistry of LIN28 was performed in 110 primary and 11 metastatic ovarian GCTs. The percentage of tumour cells stained was scored as 0, 1+ (1-30% cells), 2+ (31-60%), 3+ (61-90%), and 4+ (>90%). To determine its specificity, we stained LIN28 in 119 non-GCTs, including 37 clear cell carcinomas. Strong 4+ LIN28 staining was seen in 4/4 (100%) gonadoblastomas, 7/7 (100%) embryonal carcinomas (ECs), and 41/41 (100%) yolk sac tumours (YSTs). Among 39 dysgerminomas, 4+ staining was seen in 37 and 3+ staining in two (strong in 37; mixed weak and strong in two). Twelve of 14 immature teratomas showed variable LIN28 staining (1+ to 4+) in the immature neuroepithelium (weak to strong staining), whereas mature teratomas, carcinoids, struma ovarii and strumal carcinoids were negative. Only 5/117 non-GCTs (1/37 clear cell carcinomas) showed weak to moderate 1-2+ staining. CONCLUSIONS: LIN28 is a sensitive marker for gonadoblastomas, dysgerminomas, ECs, and YSTs. LIN28 can be used to distinguish them from non-GCTs.

Web-based synoptic reporting for cancer checklists.

BACKGROUND: The surgical pathology report remains the primary source for information to guide the treatment of patients with cancer. Failure to report critical elements in a cancer report is an increasing problem in pathology because of the heightened complexity of these reports and number of elements that are important for patient care. The American College of Surgeons Commission on Cancer (ACS-CoC) in concert with the College of American Pathologists (CAP) developed checklists that contain all of the scientifically validated data elements that are to be reported for cancer specimens. Most institutions do not as of yet have pathology information systems in which CAP checklists are embedded into the laboratory information system (LIS). Entering the required elements often requires extensive text editing, secretarial support and deletion of extraneous elements that can be an arduous task. MATERIALS AND METHODS: We sought to develop a web-based system that was available throughout the workstations in our department and was capable of generating synoptic reports based on the CAP guidelines. The program was written in a manner that allowed automatic generation of the web-based checklists through a parsing algorithm. RESULTS: Multiple web-based synoptic report generators have been developed to encompass required elements of cancer synoptic reports as required by the ACS-CoC/ CAP. In addition, utilizing the same program, report generators for certain molecular tests (KRAS mutation) and FISH studies (UroVysion(tm)) have also been developed. The output of these reports can be cut-and-pasted into any text-based anatomic pathology LIS. In addition, the elements can be compiled in a database. CONCLUSIONS: We describe a simple method to automate the development of web-based synoptic reports that can be entered into the anatomic pathology LIS and database.

Primary renal carcinoid tumors: clinicopathologic features of 9 cases with emphasis on novel immunohistochemical findings.

Primary renal carcinoid tumors are rare neoplasms. Because of the rarity of these neoplasms, clinicopathologic and immunohistochemical characteristics have not been fully characterized. Immunohistochemistry for renal cell lineage transcription factors, such as paired box gene 2 and paired box gene 8, has not been studied in renal carcinoid tumors and may be useful in demonstrating nephrogenic differentiation. We studied the clinical, morphological, and immunohistochemical features in 9 primary renal carcinoid tumors from multiple institutions with particular emphasis on immunohistochemical findings, in particular, expression of paired box gene 2 and paired box gene 8. All 9 cases expressed at least 1 neuroendocrine marker (CD56, synaptophysin, chromogranin). The renal-associated (paired box gene 2/paired box gene 8), gastrointestinal (caudal-related homeobox-2), and pulmonary/thyroid (thyroid transcription factor-1) transcription factors were not expressed in renal carcinoids (0/9). Of interest, CD99 was expressed in 8 of 9 cases, with the one negative case representing an atypical carcinoid. Perinephric extension and nodal and distant metastases are common. The absence of expression of paired box gene 2 and paired box gene 8, although not conclusive, supports the theory that these are derived from nonnephrogenic elements. CD99 was expressed in almost all cases (8/9); recognition of this could prevent misdiagnosis of a renal primitive neuroectodermal tumor.