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Primary cutaneous gamma-delta T-cell lymphoma (CGD-TCL) is a rare cutaneous T-cell lymphoma characterized by a rapidly progressive clinical course and a poor prognosis. We report a case of a 52-year-old man with a 10-year history of erythematous nodules and a rapid terminal progression diagnosed as CGD-TCL. Biopsies taken at the time of progression showed a dense lymphocytic infiltrate involving the subcutaneous adipose tissue and deep dermis. One of the biopsies displayed much more limited involvement by CGD-TCL that was nearly identical to the biopsies of the erythematous lesions 10 years before. In conclusion, this case demonstrates a case of CGD-TCL presenting as a longstanding indolent disease with a rapid terminal progression. The indolent clinical course and histological heterogeneity make diagnosing this entity during the initial stage extremely challenging. This case underscores a diverse clinical presentations and a need to consider CGD-TCL in patients showing subcutaneous lesions with an indolent clinical course.

The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.

Inverted papilloma of the urinary bladder is rare, accounting for

Diverticula are saccular evaginations of urinary bladder mucosa that are encountered in all age groups with a prevalence of 1% to 10%. Intradiverticular neoplasms pose diagnostic and management challenges. The aim of this study was to document the common morphologic changes and neoplasms found in a large series of adult and pediatric vesical diverticula. A total of 174 diverticula from 133 patients were reviewed including 48 pediatric (mean age, 7.1 years) and 85 adult (mean age, 63.93 years); 92% were male. Of the 85 nonneoplastic cases, prominent morphologic findings included significant chronic inflammation (59), granulomatous inflammation including foreign body giant cell reaction (6), acute inflammation (7), squamous metaplasia (9), cystitis glandularis (10), and nephrogenic metaplasia (2). The pediatric cases showed no malignancy. Thirty-three of the 48 neoplastic cases had high-grade urothelial carcinoma, 4 had carcinoma in situ, 7 had low-grade papillary urothelial carcinoma, 2 had primary squamous cell carcinoma, 1 had primary melanoma, and 1 had urothelial dysplasia. Nine of the neoplastic cases had variant morphology. Diverticula from 31 cases were involved by primary tumors, of which 6 had coexisting intravesical neoplasia (3 had carcinoma in situ with invasion elsewhere). In 19 of 33 high-grade urothelial carcinomas, infiltration into adjacent fat was noted. Seven of these cases arose within diverticula. Diverticula may harbor neoplasms, most commonly urothelial carcinoma. Attenuation of the muscle layer associated with diverticulum formation may facilitate tumor invasion into peridiverticular soft tissues. It is emphasized that pT2 stage should be eliminated to avoid the confusion in staging these neoplasms.

OCT4 immunostaining has become an essential resource in diagnosing germ cell neoplasia. OCT4 is a transcription factor with a characteristic nuclear staining pattern specific to germ cell neoplasms. Our institution has observed that paraganglionic tissue consistently displayed intense cytoplasmic staining by utilizing monoclonal OCT4 antibody, and we intended to determine whether OCT4 could provide additional diagnostic utility in adrenal tumors. We used monoclonal and polyclonal OCT4 antibodies for comparison of staining patterns and intensities. Thirty-eight pheochromocytomas (8 metastatic), 22 adrenal cortical carcinomas (2 metastatic), 15 metastatic tumors to the adrenal glands, and 10 normal adrenal glands containing cortical and medullary tissue were immunostained with OCT4. A 4-tier system (0 to 3), for recording intensity and extent of cytoplasmic staining, was used. All 30 primary pheochromocytomas displayed strong and diffuse (3+3) cytoplasmic immunoexpression. Six of 8 metastatic pheochromocytomas showed strong immunoexpression (3+3), whereas the remaining 2 showed moderate intensity (2+3). All 22 adrenal cortical carcinomas, including metastatic cases, were completely negative. Only 2 metastatic tumors to the adrenal gland showed weak, cytoplasmic positivity: a small cell carcinoma and a Merkel cell carcinoma. Controls stained in an appropriate nuclear manner. Immunoelectron microscopy demonstrated the antibody interacting with neurosecretory granules. To our knowledge, the cytoplasmic expression of OCT4 in adrenal medulla and pheochromocytoma has not been specifically studied. The goal of this study is to analyze the immunoreactivity of adrenal cortical carcinoma and pheochromocytoma to OCT4 and determine the sensitivity and specificity of this particular staining pattern and to compare monoclonal and polyclonal antibodies.

Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.

Alexander R E, Lopez-Beltran A, Montironi R, MacLennan G T, Post K M, Bilbo S A, Jones T D, Huang W, Rao Q, Sen J D, Meehan K, Cornwell A, Miravalle L & Cheng L (2012) Histopathology KRAS mutation is present in a small subset of primary urinary bladder adenocarcinomas Aims: To determine whether KRAS mutations occur in primary bladder adenocarcinoma. Methods and results: Twenty-six cases of primary urinary bladder adenocarcinoma were analysed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and amplified with shifted termination assay technology, which recognizes wild-type or mutant target sequences and selectively extends detection primers with labelled nucleotides. A mutation in KRAS was found in three (11.5%) of 26 primary bladder adenocarcinomas. Two of these three cases exhibited a G13D mutation, whereas the remaining case contained a mutation in G12V. None of the ten cases of urothelial carcinoma with glandular differentiation displayed KRAS mutation. Colonic adenocarcinoma contained a KRAS mutation in 18 (33%) of 55 cases. There was no distinct difference with regard to grade, stage or outcome according to the limited clinicopathological data available. However, the two youngest patients, aged 32 and 39 years, in our study group, with a mean population age of 61 years, were found to have mutations in KRAS. Conclusions: KRAS mutations are present in a small subset of primary urinary bladder adenocarcinomas. Future clinical trials for treatment of bladder adenocarcinoma, employing targeted therapies similar to those used for treatment of colon cancer, may also benefit from the predictive implications of KRAS mutational testing.

The majority of lung adenocarcinoma patients with epidermal growth factor receptor- (EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

The diagnosis of branchiogenic carcinoma is one of significant controversies in the field of head and neck oncology. Those who support its existence adhere to rigid criteria to validate its existence. Those that deny it, purport that the entity is simply metastatic disease masquerading as a branchial cleft primary. One aspect of agreement between the two opposing views is that a separate head and neck primary disqualifies the diagnosis of branchiogenic carcinoma. We report a case in which branchiogenic carcinoma was diagnosed in the presence of an additional base of tongue primary squamous cell carcinoma based on morphologic dissimilarity and evidence of origination from the basal layer of the branchial cleft epithelium. In doing so, we attempt to make the case that unequivocal histologic evidence of branchial cleft origin is the defining feature of branchiogenic carcinoma and, as with many other carcinomas, should be the diagnostic criterion of choice in issuing the diagnosis. A brief pertinent literature review is presented.

Lymphadenectomy (LAD) is an important staging and treatment modality of oncologic surgery. LAD in genitourinary malignancies presents inherent difficulties to the urologist and pathologist because of the differences in anatomic sites and primary histologic type. This review focuses on pathologic evaluation and how communication between urologist and pathologist is necessary to provide optimal care. Recommendations covering general specimen submission and processing are discussed, as well as more specific recommendations concerning the kidney, upper urinary tract, urinary bladder, prostate, testes, and penis. Emerging areas of prognostic significance and the impact that improved molecular techniques are contributing to diagnostic interpretation are highlighted.

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs - allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.

Sarcomatoid carcinoma of the urinary bladder is an unusual malignancy composed of both carcinomatous and sarcomatous components. It is an aggressive tumor that presents at an advanced stage and confers a much poorer prognosis than conventional urothelial carcinoma. The proper nomenclature and histogenesis of these tumors have been subjects of debate for some time. There is an emerging consensus that sarcomatoid carcinoma is the most appropriate term for these neoplasms. The recent World Health Organization classification has applied this term to all tumors showing morphologic and/or immunologic evidence of both malignant epithelial and mesenchymal differentiation. Such tumors have been postulated to represent either multiclonal collision tumors or monoclonal cancers with divergent differentiation; recent molecular studies favor the latter theory. In this study, we discuss the nomenclature, clinical features, pathology, differential diagnosis, molecular genetics, and histogenesis of sarcomatoid carcinoma. We emphasize the importance of molecular genetic studies in providing insight into the histogenesis of this neoplasm. Sarcomatoid carcinoma seems to represent the final common pathway of urothelial carcinoma dedifferentiation.

The invention and development of the CT scanner is one of the most fascinating tales in the history of radiology. It includes of one of the 20th century's most important recording companies, perhaps the most influential recording group of all time, and a Nobel laureate in medicine and physiology who never attended medical school or earned a PhD. The story of the CT scanner offers important lessons for radiologists on the interaction between medicine and business that are at least as important today as they were decades ago.

The discovery that the role human papillomavirus (HPV) plays in the induction of human cancer represents an important achievement in oncologic research. It has taken on even greater importance since the development of vaccines, which promise the hope of preventing these cancers from ever occurring. Because of these important implications, many have attempted to determine a possible role for the virus in cancers of the urinary bladder-an organ in close anatomic proximity to the primary sites of HPV-induced neoplasia and one which already has an established oncogenic infectious agent in Schistosoma haematobium. Here we review the current literature exploring this possible role in the most common subtype of cancer of the urinary bladder, urothelial carcinoma, and two much more rare histologic subtypes that have well established roles for HPV-induced neoplasia in other anatomic sites-squamous cell carcinoma and adenocarcinoma.

Patient: 80-year-old Caucasian female Chief Complaint: Fatigue, flank pain, and hematuria History of Present Illness: The patient was admitted to the regional hospital after transfer orders from her primary care physician (PCP) subsequent to results of a CBC and a several week history of fatigue and hematuria. The PCP gave her ciprofloxacin to treat the presumed urinary tract infection (UTI). Upon a 1-month follow-up, the patient’s symptoms had not resolved, and the PCP discontinued the ciprofloxacin and started the patient on cephalexin. The patient again presented to her PCP, prior to this admission, with flank pain, in addition to the previous symptoms. Performance of a CBC revealed a hemoglobin level of 4.6 g/dL, and the patient was subsequently transferred to the hospital for treatment of profound anemia. Past Medical and Surgical History: Hypothyroidism Family History: Multiple myeloma Social History: Tobacco use (quit 15 years ago) Physical Examination Vital Signs: Temperature: 36.2°C; pulse 82 beats per minute; respiratory rate, 20 breaths per minute; blood pressure, 133/65. Principal Laboratory Findings: Table 1 Additional Testing: Reference Lab Pre-transfusion Workup Cell Studies: Direct antiglobulin test (DAT) positive to polyspecific anti-human globulin (AHG), anti-immunoglobulin G (IgG), and anti-complement; elution studies were not performed at the time. Serum/Plasma Studies: Autoantibody Reactivity: positive Adsorption Studies: Alloadsorption performed: no alloantibodies to common antigens detected Recommendations: Group O; Rh (D) compatible; least serologically incompatible; cross-matched red cells. Consideration should be given to the use of a properly monitored blood warmer; keep all fluids warm; keep patient warm. 1. What are the patient’s most striking clinical and laboratory findings? 2. What is the differential diagnosis for a patient with these findings? 3. What is the patient’s most likely diagnosis? 4. What protocol needs to take place to differentiate among the different types of autoimmune hemolytic anemias (AIHA)? 5. What is the recommended treatment and management …

To examine the expression of nuclear factor kappaB (NFkappaB), intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1) levels in rheumatic heart disease patients who suffer from atrial fibrillation and those who do not.Twenty-six patients with rheumatic heart disease were enrolled. Ten patients had no history of atrial fibrillation and 16 had atrial fibrillation. Atrial tissue was obtained from the right atrial appendage during heart surgery. The expression levels of NFkappaB, ICAM1, and VCAM1 were examined with immunohistochemical staining.Myocardial inflammation and fibrosis were both increased in patients with atrial fibrillation. The levels of NFkappaB, ICAM1, and VCAM1 were significantly elevated in patients with atrial fibrillation as compared with the control group (all p0.05).Overexpression of NFkappaB, ICAM1, and VCAM1 may be involved in the development and maintenance of atrial fibrillation in patients with rheumatic heart disease.

Prostatic adenocarcinoma is the most common noncutaneous malignancy in men and the second leading cause of cancer death in Western populations. Despite its prevalence, an understanding of the molecular alterations affecting the development, progression, and treatment of the disease was largely lacking until recently. Rapid advances in molecular techniques in the past decade have seen a dramatic increase in our understanding of the role molecular alterations play in prostate cancer. Though still early, these developments have provided insight into distinct subsets of prostate cancer that promise to change how the disease is both diagnosed and managed. The molecular alterations discovered have shown that prostate cancer development involves multiple genetic abnormalities and that detection or targeting of a single genetic event is unlikely to impact all cases of prostate cancer. Of the ones that have shown the most promise to changing diagnostic and treatment paradigms are the gene fusion of TMPRSS2 and members of the ETS family of transcription factors, primarily ERG, as well as the inactivation of the tumor suppressor PTEN. A greater understanding of the molecular alterations present in prostate cancer will lead to further improvements in diagnosis, prediction of prognosis, stratification for specific therapies, and ultimately better outcomes for patients.

To determine whether KRAS mutations occur in primary bladder adenocarcinoma.Twenty-six cases of primary urinary bladder adenocarcinoma were analysed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and amplified with shifted termination assay technology, which recognizes wild-type or mutant target sequences and selectively extends detection primers with labelled nucleotides. A mutation in KRAS was found in three (11.5%) of 26 primary bladder adenocarcinomas. Two of these three cases exhibited a G13D mutation, whereas the remaining case contained a mutation in G12V. None of the ten cases of urothelial carcinoma with glandular differentiation displayed KRAS mutation. Colonic adenocarcinoma contained a KRAS mutation in 18 (33%) of 55 cases. There was no distinct difference with regard to grade, stage or outcome according to the limited clinicopathological data available. However, the two youngest patients, aged 32 and 39 years, in our study group, with a mean population age of 61 years, were found to have mutations in KRAS.KRAS mutations are present in a small subset of primary urinary bladder adenocarcinomas. Future clinical trials for treatment of bladder adenocarcinoma, employing targeted therapies similar to those used for treatment of colon cancer, may also benefit from the predictive implications of KRAS mutational testing.

Two classes of anti-EGF receptor (EGFR) agents, monoclonal anti-EGFR antibodies and small-molecule EGFR tyrosine kinase inhibitors, have been used for the treatment of non-small-cell lung cancer (NSCLC). However, only a subset of patients will benefit from EGFR-targeted therapy. The discovery of biomarkers that select the appropriate patients for the therapy and predict the responses to the therapy is urgently needed. Molecular genetic analyses provide new insights into EGFR pathway alterations and demonstrate promise for predicting the clinical outcome of patients with NSCLC. In this article, we summarize the latest available knowledge on the clinical impact of EGFR mutations, gene copy number, EGFR overexpression, phosphorylation expression and the alteration of the EGFR pathway downstream factors in predicting the response to EGFR-targeted therapy in NSCLC patients. The role of KRAS and BRAF mutations and ALK rearrangement in lung cancer-targeted therapy, are also reviewed.

Answer: a dicotyledonous plant seed. A differential identification of the object initially included both a small intestinal fluke and a cross-section of a nematode, among other possibilities. However, close inspection of the object did not reveal internal structures, such as reproductive and

A 13-year-old male presented to the Riley Hospital for Children at Indiana University Health emergency department with a 2-day history of constipation and a 1-day history of rectal bleeding. He had also passed several stools containing blood following administration of a laxative. At the time of evaluation, the patient was afebrile and denied anti-inflammatory drug ingestion, illicit substance abuse, epistaxis, hematemesis, travel outside Indiana, and consumption of raw or undercooked meat. Digital rectal examination revealed an ulcer in the posterior wall and a hemorrhoid in the anterior wall, while the remainder of the physical examination was unremarkable. A complete blood count and coagulation studies indicated mild anemia and an elevated neutrophil count, but other parameter values were within normal limits. A radiograph of the child's abdomen was also performed, which showed only a moderate amount of gas and stool retention. The patient's medical history was significant for developmental delay and Nissen fundoplication for esophageal reflux. Based on these findings, the patient was admitted for further evaluation by the gastrointestinal service. A colonoscopy performed the following morning confirmed the presence of a raised, erythematous, and friable rectal ulcer, while the rest of the colon and terminal ileum appeared normal. Biopsy specimens of the colon, terminal ileum, and rectal ulcer obtained during the colonoscopy did not reveal an obvious cause of the rectal ulcer, and the intestinal mucosa was unremarkable. However, one hematoxylin-and-eosin-stained section of the colon biopsy specimen revealed an ovoid object containing abundant eosinophilic granules measuring 1.0 by 0.75 mm in the greatest dimension (Fig. 1) in the lumen. The pathologist queried as to the presence of an intestinal parasite. FIG 1 Hematoxylin-and-eosin-stained colon biopsy specimen of the ovoid object (left; ×100 total magnification). The higher magnification demonstrates the cellular structure and outer wall (right; ×600 total magnification). (For answer and discussion, see page 3138 in this issue [doi:10.1128/JCM.00700-13].)