Riley E. Alexander

Molecular pathology of lung cancer: key to personalized medicine.

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.

Sarcomatoid Carcinoma of the Urinary Bladder: The Final Common Pathway of Urothelial Carcinoma Dedifferentiation

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.

P16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma

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.

The landscape of EGFR pathways and personalized management of non-small-cell lung cancer

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.

The clinical and therapeutic implications of cancer stem cell biology

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.

The spectrum of histopathologic findings in vesical diverticulum: implications for pathogenesis and staging

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.

EMI and the First CT Scanner

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 centurys 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.

Human papillomavirus is not an etiologic agent of urothelial inverted papillomas.

Inverted papilloma of the urinary bladder is rare, accounting for <1% of all bladder neoplasms. Although there is general consensus that inverted papilloma is benign in nature, little is known about its pathogenesis. Some have suggested that human papillomavirus (HPV) plays an etiologic role in the development of this neoplasm. These claims have not been adequately substantiated, and there is controversy as to the role of HPV in other urinary bladder neoplasms as well. To further investigate a possible etiologic role of HPV in urothelial neoplasia, we evaluated 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. In the urinary bladder inverted papillomas of these 27 patients (age range, 35 to 78 y; M:F ratio, 11:1), no HPV was detected by HPV immunohistochemistry or by ISH. Immunoreactivity to p16 was detected in 11/27 (41%) of the cases. Expression of p16 is seen inconsistently within these neoplasms and does not correlate with the presence of HPV antigens or genes by immunohistochemistry or ISH, respectively. Therefore, p16 is not a reliable surrogate marker for HPV infection in urothelial inverted papilloma. Our findings indicate the absence of HPV in urothelial inverted papillomas. HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases.

Cytoplasmic Staining of OCT4 Is a Highly Sensitive Marker of Adrenal Medullary-derived Tissue

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.

Bladder Diverticulum: Clinicopathologic Spectrum in Pediatric Patients

Urinary bladder diverticula are a relatively rare finding in both the adult and pediatric population. Their presence in the adult population has long been associated with the development of urothelial carcinoma within the lesion. Our goal is to analyze a relatively large pediatric patient population with urinary bladder diverticula to expand the body of knowledge on the associated clinical symptomatology, congenital syndromes associated with the entity, and treatment methods and to further investigate if there is any reason to suspect malignant transformation within the pediatric population. A search for pediatric patients (0–19 years of age) from 1990 to 2011 revealed 47 patients with 60 diverticula within the specified age range. Clinical records and histologic slides for all cases were pulled for review, and statistical analysis was performed on the results. The most common findings were vesicoureteral reflux (68%), recurrent urinary tract infection (55%), and hydronephrosis (40%). Fourteen of 47 (30%) patients had an associated congenital syndrome/malformation. Diverticular size range was 0.5–10 cm with a mean of 2.56 cm. No patient was found to have overt malignancy or dysplastic changes within the diverticula or bladder at the time of pathologic evaluation. High association with recognizable clinical symptoms and additional urinary tract abnormalities leads to early identification and treatment. A sizable percentage of those found to have bladder diverticula within the pediatric population will have a congenital syndrome. No association with malignancy is seen within pediatric bladder diverticula; it is an extremely unlikely event in these young patients.