Paul Rodriguez-Waitkus

Akt1 and Akt3 exert opposing roles in the regulation of vascular tumor growth

Vascular tumors are endothelial cell neoplasms whose mechanisms of tumorigenesis are poorly understood. Moreover, current therapies, particularly those for malignant lesions, have little beneficial effect on clinical outcomes. In this study, we show that endothelial activation of the Akt1 kinase is sufficient to drive de novo tumor formation. Mechanistic investigations uncovered opposing functions for different Akt isoforms in this regulation, where Akt1 promotes and Akt3 inhibits vascular tumor growth. Akt3 exerted negative effects on tumor endothelial cell growth and migration by inhibiting activation of the translation regulatory kinase S6-Kinase (S6K) through modulation of Rictor expression. S6K in turn acted through a negative feedback loop to restrain Akt3 expression. Conversely, S6K signaling was increased in vascular tumor cells where Akt3 was silenced, and the growth of these tumor cells was inhibited by a novel S6K inhibitor. Overall, our findings offer a preclinical proof of concept for the therapeutic utility of treating vascular tumors, such as angiosarcomas, with S6K inhibitors.

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin

Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCα, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions.

A Rare Case of Gastric Fundic Gland Adenocarcinoma (Chief Cell Predominant Type)

A 79-year-old Caucasian male with gastritis, reflux esophagitis, and esophageal stricture requiring dilatations in 2000 and 2005 presented again with intermittent solid food dysphagia for 2 months. The patient’s other past medical history includes hiatal hernia, hypertension, hypercholesterolemia, and lifetime smoking. He was prescribed proton pump inhibitors (PPI), which helped relieve his reflux symptoms, but he used it intermittently. Of note, the patient did have repeated colonoscopies since 2000 which revealed sporadic tubulovillous adenomas, tubular adenoma with no high-grade dysplasia, hyperplastic polyps, and lymphocytic colitis. Most recent upper GI endoscopy in November 2011 indicated mild distal reflux esophagitis with no evidence of bleeding nor stricture. However, further advancement of endoscope into the stomach showed a small elevated mass approximately 2 cm in length on the posterior wall near the greater curvature of the upper portion of the body of the stomach (Fig. 1a, b). The mass was biopsied, and the histological findings were consistent with a diagnosis of a fundic gland adenocarcinoma. An endoscopic ultrasound was performed to evaluate the possibility of endoscopic mucosal resection of the mass. This identified a hypoechoic and homogenous oval mass in the body of the stomach that measured 12 mm. There was evidence of extension of the mass onto the luminal interface and superficial mucosa. There was minimal submucosal involvement (Fig. 1c). The mass was removed via endoscopic mucosal resection (EMR) and the specimen was sent to surgical pathology for further evaluation. The patient underwent positron emission tomography/ computed tomography (PET/CT) scan, which indicated no signs of metastasis. A repeat upper endoscopy with biopsy at the area 2 months following EMR revealed no evidence of neoplasm (Fig. 1d).

Cutaneous squamous cell carcinoma and related entities: Epidemiology, clinical and histological features, and basic science overview.

Cutaneous squamous cell carcinoma (cSCC) corresponds to approximately 20% of all nonmelanoma skin cancer (NMSC) cases and is currently the second most common human malignancies worldwide, trailing behind only basal cell carcinoma (BCC). However, in contrast with BCCs, certain aggressive cSCC variants as well as tumors equal to or larger than 2 cm in diameter and 2 mm in thickness exhibit a much more aggressive clinical behavior with significant risk for local recurrence and distant metastases. We review various aspects of cSCC, including its precursor and related entities: actinic keratosis (AK) and keratoacanthoma (KA). We include up to date epidemiologic data, clinical and histopathologic presentations, as well as the molecular alterations present in these entities.

Metachromatic Leukodystrophy and Its Effects on the Gallbladder: A Case Report

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A enzyme. This deficiency leads to accumulation of sulfatides in the central nervous system and other organs, such as the gallbladder. Here the authors discuss a 9-year-old Middle Eastern patient with late-infantile-type MLD who presented with symptoms of cholecystitis. Radiographic studies revealed an enlarged gallbladder with a thickened wall and a pericholecystic fluid collection with peripheral calcifications. Gross examination of the gallbladder showed multiple small to medium-sized papillary projections involving the entire mucosal surface. Sections through the gallbladder wall revealed multilocular dilated mucin-producing cystic spaces. Microscopically, the mucosa showed numerous papillary projections with complex folds lined by mucin-producing cuboidal to tall columnar cells. The cystic spaces were composed of numerous markedly distended Rokitansky-Aschoff sinuses filled with mucin. Ultrastructurally, the epithelial cells and macrophages showed frequent secondary lysosomes containing closely packed lamellar amorphous to prismatic material with alternating leaflets and tubules, imparting a “herringbone” or “tuffstone” pattern. This case illustrates the features of gallbladder involvement in MLD and the potential role of ultrastructural examination in diagnosis of MLD.

Comparing whole slide digital images versus traditional glass slides in the detection of common microscopic features seen in dermatitis.

Background: The quality and limitations of digital slides are not fully known. We aimed to estimate intrapathologist discrepancy in detecting specific microscopic features on glass slides and digital slides created by scanning at ×20. Methods: Hematoxylin and eosin and periodic acid-Schiff glass slides were digitized using the Mirax Scan (Carl Zeiss Inc., Germany). Six pathologists assessed 50-71 digital slides. We recorded objective magnification, total time, and detection of the following: Mast cells; eosinophils; plasma cells; pigmented macrophages; melanin in the epidermis; fungal bodies; neutrophils; civatte bodies; parakeratosis; and sebocytes. This process was repeated using the corresponding glass slides after 3 weeks. The diagnosis was not required. Results: The mean time to assess digital slides was 176.77 s and 137.61 s for glass slides (P < 0.001, 99% confidence interval [CI]). The mean objective magnification used to detect features using digital slides was 18.28 and 14.07 for glass slides (P < 0.001, 99.99% CI). Parakeratosis, civatte bodies, pigmented macrophages, melanin in the epidermis, mast cells, eosinophils, plasma cells, and neutrophils, were identified at lower objectives on glass slides (P = 0.023-0.001, 95% CI). Average intraobserver concordance ranged from κ = 0.30 to κ = 0.78. Features with poor to fair average concordance were: Melanin in the epidermis (κ = 0.15-0.58); plasma cells (κ = 0.15-0.49); and neutrophils (κ = 0.12-0.48). Features with moderate average intrapathologist concordance were: parakeratosis (κ = 0.21-0.61); civatte bodies (κ = 0.21-0.71); pigment-laden macrophages (κ = 0.34-0.66); mast cells (κ = 0.29-0.78); and eosinophils (κ = 0.31-0.79). The average intrapathologist concordance was good for sebocytes (κ = 0.51-1.00) and fungal bodies (κ = 0.47-0.76). Conclusions: Telepathology using digital slides scanned at ×20 is sufficient for detection of histopathologic features routinely encountered in dermatitis cases, though less efficient than glass slides.

Basal cell carcinoma: Epidemiology, clinical and histologic features, and basic science overview

Basal cell carcinoma (BCC) is a quite ubiquitous entity in dermatology and dermatopathology, and, together with cutaneous squamous cell carcinoma (cSCC), constitutes the bulk of the socalled “nonmelanoma skin cancer” (NMSC) cases. Both BCC and cSCC arise in a similar clinical background of chronic sun damage and immunosuppression, among other risk factors. However, it is important to emphasize that BCC represents more of a locally aggressive tumor that rarely metastasizes, compared with cSCC, particularly some subtypes, which may have a higher risk of metastatic spread and even death. BCC can be classified into several variants that demonstrate different clinical behaviors, particularly in terms of local recurrence rates. We review the different facets of BCC to include up to date epidemiologic data, clinical and histopathologic presentations, as well as the latest findings on the molecular alterations driving this entity.

Sebaceous Carcinoma of the Eyelid.

BACKGROUND Periocular sebaceous carcinoma (PSC) is a rare but aggressive neoplasm that tends to clinically and histopathologically mimic other conditions. PSC can be challenging to diagnose using histomorphology alone given its overlap with 2 more common tumors that occur in this area (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]). Use of immunohistochemistry can help resolve this differential diagnosis. METHODS A review of the literature was performed, focusing on the epidemiology, morphology, and immunohistochemical features of PSC. RESULTS The most useful immunostains in the differential diagnosis of PSC are epithelial membrane antigen, Ber-Ep4, androgen receptor (AR), and adipophilin. To discern PSC from BCC, one should use EMA, Ber-Ep4, AR, and adipophilin, whereas discerning PSC from SCC can be achieved by evaluating AR and adipophilin. In addition, p53 and ERBB2 (formally known as HER2/neu) are other potentially useful immunohistochemical markers for the differential diagnosis of PSC. CONCLUSIONS Use of new immunohistochemical techniques, as well as the elucidation of molecular alterations, such as the presence of ERBB2 amplification, will advance our understanding of PSC.

IgG4‐related skin disease may have distinct systemic manifestations: a systematic review

IgG4‐related disease (IgG4‐RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi‐organ infiltration of IgG4‐bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4‐related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck – lymphatics, orbit, salivary, and lacrimal glands – but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4‐RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4‐related skin disease, but obliterative venulitis is less common than in the prototypical IgG4‐related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4‐positive plasma cells per high‐power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4‐related skin disease defines a unique systemic disease complex along the spectrum of IgG4‐RD.

Gastrointestinal Histoplasmosis in a Hepatitis C-Infected Individual

Gastrointestinal histoplasmosis is a rare manifestation of this fungal infection, typically identified in immunocompromised patients, such as those with HIV/AIDS. Here, we report a case of disseminated histoplasmosis with gastrointestinal involvement in a Hepatitis C-infected patient. The fungal agent was confirmed to be Histoplasma capsulatum by a DNA probe assay performed on a bone marrow sample. We propose that this fungal disease should be kept on the differential of patients infected with the Hepatitis C virus, as it has been reported to have numerous damaging effects on the adaptive immune system.