A Primary Epithelioid Angiosarcoma Arising in a Bilharzial Urinary Bladder: A Reappraisal and Case Report.

BACKGROUND: Angiosarcoma (AS) of the urinary bladder is a very rare and aggressive malignancy with a dismal outcome. CASE REPORT: Here, we report a primary epithelioid angiosarcoma (EAS) of the urinary bladder in a forty-nine-year-old male patient who presented with severe hematuria. Cystoscopic examination revealed hemorrhagic ulcerated bladder mucosa but no definite mass lesions. Intractable hematuria raised the initial clinical impression of idiopathic hemorrhagic cystitis. Analysis of the cystoscopic biopsy revealed features of old bilharzial cystitis, markedly atypical epithelioid endothelial cells arranged as primitive anastomosing vascular structures and expressing vascular markers. The diagnosis of EAS was established. The patient developed intractable severe hematuria, and a radical cystoprostatectomy was performed. The patient was started on chemotherapy but suddenly developed widespread distant metastasis (liver, lung, suprarenal glands, and lymph nodes) and succumbed to death two months after the surgery. CONCLUSION: To the best of these authors' knowledge, we presented the first report of primary EAS arising in a bilharzial bladder. The relevant studies were discussed.

Dermatofibromas with Aberrant Expression of CD34 Protein: A Systematic Review and a Reappraisal of Clinicopathological Features and Histogenesis.

BACKGROUND: Dermatofibromas (DFs) are benign fibrohistiocytic lesions that usually do not express CD34 protein. This study aimed to analyze the literature concerning the immunohistological and ultrastructural features of DFs. It also related these features to the histogenesis of these lesions. METHODS: This study included a PubMed literature search for studies addressing the clinicopathological, ultrastructural, and immunohistochemical features of DFs. It also presented some current cases of CD34-negative DFs and a subset of these lesions with aberrant expression of this protein. RESULTS: Analysis of the PubMed literature revealed that DFs with an aberrant expression of CD34 are rare tumors that commonly affect the extremities of adult females. Separating these tumors from dermatofibrosarcoma protuberans (DFSP, CD34-positive tumors) requires using a large panel of immunostains. Ultrastructurally, DFs are composed of diverse cell types, including cells with histiocytic, myofibroblastic, and fibroblastic features. An analysis of the DFs described by this study revealed that cases with an aberrant expression of CD34 protein had slightly high mean age and male sex predominance when compared to CD34-negative cases. The former commonly affected the extremities. There was no evidence of local recurrence or distant metastasis on follow-up. CONCLUSIONS: DFs have the potential to express CD34 protein, defining a rare aberrant phenotype, which was not associated with any differences in the outcome as compared to CD34-negative DFs.

Membranoproliferative Glomerulonephritis Type I Associated with Intravenous Immunoglobulin Administration Arising in a Child with X-Linked Agammaglobulinemia: A Case Report and a Reappraisal.

In 1952, X-linked agammaglobulinemia (XLA) was discovered as a rare inherited disorder. It markedly compromises the ability of the body to combat infectious microorganisms. Membranoproliferative glomerulonephritis (MPGN) Type I is characterized by subendothelial immune complex deposits. Patients with XLA can rarely develop immune-complex-induced diseases. Here, we report a case of MPGN Type I in a 12-year-old male patient with a past and family history of XLA. The patient presented with fever, productive cough, vomiting, and lower limb edema. Clinical and radiological examinations established a diagnosis of bronchopneumonia. The laboratory findings revealed proteinuria and hematuria, and a renal biopsy was performed. The histological examination of this biopsy revealed mesangial hypercellularity and thickened basement membranes. Immunofluorescence studies showed mesangiocapillary staining for Complement 3 and Immunoglobulin (Ig) G and, to a lesser extent, for IgA, IgM, and Complement 1q. Ultrastructural studies revealed partly thick, double-contoured glomerular basement membranes, glomerular endothelial cells with swollen cell bodies, and podocytes with effaced foot processes. Small subendothelial and mesangial eosinophilic deposits were identified. The diagnosis of MPGN type I was established. The patient was started on prednisolone. To the best of our knowledge, this is a rare case of MPGN Type I in a patient with XLA. The pathogenetic mechanisms underlying the development of MPGN Type I were not apparent in our patient. However, residual humoral immunity may play a role in the development of MPGN.

Neurogenic Appendicitis: A Reappraisal of the Clinicopathological Features and Pathogenesis.

In 1921; Masson and Maresch first coined the term "neurogenic appendicitis (NA)" to describe "neuroma-like" lesions in the appendix. To date, our knowledge about NA is limited; therefore, we conducted a comprehensive analysis of the literature (1921 to 2020) to examine the clinicopathological features of NA. We also addressed the pathophysiology of acute abdominal pain and fibrosis in this entity. We performed a meta-analysis study by searching the PubMed database, using several keywords, such as: "appendix," "neurogenic," "obliterative," "neuroma," "fibrous obliteration," "appendicopathy," and "appendicitis." Our study revealed that patients with NA usually present clinically with features of acute appendicitis, bud2t they have grossly unremarkable appendices. Histologically, the central appendiceal neuroma was the most common histological variant of NA, followed by the submucosal and intramucosal variants. To conclude, NA represents a form of neuroinflammation. The possibility of NA should be considered in patients with clinical features of acute appendicitis who intraoperatively show a grossly unremarkable appendix. Neuroinflammation and neuropeptides play roles in the development of pain and fibrosis in NA.

A Unique Coexistence of Rectal Adenocarcinoma and Gastric Antral Gastrointestinal Stromal Tumor: A Case Report and Minireview.

Several studies have reported the coexistence of gastric gastrointestinal stromal tumors (GISTs) with many primary carcinomas such as gastric and renal cell carcinomas. However, to date reports about the coexistence of gastric GISTs and colorectal adenocarcinoma are limited. Herein we report a unique case of gastric GIST coexisting synchronously with rectal adenocarcinoma in a 36-year-old male patient who presented with weight loss, vomiting, and bleeding per rectum. Computed tomography (CT) revealed circumferential rectal mass coexistent with an irregular gastric soft tissue mass. The diagnosis of rectal adenocarcinoma and gastric GIST was established by immunohistological evaluation of the colonoscopic (rectum) and CT-guided (stomach) biopsies. The patient received concomitant chemoradiotherapy for the rectal adenocarcinoma and neoadjuvant imatinib for the gastric GIST. This was followed by low anterior resection with total mesorectal excision and wedge resection of the gastric mass. Follow-up of the patient for 1.5 years revealed no evidence of disease recurrence. We also present a minireview of the literature that provides insights into this subject as a separate section.

Primary Localized Amyloidosis of the Intestine: A Pathologist Viewpoint.

BACKGROUND: Localized amyloidosis of the intestine is a rare entity, which can clinically masquerade several conditions such as colitis, polyps, and malignant tumors. This study aims to evaluate the clinicopathological features of this entity. METHODS: To evaluate the clinicopathological features of this entity, a comprehensive search of the literature (1960 to 2019) was done using the following keywords: "amyloidosis" and "small intestine" or "duodenum" or "ileum" or "jejunum" or "colon". We identified 756 studies about gastrointestinal amyloidosis. Data were examined for 27 studies about localized intestinal amyloidosis. The clinicopathological features were described. RESULTS: The age at presentation ranged from 29 to 88 years. The male to female ratio was 3:1. The jejunum and sigmoid colon were the most commonly involved sites. Abdominal pain and intestinal obstruction (small intestine), or rectal bleeding (sigmoid region) were the most common clinical presentations. Colonoscopic findings included wall thickening, mucosal ulcerations (small intestine), and tumor-like masses (colon). CONCLUSIONS: The clinical presentations of localized intestinal amyloidosis depend on the site of the deposition of the amyloid. In most cases, amyloid deposits consisted of light chain protein.

Ultra-structural study of the indomethacin-induced apoptosis and autophagy in rat gastric parietal cells.

BACKGROUND AND AIM OF THE WORK: Indomethacin (IND), a non-steroidal anti-inflammatory drug, can induce gastric mucosal ulcerations. To date, the ultra-structural changes in the parietal cells (PCs) of the gastric mucosa following the intake of IND are mostly unknown. We carried out the current investigation to get insights into this issue. MATERIALS AND METHODS: We established an animal model consisting of 35 adult male Sprague Dawley rats. The animals were divided into three groups, including; control (normal feeding), fasting, and indomethacin-treated groups. After treatment of 18-h fasting rats with IND, they were sacrificed at 3, 6, and 12-h intervals. The morphological features, including the apoptotic, and autophagic changes in the gastric mucosa PCs were examined using transmission electron microscopy. RESULTS: In normal feeding animals (control group), the gastric PCs were present in various stages of activity. Fasting was associated with the predominance of the inactive parietal cells with features of up-regulated autophagy. In the IND -treated animals (at 3-h interval), PCs showed prominent autophagic changes, and subtle apoptotic cell death. In the IND -treated animals (at 6-12-h interval), PCs showed prominent apoptotic changes, and subtle autophagic features. CONCLUSIONS: Our study indicates that IND treatment could induce gastropathy through time-dependent alterations in the autophagic and apoptotic machinery of PCs. Further studies are needed to examine the underlying molecular mechanisms.

Increased expression of TGF-ß protein in the lesional skins of melasma patients following treatment with platelet-rich plasma.

Background: Melasma is a common acquired facial hyperpigmented skin disorder. Platelet-rich plasma (PRP) is autologous plasma containing higher than normal platelets concentrations. Recently, PRP has been used as a therapeutic modality in melasma with significant clinical improvement, possibly due to its abundant contents of growth factors such as TGF-ß. The latter represents a natural multifunctional polypeptide that negatively regulates melanocyte differentiation and therefore reduces skin hyperpigmentation. To date, the expression pattern of TGF-ß protein in skin of melasma patients following PRP injection is unknown. Here we hypothesize that "injection of PRP in the lesional skin of melasma patients is associated with alterations of TGF-ß protein expression".Patients and Methods: The study included 20 adult patients with melasma. Autologous PRP was delivered into the lesional skin either through microneedling or as intradermal microinjections. TGF-ß protein expression was immunohistochemically examined in the perilesional and lesional skins before and after PRP treatment and in the healthy skins of nine volunteers (control group).Results: TGF-ß protein was expressed within the epidermis, dermal adnexal structures, vascular endothelium, nerves and arrector pili muscle fibers of the healthy skins (control group), perilesional and lesional skins of melasma patients before and after treatment with PRP. Before treatment with PRP, the expression ofTGF-ß protein in the lesional (1.26 ± 0.41) and perilesional (1.68 ± 0.51) skins of melasma patients were significantly lower than that in the healthy skins (2.26 ± 0.37, p value<.05). After treatment with PRP, the expression of TGF-ß protein was significantly increased in the lesional (2.15 ± 0.44) skin of melasma patients.Conclusions: Our study provides the first indication about increased TGF-ß protein expression in skin of melasma patients after PRP treatment. The alterations of TGF-ß protein in skin of melasma patients not only support its roles in the development of this condition but also have some therapeutic ramifications.

Platelet-rich plasma is a useful therapeutic option in melasma.

Background: Melasma is a cosmetically disfiguring disorder of facial pigmentation. Objectives: We evaluated the value of platelet-rich plasma (PRP) in the treatment of melasma using two different delivery techniques: microneedling using dermapen versus microinjections using mesoneedles. Patients and methods: Twenty-three adult Egyptian melasma patients were enrolled. Wood's light was used to determine the histological type of melasma. Autologous PRP was delivered into the lesional melasma skins through microneedling with dermapen on the right side of the face and intradermal microinjections using mesoneedles on the left side of the face (for each patient). The treatment was done regularly (three sessions, each month). The response to PRP therapy was measured using melasma area and severity index (MASI) and modified melasma area and severity index (mMASI) that were calculated before and after three treatment sessions. Hemi-MASI was used to compare the effectiveness of the two delivery techniques. Results: Following PRP treatment, MASI and mMASI scores decreased significantly from 11.86 ± 5.25 to 6.96 ± 4.82, and from 5.71 ± 2.56 to 2.90 ± 2.05, respectively (p < .000,). A statistically significant decrease was noted in the hemi-MASI score on each side of the face following PRP treatment (p < .000), but there was no significant difference in comparing both sides. Conclusions: Our study provides the first indication about the value of PRP as a useful and new therapeutic option in melasma. Moreover, our study was the first to compare PRP delivery through microneedling versus microinjections.

Renal damage following Alloxan-induced diabetes is associated with generation of reactive oxygen species, alterations of p53, TGF-ß1, and extracellular matrix metalloproteinases in rats.

Renal damage is a common problem in diabetes. Alloxan, a potent hyperglycemic and diabetogenic molecule, can induce diabetes through oxidative stress-related mechanisms. Here, we hypothesize that "Alloxan-induced renal damage is associated with alterations of p53, TGF-ß1, and extracellular matrix metalloproteinases." To test our hypothesis, we established an animal model (male abino rats) and induced diabetes by intraperitoneal injection of Alloxan monohydrate. Rats with fasting blood glucose level ≥ 200 mg/dL were considered diabetic and were sacrificed after 14, 28, and 42 day intervals. Tissue levels of malondialdehyde and glutathione levels (markers of oxidative stress), and serum MMP-1 were measured. The expression patterns of p53, TGF-ß1were evaluated using Western blot and immunohistochemical methods. TIMP-1 expression pattern was determined using RT-PCR and immunohistochemical methods. Alloxan treatment induced histological features of renal damage (inflammation and fibrosis) and was associated with deterioration of the renal functions (elevated blood urea nitrogen and creatinin levels), hyperglycemia, and oxidative stresss (increased malondialdehyde and decreased glutathione levels). There was over-expression of the TGF-ß1 protein (profibrogenic protein), p53 (proapoptotic protein), and alterations of extracellular matrix proteins (low level of serum MMP-1 and over-expression of TIMP-1). Alterations of TGF-ß, p53, and extracellular matrix metalloproteinases contribute to the pathogenesis of Alloxan-induced renal damage.

Age-associated decrease in GDNF and its cognate receptor GFRα-1 protein expression in human skin.

Glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor (GFRα-1) are expressed in normal human skin. They are involved in murine hair follicle morphogenesis and cycling control. We hypothesize that 'GDNF and GFRα-1 protein expression in human skin undergoes age-associated alterations. To test our hypothesis, the expression of these proteins was examined in human skin specimens obtained from 30 healthy individuals representing three age groups: children (5-18 years), adults (19-60 years) and the elderly (61-81 years). Immunofluorescent and light microscopic immunohistologic analyses were performed using tyramide signal amplification and avidin-biotin complex staining methods respectively. GDNF mRNA expression was examined by RT-PCR analysis. GDNF mRNA and protein as well as GFRα-1 protein expressions were detected in normal human skin. We found significantly reduced epidermal expression of these proteins with ageing. In the epidermis, the expression was strong in the skin of children and declined gradually with ageing, being moderate in adults and weak in the elderly. In children and adults, the expression of both GDNF and GFRα-1 proteins was strongest in the stratum basale and decreased gradually towards the surface layers where it was completely absent in the stratum corneum. In the elderly, GDNF and GFRα-1 protein expression was confined to the stratum basale. In the dermis, both GDNF and GFRα-1 proteins had strong expressions in the fibroblasts, sweat glands, sebaceous glands, hair follicles and blood vessels regardless of the age. Thus there is a decrease in epidermal GDNF and GFRα-1 protein expression in normal human skin with ageing. Our findings suggest that the consequences of this is that GFRα-1-mediated signalling is altered during the ageing process. The clinical and therapeutic ramifications of these observations mandate further investigations.

Alterations of mTOR and PTEN protein expression in schistosomal squamous cell carcinoma and urothelial carcinoma.

BACKGROUND: mTOR signaling pathway is commonly activated in cancer. PTEN, a tumor suppressor gene, is a potent inhibitor of this pathway. To date the expression pattern of mTOR and PTEN in schistosomal bladder squamous cell carcinoma and urothelial carcinoma was not investigated. Also, whether alterations of these proteins are associated with pathological parameters was not established. HYPOTHESIS: We hypothesize that "expression of mTOR and/or PTEN will be altered in schistosomal-related urothelial and squamous cell carcinomas". PATIENTS AND METHODS: To test our hypothesis we examined the expression pattern of mTOR and PTEN in normal and hyperplastic urothelium, squamous metaplasia, schistosomal urothelial carcinomas (70 cases) and squamous cell carcinomas (47 cases) using immunohistochemical methods. RESULTS: mTOR protein expression was absent in the normal, hyperplastic urothelium and metaplastic squamous epithelium. mTOR was over-expressed in muscle invasive urothelial and high grade squamous cell carcinomas. In contrast, PTEN protein expression was seen in the normal and hyperplastic urothelium. The expression was reduced (metaplastic squamous epithelium) or lost in muscle invasive urothelial and high grade squamous carcinomas. Alterations of these proteins were associated with some clinicopathological features. mTOR expression was negatively correlated with PTEN expression in urothelial carcinoma only. CONCLUSIONS: We report, for the first time, altered expression of mTOR and PTEN proteins in schistosomal urothelial and squamous cell carcinomas. Alterations of these proteins may contribute to the progression and aggressive behavior of schistosomal bladder carcinoma. Targeting mTOR, may be a promising therapeutic strategy in these tumors.

Immunohistochemical Analysis of GDNF and Its Cognate Receptor GFRα-1 Protein Expression in Vitiliginous Skin Lesions.

BACKGROUND: Vitiligo is an idiopathic skin disease, characterized by circumscribed white macules or patches on the skin due to loss of the functional melanocytes. Glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor (GFRα-1) are distal members of the transforming growth factor-ß superfamily. GDNF, produced by the basal cell keratinocytes, is involved in the migration and differentiation of the melanocytes from the neural crest to the epidermis. This study examines the hypothesis that expression of GDNF protein and its cognate receptor GFRα-1 protein is altered in vitiliginous skin. PATIENTS AND METHODS: To test our hypothesis, we examined the expression patterns of these proteins in vitiliginous and corresponding healthy (control) skin biopsies (20 specimens each) using immunoperoxidase staining techniques. RESULTS: We found variations between the vitiliginous skin and healthy skin. In healthy skin, the expression of GDNF and GFRα-1 proteins was strong (basal cell keratinocytes and melanocytes), moderate (spinous layer), and weak (granular cell layer). In contrast, weak expression of GDNF protein was observed in all epidermal layers of vitiliginous skin. GFRα-1 protein expression was strong (basal cell keratinocytes and melanocytes), moderate (spinous layer), and weak (granular cell layer). In both healthy skin and vitiliginous skin, the expression of GDNF and GFRα-1 proteins was strong in the adnexal structures. CONCLUSIONS: We report, for the first time, decreased expression of GDNF proteins in the epidermal keratinocytes of vitiliginous skin. Our findings suggest possible pathogenetic roles for these proteins in the development of vitiligo. The clinical ramifications of these observations mandate further investigations.

Drug-induced skin reactions: a pathologist viewpoint.

Cutaneous drug reactions are common adverse effects that occur in about 2-3% of the hospitalized patients. They have both immunologic and non-immunologic underlying mechanisms. These reactions are clinically and histologically similar to dermatoses. Their significant clinical indicators include: history of drug intake, atypical clinical features and improvement after cessation of the offending drugs. Their diagnostic histological clues include the presence of mixed histological patterns, apoptotic keratinocytes, eosinophils (dermis and epidermis), papillary dermal edema and extravasations of erythrocytes. However, no single clinical or histological feature is specific of drug eruptions. This work attempts to classify the histomorphologic reactions to various drugs in defined categories for assistance in morphologic diagnosis.

Mesenteric panniculitis: an update.

In 1924, mesenteric panniculitis was first described in the medical literature by Jura et al. as 'retractile mesenteritis.' It represents a spectrum of disease processes characterized by degeneration, inflammation and scarring of the adipose tissue of the mesentery. The clinical presentations vary according to the stage of the disease and they include abdominal pain, weight loss, nausea and vomiting. Computed tomography findings are usually diagnostic. The gross findings include thickening of the mesentery, mass lesions and adhesion to the surrounding organs. Histologically, there is a chronic inflammatory process involving the adipose tissue with fat necrosis, inflammation and fibrosis. Herein, the authors address the clinicopathological features, course, treatment and pathogenetic mechanisms of mesenteric panniculitis.

Atypical fibroxanthoma: new insights.

Atypical fibroxanthoma (AFX) is an ultraviolet radiation-associated dermal neoplasm. To address the clinicopathologic and molecular features of this particular neoplasm. The author conducted a literature review using PubMed searching for articles relating to AFX. AFX usually appears as a rapidly growing nodular or nodulo-ulcerative lesion. It occurs on sun-exposed skin of elderly peoples. AFX may be composed predominantly of pleomorphic, spindle, epithelioid cells, or admixture of these cells. The differential diagnosis of AFX includes pleomorphic dermal sarcoma, squamous cell carcinoma, malignant melanoma and leiomyosarcoma. Several observations favor a mesenchymal origin for AFX. These reviews address the clinicopathologic features, molecular pathology, prognosis and treatment of this neoplasm.

Cutaneous pseudolymphomas: inflammatory reactive proliferations.

Skin is an organ of the immune and lymphoid systems. Lymphoid tissue analogous to gut mucosa-associated lymphoid tissue proliferates in the skin in response to antigenic stimulation. This putative skin-associated tissue is called skin-associated lymphoid tissues (SALT). In the opinion of this author, cutaneous pseudolymphomas represent inflammatory, reactive proliferations of SALT following antigenic stimulation of the cutaneous immune cells. Cutaneous pseudolymphomas commonly involve the exposed areas such as head and neck region and upper extremities. They appear as localized nodules, plaques or noduloplaques. They include B- and T-cell pseudolymphomas. Their histologic patterns include nodular, diffuse, band-like and folliculitis-like morphology. Most pseudolymphomas are idiopathic, but some are secondary to known etiologies (drug intake, arthropod assaults, infectious agents and traumas). Cutaneous pseudolymphomas are usually polyclonal proliferations that regress spontaneously or after treating the underlying etiology. Rare cases harbor clonal lymphoid populations and can progress to low-grade lymphomas. Herein, the author reviews the etiology, clinicopathologic features and diagnosis of the cutaneous pseudolymphomas.