A new paradigm for epidermal growth factor receptor expression exists in PTC and NIFTP regulated by microRNAs.

Intoduction: Identification of molecular alterations associated with tumor behavior is necessary to guide clinical management. The 2022 WHO classification has organized the thyroid follicular cell-derived neoplasms into benign, low-risk and high-risk neoplasms, and emphasized the value of biomarkers that may provide differential diagnostic and prognostic information to avoid overtreatment of low risk neoplasms. This work aims to study the epidermal growth factor receptor (EGFR) expression, functional and spatial dynamics in relation to specific miRNAs alterations in papillary thyroid cancer (PTC) and in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) considered as models of high-risk and low-risk thyroid tumors respectively. Methods: Primary thyroid cultured cells were used for miRNA gain/loss of function and luciferase reporter assays. Paraffin embedded tissues were used for real time PCR, immuno-fluorescence stain and confocal microscopy experiments. Results: Our results showed that in PTC, EGFR mRNA is reduced as an effect of miR-146b-5p upregulation. The EGF expression is low and the ERK pathway is inhibited. The EGFR protein high cytoplasmic expression and colocalization with the endosomal/exosomal markers, ALIX and CD63, suggest the occurrence of stress-induced EGFR internalization, accumulation in endosomal vesicles and secretion via exosomes. In NIFTP EGFR transcription is increased in association with downregulation of miR-7-5p and the EGFR/ERK pathway is active indicating dependence on the canonical EGFR pathway for growth. Conclusion: Downregulation of transcript level along with cytoplasmic accumulation of undegraded protein is a new pattern of EGFR regulation associated with malignancy in thyroid. Further research is needed to elucidate the intracellular trafficking defects responsible for this specific EGFR dynamic in PTC.

Spindle Epithelial Tumor With Thymus-Like Differentiation (SETTLE) Misdiagnosed as Papillary Thyroid Carcinoma: A Case Report.

Spindle epithelial tumor with thymus-like differentiation (SETTLE), a rare tumor of the thyroid gland, is difficult to diagnose irrespective of its unique morphology. It is usually misdiagnosed as synovial sarcoma, thymoma, teratoma, or other thyroid carcinomas. In the current case report, we detail a case of a 36-year-old male patient who presented with thyroid swelling that was initially misdiagnosed as papillary thyroid carcinoma instead of SETTLE. Based on fine needle aspiration, the tumor showed a variable pattern with features suggestive of follicular neoplasm in the right lobe and atypia of undetermined significance in the left lobe. Pathological examination showed multiple nodules on both the right and left lobes, with the largest nodule measuring 4.8 x 4.5 x 3 cm. On microscopic examination, a predominant papillary pattern was observed along with spindle cell areas. Immunohistochemistry revealed positive staining for thyroglobulin, CK, HMWCK, CD99, and BCL-2, which led to the diagnosis of SETTLE. The rare nature of the condition and the reduced awareness about it make this tumor a diagnostic challenge. This case report concludes that in case of any biphasic tumor with epithelial and spindle cells in the thyroid gland, it is important to consider the differential diagnosis of SETTLE. Immunohistochemistry is more useful for diagnosing SETTLE, and thus pathologists are encouraged to judiciously advise the patients for immunohistochemistry to establish accurate and efficient diagnosis.

The stress-activated protein kinase pathway and the expression of stanniocalcin-1 are regulated by miR-146b-5p in papillary thyroid carcinogenesis.

Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. Deciphering the pathophysiological mechanisms that contribute to PTC development is essential to the discovery of optimal diagnostic and therapeutic approaches. MiR-146b-5p has been identified as a cancer-associated microRNA highly up-regulated in PTC. This study explores the hypothesis that miR-146b-5p contributes to papillary thyroid carcinogenesis through regulation of cell signaling pathways in a manner that overcomes the cellular growth suppressive events and provides survival advantage. The effect of miR-146b-5p inhibition on major cancer related signaling pathways and expression of Stanniocalcin-1 (STC1), an emerging molecule associated with stress response and carcinogenesis, was tested in cultured primary thyroid cells using luciferase reporter assays, quantitative real-time PCR, immunofluorescence staining, and flow cytometry. Our results demonstrated that miR-146b-5p inhibits the JNK/AP1 pathway activity and down-regulates the expression of STC-1 in thyroid-cultured cells and in thyroid tissue samples. In the presence of miR-146b-5p, PTC cells were resistant to cell death in response to oxidative stress. This is a novel report that miR-146b-5p directly targets STC1 and regulates the activity of JNK/AP1 pathway. Considering the importance of the JNK/AP1 pathway and STC1 in mediating many physiological and pathological processes like apoptosis, stress response and cellular metabolism, a biological regulator of these pathways would have a great scientific and clinical significance.

Down-regulation of the human major histocompatibility complex class I chain-related gene A (MICA) and its receptor is mediated by microRNA-146b-5p and is a potential mechanism of immunoediting in papillary thyroid carcinoma.

Immune escape is one of the main reasons for the rapid progression of cancer and the poor efficacy of immunotherapy. Papillary thyroid cancer (PTC) is usually accompanied by intra-tumoral lymphocytic infiltration. The mechanisms regulating this tumor associated immune response or its evasion are not well understood. The major histocompatibility complex class I chain-related proteins A (MICA) and its receptor the natural killer group 2 member D (NKG2D) are major executers of the anti-tumor defense. This work aimed to study the expression and regulation of MICA-NKG2D and its association with the lymphocytic infiltration and miRNAs in PTC. Expression of MICA and NKG2D in thyroid tissues, and in cultured primary thyroid cancer cells and lymphocytes transfected with miR-146b-5p inhibitor/mimic was tested by RT-PCR. Results were confirmed by immunofluorescence staining and confocal microscopy. MICA is expressed in malignant and benign thyroid tissues with no association with aggressive behavior. Expression of MICA and NKG2D in PTC is concomitant with the presence of tumor associated lymphocytic response and is regulated by miR-146b-5p. MiR-146b-5p indirectly downregulates NKG2D expression in cancer cells and in lymphocytes. Overexpression of miR-146b-5p in PTC down-regulates MICA expression possibly to reduce the immunogenicity of the tumor cells. Targeting of the MICA-NKG2D axis by miR-146b-5p might be one of the ways adopted by thyroid cancer cells to aid the tumor in evading the immune response. The importance of our findings resides in the potential therapeutic use of MICA, NKG2D and miRNA-146b-5p as targets or modulators to enable the immune response against cancer.

Osseous Metaplasia of the Cervix: A Rare Transformation Can Mimic a Tumor-Literature Review.

BACKGROUND: The transformation of nonosseous soft tissue into bone is known as osseous metaplasia (OM). This condition most commonly affects the musculoskeletal and central nervous systems and it is a well-known phenomenon in different soft tissue organs. Rarely, OM can affect the uterus, which can extend into the cervix. OM affecting the cervix alone is a more rare condition that has multiple different clinical presentations. The presentation can be similar to that of a tumor in extremely rare cases. CASE SUMMARY: A 23-year-old nulligravida was complaining of irregular vaginal bleeding for one-month duration. Speculum examination revealed a foul-smelling bloody purulent discharge, tender cervix, and a brownish growth located at the posterior cervical lip. A punch biopsy of the growth was performed. Histological examination of the tissue revealed multiple bone fragments with necrosis and an inflammatory exudate. Because of the unusual findings, a repeat biopsy was performed. The biopsy yielded the same findings, which confirmed the diagnosis of osseous metaplasia of the cervix. CONCLUSION: Although osseous metaplasia is a known phenomenon in different soft tissues, it is extremely rare in the uterine cervix and can mimic malignancy. Therefore, clinicians should be aware of it.

Discriminatory miRNAs for the Management of Papillary Thyroid Carcinoma and Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features.

BACKGROUND: Papillary thyroid carcinoma (PTC) variants have several overlapping clinical and pathological features. The World Health Organization recently published a new classification of thyroid tumors containing significant revisions. Encapsulated papillary thyroid carcinoma (EPTC) has been recognized as a distinctive variant of PTC. The noninvasive encapsulated follicular variant of PTC has been reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Different neoplasms are associated with different outcomes and require different clinical management. The objective of this study was to explore the miRNA expression patterns specific for classic PTC (cPTC), EPTC, follicular variant of PTC, and NIFTP in order to identify biomarkers of diagnostic and prognostic utility aiming for better clinical decisions. METHODS: The expression of 84 miRNAs was determined by quantitative real-time polymerase chain reaction in 113 thyroid tissues of PTC (classic, encapsulated, and follicular), NIFTP, and hyperplasia lesions. Expression of the same miRNAs was tested in pre- and postoperative whole-blood samples. RESULTS: Several miRNAs were differentially expressed in the different groups. Expression profile of miRNAs in the tissue was similarly reflected in the circulation. Receiver operating characteristic curve analysis showed that miR-7-5p, miR-222-3p, and miR-146b-5p can discriminate between the different groups with high sensitivity and specificity. Downregulation of miR-144-3p, miR-15a-5p, miR-20a-5p, miR-32-5p miR-142-5p, miR-143-3p, and miR-20b-5p is associated with aggressive behavior in cPTC. Circulating miR-146b-5p, miR-222-3p, miR-155-5p, and miR-378a-3p are potential diagnostic and follow up biomarkers for PTC. CONCLUSION: Downregulation of miR-7-5p discriminates NIFTP from hyperplasia. Upregulation of miR-222-3p discriminates follicular variant of PTC from NIFTP. High levels of miR-146b-5p distinctively characterize cPTC. These miRNAs are useful biomarkers in the diagnosis of PTC and NIFTP, and help to avoid unnecessary thyroidectomy and improve clinical management.

Clinicopathological study of 25 cases of diverticular disease of the appendix: experience from farwaniya hospital.

Background. Diverticular disease of the appendix (DDA) is a rare disease and it has been shown to be associated with locoregional neoplasms. This study was conducted to characterize clinicopathological features and to investigate its association with appendiceal neoplasms. Methods. We searched the records of the Department of Pathology at Farwaniya Hospital for cases of diverticular disease of the appendix between 2003 and 2011. Histological slides and patient charts were reviewed for relevant information. Consecutive cases of acute appendicitis were selected as a control group. Results. We identified 25 cases of DDA, 24 of which occurred in men. Mean age of DDA patients was 35 ± 10.1 years and was significantly greater than that of appendicitis patients (P = 0.027). The mean temperature of cases (37.9°) was significantly higher (P = 0.012) than that of the controls (37.3°). The cases had lower white blood cell (WBC) counts compared to controls (13.6 versus 16.7, P = 0.04). Pathological diagnosis identified 4 cases of diverticulosis, 5 cases of diverticulitis, 6 cases of diverticulosis with acute appendicitis, and 10 cases of diverticulitis and appendicitis. None of the cases was associated with any type of neoplasm. Conclusions. DDA is a rare disease, and clinicians and radiologists should be aware of it. Male sex and adult age seem to be risk factors associated with DDA. The disease may not have any direct association with any neoplasm.

Tonsillar Kaposi sarcoma in a patient with membranous glomerulonephritis on immunosuppressive therapy.

Kaposi sarcoma is a malignant vascular neoplasm uncommonly seen in immunosuppressed patients. Herein we report an unusual case of tonsillar Kaposi sarcoma in a patient with membranous glomerulonephritis treated with prednisolone and cyclosporine. The patient presented after 10 months of starting the treatment with a tonsillar mass. Histological examination was typical of monomorphic spindle cell proliferation with slit-like vascular channels. The tumor cells expressed CD34, D2-40 and positive nuclear stain for HHV-8. Kaposi sarcoma is associated with immunosuppression and rarely occurs in the tonsil. Clinicians should be aware of this rare presentation of Kaposi sarcoma.

Gastric carcinoid and obesity: association or coincidence? Report of two cases and literature review.

Bariatric surgery is a prevalent procedure due to the high incidence of obesity and comorbidities. Upper gastrointestinal endoscopy is one of the procedures used to evaluate the patient before surgery. However, its role is questionable. The incidental findings during endoscopy are variable including inflammatory diseases, and ulcers, and epithelial and stromal tumors. Herein a report of two obese sisters with incidental gastric carcinoids was diagnosed in prebariatric surgery endoscopy. Case Summary. 35- and 41-year-old female patients presented with obesity and BMI of 102 and 46 kg/m(2), respectively. Both patients underwent upper gastrointestinal endoscopy as part of presurgical evaluation. Multiple polyps were indentified in both patients, and biopsy was taken. Histological examination revealed tumors that were formed by nests of epithelial cells. The cells have eosinophilic cytoplasm and monomorphic nuclei, typical morphology of neuroendocrine tumors. Conclusions. (1) Upper gastrointestinal endoscopy is an important procedure for prebariatric surgery evaluation. (2) Gastric carcinoid is a rare tumor with higher incidence among obese patients.

WITHDRAWN: Syringoma: the clear cell variant made clearer.

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Cutaneous angiomyxoma and pilomatricoma: a new combination.

Superficial angiomyxomas are rare benign tumors that typically present as a solitary lesion or as a component of Carney complex and rarely have been associated with other lesions. In this article, we report 3 cases of an unusual association of superficial angiomyxoma with pilomatricoma. This combination has never been described in the literature. The 3 patients presented with variable-sized pedunculated, asymptomatic skin papules overlying firm deeply situated nodules. Histopathologic examination demonstrated that the superficial pedunculated lesion is a superficial angimyxoma with underlying pilomatricoma. Thorough clinical examination failed to reveal any further lesions. We present a rare and unique combination of angiomyxoma and pilomatricoma. This combination may be incidental, representing collision tumors or etiologically related.

Endoscopic nodular gastritis in dyspeptic adults: prevalence and association with Helicobacter pylori infection.

OBJECTIVE: To determine the prevalence and histological features of endoscopic nodular gastritis (NG) in adult dyspeptic patients and its relation to Helicobacter pylori infection. SUBJECTS AND METHODS: A retrospective endoscopic report review of 2,142 patients identified 67 patients with NG during the period from 1 September 2006 to 31 August 2007. A subset of 32 NG patients (group 1) who had had gastric biopsies during upper gastrointestinal endoscopy and had been evaluated for H. pylori infection were compared to 32 age- and gender-matched dyspeptic patients. They had undergone endoscopy during the same period, which yielded normal results, and had available biopsies that were similarly evaluated for H. pylori infection (controls, group 2). Pertinent clinical data were obtained from the patients' records. An experienced pathologist assessed the biopsies for the presence and grade of inflammation, activity, glandular atrophy, intestinal metaplasia, presence and density of H. pylori and presence of lymphoid follicles or aggregates. RESULTS: NG was identified in 67 (3.1%) patients. On histological examination, group 1 had a significantly higher grade of gastritis (p < 0.001). The presence and density of H. pylori infection was significantly higher in group 1 (p < 0.001). The H. pylori density correlated significantly with the severity of gastritis (r = 0.57, p < 0.001). The endoscopic performance of NG on H. pylori infection had high specificity (96.8%) and positive predictive value (93.3%). CONCLUSION: This study outlined the clinicopathological features of NG identified among a cohort of dyspeptic patients in Kuwait and confirmed the close association with H. pylori infection. However, our study has a limitation in that histopathologic assessment of all NG patients was not feasible.

Solitary rectal ulcer syndrome: a clinicopathological study of 13 cases.

BACKGROUND/AIMS: Solitary rectal ulcer syndrome (SRUS) is a rare disorder that has a wide spectrum of clinical presentation and variable endoscopic findings. To further characterize the clinical and pathological features, a retrospective, hospital-based clinicopathological study was conducted. MATERIALS AND METHODS: All cases of SRUS diagnosed at Farwania Hospital, Kuwait, between 2002 and 2007 were retrieved from the computerized filing system. The histological slides were reviewed by two authors to confirm the diagnosis. Immunohistochemical stain for smooth muscle actin (SMA) was performed. The clinical files were reviewed for clinical features and endoscopic findings. RESULTS: Thirteen cases were identified: 8 males and 5 females. The age range was 15-85. Rectal bleeding, constipation, and abdominal pain were the most common presenting symptoms and were seen, either alone or in various combinations, in 12 of the 13 cases. Rectal ulceration was the most common endoscopic finding, being seen in 9 of the 3 cases; 3 of these cases had multiple ulcerations. Two patients had rectal polyps, with one of them having multiple polyps. The histological examination revealed surface serration, fibromuscular obliteration of the lamina propria, and crypts' distortion in all the cases. Seven of the cases had diamond crypts. Ectatic mucosal vessels were a common finding. Positivity for SMA in the lamina propria was seen in all examined cases. CONCLUSION: SRUS is a rare disorder and only 13 cases were diagnosed in Farwania hospital over a 6-year period. The clinical presentation of our patients was variable. The presence of polyps and multiple ulcerations on endoscopy is further evidence that SRUS is a misnomer. Surface serration, fibromuscular obliteration, and crypts' distortion are the most characteristic features. The presence of diamond crypts is an additional diagnostic feature.

Ossifying fibromyxoid tumor of soft parts. Report of a rare tumor in Kuwait.

OBJECTIVE: To report a rare case of ossifying fibromyxoid tumor of soft tissue in Kuwait. CLINICAL PRESENTATION AND INTERVENTION: A 60-year-old woman presented with a painless tumor, increasing in size and located in the left buttock, which had been present for an uncertain duration. The patient underwent an excisional biopsy. Pathological examination revealed a 7.5-cm well-circumscribed mass with a lobulated cut surface. Histologically, the tumor was encapsulated by an incomplete shell of lamellar bone. The tumor had variable cellularity, and, in areas, contained myxoid stroma. The tumor cells had eosinophilic cytoplasm with vesicular round-to-oval nuclei. Sparse mitoses were noted. Immunohistochemical stains demonstrated that the tumor cells expressed vimentin, S100 and neuron-specific enolase, with the latter expressed focally. CONCLUSION: To the best of our knowledge, this is the first case of ossifying fibromyxoid tumor of soft parts to be reported in Kuwait. Therefore, pathologists and clinicians should be aware of this tumor.

Myelolipoma with adrenocortical adenoma: an unusual combination that can resemble carcinoma.

Myelolipoma is a benign tumor that occurs in the adrenal gland and rarely in extra-adrenal sites. Commonly, it is diagnosed as an incidental finding. However, some reports indicate synchronous occurrence with other lesions including adrenocortical carcinoma. It has very rarely been reported to occur in association with adrenocortical adenoma. In this paper, we report three cases of adrenal myelolipoma associated with adrenocortical adenoma; in all three patients, the radiological appearance resembled adrenocortical carcinoma. These cases emphasize the importance of this combination as a pitfall in the correct diagnosis and management of patients with adrenal masses.

Giant fibroepithelial polyp of the penis associated with long-term use of condom catheter. Case report and literature review.

BACKGROUND: A condom catheter is a commonly used drainage system for incontinent patients. However, it is associated with different complications including infection and erosion. One very rare complication that has been recognized is the development of giant fibroepithelial polyps in the penis; to date, to the best of our knowledge, seven cases have been reported in the literature. We report a new case of giant fibroepithelial polyp associated with long-term condom catheter use. CASE SUMMARY: A 43-year-old incontinent man who had been using a condom catheter for 14 years following a motor vehicle accident presented with a mass on the ventral aspect of his penis; the mass had appeared a year ago. The patient underwent excisional biopsy. Grossly, there was a mass with a maximum dimension of 4.0 cm, which had an irregular surface. Histological examination revealed a fibroepithelial polyp with vascular proliferation and edematous stroma with prominent bundles of smooth muscle. Perivascular lymphoid aggregates were seen. The morphology was similar to that in the previously reported cases; the presence of smooth muscle was distinct. CONCLUSION: Giant fibroepithelial polyps can be associated with long-term condom catheter use and pathologists and urologists should be aware of this rare complication as their size can mimic carcinoma.

Complex endocrinopathies in MEN-1: diagnostic dilemmas in endocrine oncology.

Endocrine oncology is a complex area that must determine the site of a neoplastic process and the hormonal dysregulation that ensues. Patients with endocrine tumors often have delayed diagnosis because of the nonspecific and often subtle signs and symptoms. In patients with multiple endocrine neoplasia syndromes, diagnosis and clinicopathologic correlations can be even more challenging. We report a patient with multiple endocrine neoplasia type 1 (MEN-1) and a highly complex clinical story associated with multiple atypical lesions including two pituitary adenomas, a gonadotroph macroadenoma and a corticotroph microadenoma with Crooke's hyaline change and ectopic production of corticotropin-releasing hormone (CRH) from a thymic endocrine carcinoma. These lesions resulted in a highly complex clinical story, difficult diagnoses and questions about management. This case illustrates a number of clinically relevant challenges, including the diagnosis of pituitary adenomas in MEN-1, the difficulty in diagnosing Cushing's disease, and the large differential of pituitary pathologies in this disorder, double pituitary adenomas and other decoy lesions in Cushing's disease, the pathophysiology of Crooke's hyaline change in the pituitary, and the various causes of Cushing's syndrome associated with MEN-1.

Lipomembranous panniculitis: report of a case.

Lipomembranous panniculitis is a peculiar type of fat necrosis and has been reported with several clinical conditions, commonly with peripheral vascular diseases. We are reporting a case of a 68-year-old woman with known liver cirrhosis and diabetes who presented with painful erythematous swelling of the right leg. Histological examination revealed microcystic changes within the subcutaneous fat. The microcysts were lined by acellular, eosinophilic membrane forming pseudopapillae and stained with periodic acid-Schiff stain. This histological feature is diagnostic of lipomembranous panniculitis. The pathologists should be aware of this entity because it aids the clinicians in investigating for associated clinical disorders.