Do Histologically Aggressive Subtypes of Papillary Thyroid Microcarcinoma have Worse Clinical Outcome than Non-Aggressive Papillary Thyroid Microcarcinoma Subtypes? A Multicenter Cohort Study.

Histologically aggressive micropapillary thyroid carcinomas (PTMC) subtypes are thought to be associated with an aggressive clinical course. However, evidence for unfavorable clinical outcomes in patients with aggressive PTMC subtypes is not clear. In this study, we intended to determine the difference in clinical outcomes between patients with aggressive and non-aggressive PTMC subtypes. In this multicenter cohort study, the computer-recorded clinical and histopathological data of patients who underwent thyroid surgery between January 2000 - January 2021 in 9 referral centers and were diagnosed as PTMC were analyzed. A total of 1585 patients [female 1340 (84.5%), male 245 (15.5%), mean age 47.9±11.63 years), with a mean follow-up time of 66.55±37.16 months], were included in the study. Ninety-eight cases were diagnosed as aggressive and 1487 as non-aggressive subtypes. Persistent/recurrent disease was observed in 33 (33.7% )and 41 (2.8%) patients with aggressive and non-aggressive subtypes (p<0.001). Diseases-free survival rates were markedly lower in patients with aggressive than in those with non-aggressive PTMC subtypes (66.3 vs. 94.8%, log-rank p<0.001). Moreover, in multivariate analysis, aggressive histology was an independent predictor of persistent/recurrent disease, after controlling for other contributing factors (HR 5.78, 95% CI 3.32-10, p<0.001). Patients with aggressive PTMC subtypes had higher rates of incomplete biochemical and structural response than patients with non-aggressive subtypes as well (p<0.001). Aggressive PTMC subtypes share many characteristics with histologically identical tumors>1 cm in size. Therefore, the histopathological subtype of PTMC should be taken into consideration to tailor a personalized management plan.

Diagnostic value of TROP-2 expression in papillary thyroid carcinoma and comparison with HBME-1, galectin-3 and cytokeratin 19.

In this study, we compared the diagnostic value of TROP-2 expression in distinguishing between benign and malignant thyroid lesions to those of HBME-1, CK19 and galectin-3. We selected 102 cases from our archive including 20 normal thyroid tissues, 23 follicular nodular diseases, 17 follicular adenomas, 20 follicular variant papillary carcinomas and 22 classical variant papillary carcinomas. Tissue microarrays constructed from these cases were immunohistochemically analyzed with HBME-1, CK19, galectin-3 and TROP-2. Respectively 73.8%, 83.3%, 69% and 50% of all papillary carcinomas were positive with HBME-1, CK19, galectin-3 and TROP-2. CK19 was positive respectively by 100%, 43.5% and 35.3% in cases of normal thyroid, follicular nodular diseases and follicular adenoma, while the other markers were negative. In distinguishing benign and malignant lesions, which constitutes this study, HBME-1, CK19, galectin-3 and TROP-2 were statistically significant (p < 0.001). In distinguishing cases of follicular variant papillary carcinoma from follicular nodular diseases and follicular adenoma, HBME-1 and galectin-3 were statistically significant (p < 0.001). Consequently, in this study, we found that all immunohistochemical markers were effective in distinguishing benign and malignant thyroid lesions. In determining malignancy, HBME-1 had the highest diagnostic accuracy, while CK19 was the most sensitive marker. The sensitivity increased when the markers were used together.

Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies.

Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.

Prevalence of Papillary Thyroid Carcinoma is Significantly Higher in Graves Disease with Synchronous Thyroid Nodules.

OBJECTIVE: The association between autoimmunity-related tissue injury and thyroid cancer development remains an area of interest. Evidence suggests that patients with Graves disease (GD) may have an elevated risk for differentiated thyroid cancer. Multicenter studies are needed to gain insight into the correlates of papillary thyroid carcinoma (PTC) identified in this particular group of patients. This study aimed to investigate the prevalence of PTC and synchronous thyroid nodules in thyroidectomy specimens from GD patients in an endemic goiter region. MATERIAL AND METHODS: A retrospective review of institutional pathology records at two tertiary care centers identified 237 surgically treated patients with GD. Patients were categorized as having nodular Graves disease (N-GD) if synchronous nodular thyroid was identified by ultrasonography, while those without synchronous thyroid nodules were categorized as non-nodular or simple Graves disease (S-GD). The prevalence of PTC, histopathological correlates, and demographic characteristics were recorded and compared between groups N-GD and S-GD. RESULTS: One hundred thirty-one and 106 patients were assigned to N-GD and S-GD, respectively. The mean age was significantly higher in N-GD (mean 45.52 years) compared to S-GD (mean 35.18 years) (p < 0.001). The overall frequency of PTC was 36.3% (86/237) in the entire cohort. PTC was identified in 48.1% (63/131) of N-GD and 21.7% (23/106) of S-GD (p < 0.001). Subcentimeter tumors constituted the majority of cases in both groups (76.2% in N-GD and 82.6% in S-GD) (p > 0.05). The group of S-GD was enriched in BRAF-like PTCs, whereas N-GD had equal distribution for RAS- and BRAF-like tumors. CONCLUSION: This study underscores that the majority of PTCs encountered in GD were enriched in low-risk subcentimeter PTCs with a prevalence that varies depending on the presence of underlying nodular thyroid tissue.

Clinical and histopathologic differential diagnosis of venous malformation of the uterine cervix.

OBJECTIVE: Venous malformations of the uterine cervix are extremely rare. Most lesions are asymptomatic and incidental, but sometimes, they may present with abnormal and/or intractable vaginal bleeding. The study aimed to describe a case of venous malformation of the uterine cervix and discuss the clinical and histopathologic differential diagnosis of this entity. CASE: A 50-year-old woman attended to the gynecology clinic for postcoital spotting and postmenopausal bleeding. Gynecologic examination revealed polypoid, lobulated, bluish, vascular nodular lesions 4 to 1 cm in size surrounding the cervical introitus. The lesions were completely excised via loop electrosurgical excision procedure method. Pathologic diagnosis revealed venous malformations of the uterine cervix. CONCLUSIONS: Venous malformations of the uterine cervix should be considered in the differential diagnosis of patients with cervical mass and vaginal bleeding. Pathologic examination is necessary in such a case to exclude the possibility of malignant vascular tumor or cervical neoplasm.

The Significance of Unsampled Microscopic Thyroid Carcinomas in Multinodular Goiter.

Thorough gross examination and appropriate sampling of the thyroidectomy specimens are fundamental to the diagnosis and clinical risk management of patients. This study aims to investigate the frequency and clinical significance of initially unsampled microscopic thyroid carcinomas in total thyroidectomy specimens with presumed benign multinodular thyroid disease. Seventy-two total thyroidectomy specimens belonging to multinodular goiter patients were randomly selected and included in this prospectively designed study. Inclusion criteria were set as no suspicion of malignancy before surgery as well as lack of intra-parenchymal primary thyroid carcinoma after histopathological evaluation of slides generated from initial sampling. Subsequently, the remaining thyroidectomy specimens were submitted for microscopic examination and sign-outs were finalized following the microscopic examination of the entire thyroid tissue. Microcarcinomas, with a maximum diameter of 3.5 mm, were detected in 29 cases (40.2%) after the whole gland sampling. Although most of these tumors were low-risk papillary microcarcinomas confined to the thyroid, one specimen also showed a medullary microcarcinoma measuring 1.5 mm. Three had micrometastatic nodal disease. There was no local recurrence or distant metastatic disease during the follow-up (mean 51.4 months). This study further supports microscopic carcinomas, including papillary microcarcinoma, and medullary microcarcinoma might stay hidden in thyroidectomy specimens. Increased glandular weight, male gender, and advanced age were significant risk factors in the detection of microcarcinomas in this series. While each multinodular thyroidectomy specimen is unique, we recommend dynamic extensive sampling (rather than bare-minimum approach) strategy based on careful gross and initial histologic examination findings as well as by taking into consideration risk factors.

A case with multisystemic involved of Tuberculosis.

Cases of tuberculosis with multisystemic involvement are rarely reported and these are often children and patients with AIDS whose and immune system is suppressed. Tuberculosis can mimic and present with various disorders. A 18-year-old Georgian male patient was admitted to the hospital with double vision, swelling and wound on the 3rd digit of the right hand. We defined the multisystemic tuberculous disease including orbital bone with soft tissue tuberculosis, tuberculosis spondylitis, tuberculosis dactylitis, scrofuloderma and pulmonary tuberculosis in these patient.

Heterotopic pancreatic tissue located in the gallbladder wall. A case report.

CONTEXT: Heterotopia of the pancreas can be defined as the presence of pancreatic tissue in an abnormal location without any continuity with the main body of the pancreas. Heterotopic pancreatic tissue located in the gallbladder is a rare entity. Despite being a congenital condition, it takes years for heterotopic pancreas to become symptomatic. CASE REPORT: An 80-year-old male patient presented to our hospital with a two-week history of abdominal pain, nausea and vomiting aggravated after meals. Abdominal ultrasonography revealed minimal wall edema and small grain-sized gallstones in the gallbladder. The patient was hospitalized and laparoscopic cholecystectomy was performed for acute cholecystitis. Pathologic examination showed a 6 mm nodular mass of pancreatic tissue in the gallbladder wall, comprised mainly of ductal and acinic structures and a few endocrine cells. CONCLUSION: We found this case of pancreatic heterotopia worth reporting because of its rare incidence.

Do You Know the Details of Your PAX8 Antibody? Monoclonal PAX8 (MRQ-50) Is Not Expressed in a Series of 45 Medullary Thyroid Carcinomas.

Medullary thyroid carcinomas display cytologic and architectural features that can simulate various primary and metastatic neoplasms. PAX8 immunoexpression in neuroendocrine neoplasms yielded antibody-dependent findings. Since the data regarding the expression profile of monoclonal PAX8 (MRQ-50) antibody is limited in large series of medullary thyroid carcinomas, this study investigated the expression profile of PAX8 (MRQ-50) in a series of 45 medullary thyroid carcinomas. PAX8 (MRQ-50) expression was noted in the thyroid follicular epithelial cells surrounding the tumor and was negative in all medullary thyroid carcinomas. In addition, twenty medullary thyroid carcinomas showed scattered entrapped thyroid follicular epithelial cells at the periphery of the tumor. Entrapped follicular epithelial cells were positive for PAX8 and thyroglobulin, and were negative for monoclonal CEA and calcitonin. A panel approach combining monoclonal antibodies to transcription factors, hormones and cell-specific peptides often assist diagnosticians in the workup of the cellular origin of a neuroendocrine neoplasm. Since PAX8 immunostaining is dependent on the antibody characteristics in neuroendocrine neoplasms, pathologists should be aware of the details of the PAX8 antibody used in a particular case.

Immunohistochemical Analysis of the Metabolic Phenotype of Adrenal Cortical Carcinoma.

Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (n = 42), adrenal cortical adenoma (ACA; n = 50), and normal adrenal cortical tissue samples (n = 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (p < 0.001 and p = 0.014, respectively) or normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (p = 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (p = 0.003) or normal adrenal cortical tissue samples (p = 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (p < 0.001 and p = 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.

Positivity for GATA3 and TTF-1 (SPT24), and Negativity for Monoclonal PAX8 Expand the Biomarker Profile of the Solid Cell Nests of the Thyroid Gland.

Solid cell nests (SCNs) are usually distinguished on conventional H&E-stained sections; however, the morphological heterogeneity in SCNs and hyperplasia of these ultimobranchial body remnants can mimic other diagnostic entities including but not limited to papillary microcarcinoma. In order to confirm the thyroid follicular epithelial origin and exclude the possibility of SCNs, most diagnosticians use immunohistochemical biomarkers of thyroid follicular epithelial cells and/or those of SCNs. While the expression profile of monoclonal PAX8 has not been reported previously in SCNs, the status of TTF-1 expression using the 8G7G3/1 clone has been inconsistent among several studies. Given the potential diagnostic pitfalls, this series investigated the expression profile of GATA3, monoclonal PAX8, and TTF-1 (SPT24), along with p63, p40, monoclonal calcitonin, monoclonal CEA, and HBME-1 in a tissue microarray (TMA) of 56 SCNs. SCNs were all diffusely and strongly positive for TTF-1 (SPT24), p63, and p40, and were negative for monoclonal PAX8 and calcitonin. Positivity for GATA3 and monoclonal CEA was identified in 41 (73.2%) and 36 (64.3%) of SCNs. In addition, 18 (32.1%) SCNs displayed HBME-1 reactivity. These findings expand the immunohistochemical correlates of SCNs by demonstrating positivity for GATA3 and TTF-1 (SPT24), and negativity for monoclonal PAX8. The identification of monoclonal CEA expression and HBME-1 in SCNs also underscores the limitations of these select biomarkers in the distinction of C cell proliferations and papillary microcarcinoma, respectively. The findings of this series also suggest that positivity for TTF-1 (SPT24) alone should not be used to confirm the thyroid follicular epithelial origin. Therefore, the combined use of TTF-1 (SPT24) and monoclonal PAX8 in association with p63 or p40 provides an accurate distinction of SCNs.

The repair using a fibular graft of cervical vertebral collapse due to renal cell carcinoma: Late results with a case report.

The most common cause of spinal tumors is metastases, but the cervical vertebra is the least common region of spinal metastasis, and relatively, little is published about surgery in metastasis to the cervical vertebra. While spinal metastasis is most often caused by neoplasms originating from the lung, breast, and prostate, renal cell carcinoma (RCC) metastasis is very rare. A 47-year-old patient introduced here presented with severe pain spontaneously on his neck and in his arm. In the radiology of the patient without neurological deficit, a pathologic vertebral collapse was detected in the C6 vertebral corpus. The patient underwent anterior cervical corpectomy. The fibula graft taken from his right leg was implanted in the emptied area and supported by an anterior plaque, and restoration of physiological cervical lordosis was established. From the pathological tissue that was taken, it was determined that the cause of the lysis was an RCC metastasis. After surgical repair of the cervical spine, a primary pathology with a diameter of 10 cm was detected in the patient's kidney, and a radical nephrectomy was performed. After 6 years of follow-up, there was no recurrence, and the patient continued his normal daily life. Radiologically between the autologous fibula graft and its own vertebral body was observed to achieve very good fusion. In this study, we emphasized the importance of resection of metastasis together with a primary tumor in a metastatic RCC case to cure the patient and provide the desired quality of life.

Diagnostic and Prognostic Biomarkers of Adrenal Cortical Carcinoma.

The diagnosis of low-grade adrenal cortical carcinoma (ACC) confined to the adrenal gland can be challenging. Although there are diagnostic and prognostic molecular tests for ACC, they remain largely unutilized. We examined the diagnostic and prognostic value of altered reticulin framework and the immunoprofile of biomarkers including IGF-2, proteins involved in cell proliferation and mitotic spindle regulation (Ki67, p53, BUB1B, HURP, NEK2), DNA damage repair (PBK, γ-H2AX), telomere regulation (DAX, ATRX), wnt-signaling pathway (beta-catenin) and PI3K signaling pathway (PTEN, phospho-mTOR) in a tissue microarray of 50 adenomas and 43 carcinomas that were characterized for angioinvasion as defined by strict criteria, Weiss score, and mitotic rate-based tumor grade. IGF-2 and proteins involved in cell proliferation and mitotic spindle regulation (Ki67, p53, BUB1B, HURP, NEK2), DNA damage proteins (PBK, γ-H2AX), regulators of telomeres (DAXX, ATRX), and beta-catenin revealed characteristic expression profiles enabling the distinction of carcinomas from adenomas. Not all biomarkers were informative in all carcinomas. IGF-2 was the most useful biomarker of malignancy irrespective of tumor grade and cytomorphologic features, as juxtanuclear Golgi-pattern IGF-2 reactivity optimized for high specificity was identified in up to 80% of carcinomas and in no adenomas. Loss rather than qualitative alterations of the reticulin framework yielded statistical difference between carcinoma and adenoma. Angioinvasion defined as tumor cells invading through a vessel wall and intravascular tumor cells admixed with thrombus proved to be the best prognostic parameter, predicting adverse outcome in the entire cohort as well as within low-grade ACCs. Low mitotic tumor grade, Weiss score, global loss of DAXX expression, and high phospho-mTOR expression correlated with disease-free survival, but Weiss score and biomarkers failed to predict adverse outcome in low-grade disease. Our results underscore the importance of careful morphologic assessment coupled with ancillary diagnostic and prognostic biomarkers of ACC.

The Role of p16, p21, p27, p53 and Ki-67 Expression in the Differential Diagnosis of Cutaneous Squamous Cell Carcinomas and Keratoacanthomas: An Immunohistochemical Study.

BACKGROUND: Distinguishing squamous cell carcinoma (SCC) from keratoacanthoma (KA) by histopathological features may not be sufficient for a differential diagnosis, as KAs may, in some cases, imitate well-differentiated SCCs. AIMS: In this study, we investigated whether the expression of the p16, p21, p27, p53 genes and a Ki-67 proliferation index are useful in distinguishing between these two tumors. STUDY DESIGN: Cross-sectional study. METHODS: Immunohistochemistry was used to investigate the expression of the p16, p21, p27, p53 genes and the Ki-67 proliferation index was investigated in well-differentiated SCC with KA-like features (n=40) and KA (n=30). RESULTS: The results of all of the examined markers, except for p27 (p16, p21, p53, and Ki-67) were found to be significantly different between the SCC and KA samples (p<0.05). CONCLUSION: In well-differentiated SCC with KA-like features and KA cases where the differential diagnosis is difficult from a histopathological perspective, the use of p16, p21, p53 expression and a Ki-67 proliferation index can be useful for the differential diagnosis of SCCs and KAs.

Ligamentum flavum hematomas: Why does it mostly occur in old Asian males? Interesting point of reported cases: Review and case report.

Hematoma of the ligamentum flavum (LF) is a rare cause of neural compression and sciatica. Currently, the etiology and epidemiological characteristics of ligamentum flavum hematoma (LFH) are unknown and epidemiological investigations using rewieving of reported cases have not been performed. We report the case of a 63-year-old man with a LFH compressing the spinal canal at the left L2-L3 level, rewieved relevant literature. In Medline research, wefound a total of 50 reported cases with LFHs, and the interesting point of these cases were analyzed. Many of cases were old males. Interestingly, 39 of the 50 cases were reported from Asian countries. The ages of 42 patients could be verified. The youngest age was 45 years, oldest age was 81 years, and mean age was 66.07 years. Thirty-three out of these 42 patients (78.53%) were older than 60 years. An important aspect of the present review is to bring attention for occurrence in older Asian males. With an increasing number of elderly people in the general population, there is a need to investigate risk factors such as sexual gender, age, and geographic location for LFH.

The Value of HBME-1 and Claudin-1 Expression Profile in the Distinction of BRAF-Like and RAS-Like Phenotypes in Papillary Thyroid Carcinoma.

This study compared the expression profile of HBME-1 and claudin-1 in 90 papillary thyroid carcinomas (PTCs) with respect to the tumor architecture and invasive growth as reflected in 46 BRAF-like, 31 non-invasive RAS, and 13 invasive RAS-like phenotypes. Individual tumors were given an expression score (max 300) by multiplying the percent positive tumor cells by the intensity score (range 0-3). The higher expression of HBME-1 and claudin-1 distinguished BRAF-like phenotype from RAS-like phenotype. The same correlation was also retained for both markers when comparing BRAF-like phenotype with non-invasive and invasive RAS-like phenotypes. The expression scores and positivity rates for both markers did not yield any statistical difference among BRAF-like PTCs. Except the higher positivity rate of HBME-1, invasive RAS-like tumors were not statistically different than their non-invasive counterparts with respect to the positivity rate of claudin-1 and the expression scores of both markers. A central lymph node dissection or selective lymph node sampling was available in 20 specimens. The absence of claudin-1 expression has not been a feature of lymph node metastasis in this series. Despite the limited number of nodal sampling, BRAF-like phenotype and claudin-1 positivity status have been considered the best determinants of positive predictive value and negative predictive value in the prediction of lymph node metastasis among variables, respectively. Adoption of the simplified architectural classification approach to PTCs showed distinct biomarker expression profile in this series; however, immunohistochemistry for HBME-1 and claudin-1 does not seem to be useful in the distinction of invasive RAS-like PTCs from their non-invasive counterparts. Given the overlapping molecular signatures within the RAS-like phenotype, further studies with additional biomarkers are still needed to identify distinct protein expression signatures of non-invasive RAS-like phenotype as this diagnostic category still remains a surgical diagnosis at this time.

Thyroglossal Duct Cyst Associated with Xanthogranulomatous Inflammation.

Xanthogranulomatous inflammation (XGI) is an uncommon destructive chronic inflammatory process mainly occurring in the kidney and gallbladder, characterized by the accumulation of foamy histiocytes, multinucleated giant cells (Touton type), cholesterol clefts and chronic inflammatory cells. The head and neck region is an uncommon site for XGI. This type of inflammatory reaction has been defined in branchial cleft cyst, salivary gland tumors following fine-needle aspiration biopsies, Rathke's cleft cyst in the pituitary gland, and colloid cyst in the 3rd ventricle. We present herein a unique case of ruptured thyroglossal duct cyst leading to XGI, characterized by an infiltrative subcutaneous central neck lesion, clinically mimicking a thyroid carcinoma. In addition, we also summarize current insights into the pathogenesis of XGI in the head and neck region.