Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past ...decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be “sporadic” is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.
Introduction and Design
Endocrine pathologists, surgeons, and oncologists who manage patients with thyroid carcinomas confront many critical dilemmas. Controversies surrounding diagnostic criteria ...that distinguish benign from malignant thyroid follicular lesions have been brought to the attention of this community. In this article, we confront another controversy, the definition of a thyroid “capsule” to clarify what constitutes extrathyroidal extension (ETE) and its clinical significance in the management of patients with differentiated thyroid carcinomas.
Results and Conclusion
Our review of the anatomy of the thyroid gland confirms that this structure has no defined anatomical fibrous capsule. Moreover, the presence of adipose tissue within the thyroid gland and its pseudocapsule implies that thyroid tumor within fat tissue cannot be accepted as a criterion of ETE by that thyroid carcinoma. While invasion of skeletal muscle is a more reliable feature of ETE, at the isthmus, these fibers can be normally present within the gland, and this criterion does not have value. This implies that anatomical localization is a critical element in the determination of ETE. Clarification of such issues should be reflected in future revisions of the UICC/AJCC staging criteria to allow more rational management of patients with these increasingly common cancers.
Tumors with papillary cribriform and morular architecture were initially considered to be variants of papillary thyroid carcinoma; however, recent observations have challenged this view. In this ...study, we reviewed the demographical, histopathological, and immunohistochemical features of the largest case series, consisting of 33 tumors. The age at time of pathological diagnosis ranged from 18 to 59 (mean 33) years, and all patients except one were female. Sixteen patients had multifocal and fifteen had unifocal disease. The status of focality was unavailable in two patients. Tumors were well-circumscribed, ranging in size from 0.1 to 8.0 cm. The cribriform component was admixed with morulae in the majority, except seven had a cribriform-predominant architecture and two had predominantly solid growth. Variable degrees of nuclear enlargement, elongation, overlapping, and grooves were seen but florid nuclear convolution, intranuclear pseudoinclusions, and optically clear nuclei due to chromatin margination were not appreciated. There was no or little colloid material within the cribriform spaces. Two solid tumors had high-grade features. Immunohistochemical studies showed beta-catenin nuclear and cytoplasmic positivity in all cases. The cribriform component was positive for TTF1 and negative for thyroglobulin. PAX8 was absent in half of these tumors and focal in the remainder. Morulae were positive for keratin 5 and CD5 and negative for p63, p40, TTF1, and PAX8. Molecular studies revealed germline
APC
mutations in 12 tumors and were negative in 5 sporadic tumors in a subset of tested tumors. Irrespective of the antibody used in this cohort, all cribriform-morular carcinomas express TTF1; however, PAX8 immunoreactivity is weak, focal or negative, and all tumors lack thyroglobulin reactivity; these findings raise questions about tumor cell origin and may indicate that these are not of thyroid follicular epithelial differentiation. We postulate that morulae may represent divergent thymic/ultimobranchial pouch-related differentiation. Given their unique cytomorphology, immunohistochemical profiles, and genetic features that have little overlap with traditional follicular cell-derived thyroid carcinomas, we propose that these tumors represent a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells.
Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal ...(80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease.
Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype-phenotype correlations in ...adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations (
, and
) involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that
-mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring
, and
mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations (
, and
) involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH) have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating
germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.
Thoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index ...cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.
Purpose
Technetium-99 m sestamibi parathyroid scintigraphy (MIBI scan) has been used to localize abnormal glands in patients with primary hyperparathyroidism to guide parathyroidectomy. This series ...aimed to identify the biochemical and histopathological correlates of MIBI scan findings in patients with parathyroid adenoma.
Methods
A total of 378 patients with histologically and biochemically proven parathyroid adenoma were included. The results of MIBI scan, histopathological (gland volume and weight, oxyphil cell ratio), biochemical (blood and 24 h urine calcium, creatinine, glomerular filtration rate, parathormone, alkaline phosphate, and vitamin D3) variables were recorded. A positive uptake on the MIBI scan referred to a localized adenoma. Among histological variables, a cutoff of 30% was applied to define parathyroid adenomas with low (≤ 30%) and high (> 30%) oxyphil cell content. Statistical analyses were performed to assess the relationship among variables.
Results
MIBI scan localized the adenoma in 306 patients. Parathyroid gland volume and weight, and oxyphil ratio were significantly higher in the MIBI scan-positive group. Among the biochemical variables, only PTH was found to be significantly increased in the MIBI scan-positive group. Binary logistic regression models identified statistically significant cutoffs for the gland volume (1700 mm
3
), gland weight (1.3 g) and PTH levels (170 pg/mL) that can be used to predict the MIBI scan positivity.
Conclusion
In addition to PTH levels, this series underscored the impact of cellular composition along with the parathyroid gland volume and weight, both of which correlate with sestamibi positivity in patients with benign uniglandular parathyroid disease.
Careful morphological evaluation forms the basis of the workup of an adrenal cortical neoplasm. However, the adoption of immunohistochemical biomarkers has added tremendous value to enhance ...diagnostic accuracy. The authors provide a brief review of immunohistochemical biomarkers that have been used in the confirmation of adrenal cortical origin and in the detection of the source of functional adrenal cortical proliferations, as well as diagnostic, predictive, and prognostic biomarkers of adrenal cortical carcinoma. In addition, a brief section on potential novel theranostic biomarkers in the prediction of treatment response to mitotane and other relevant chemotherapeutic agents is also provided. In the era of precision and personalized medical practice, adoption of combined morphology and immunohistochemistry provides a new approach to the diagnostic workup of adrenal cortical neoplasms, reflecting the evolution of clinical responsibility of pathologists.
The expression of programmed death-ligand 1 (PD-L1) is an established prerequisite for the administration of checkpoint inhibitor therapy and is of prognostic value in several cancer types. Data ...concerning the potential effect of PD-L1 on the prognosis of thyroid carcinoma are limited. Therefore, this study aimed to provide a systematic review of the published data on this topic. The literature was reviewed to gather and quantify evidence on the prognostic role of PD-L1 in follicular epithelial derived thyroid carcinomas and determine its association with clinicopathological parameters. A meta-analysis was performed using the DerSimonian-Laird random-effects model. The quality of studies was evaluated with the Newcastle-Ottawa Scale and a modified GRADE approach used to rate the quality of evidence. Out of 445 papers, 18 were included and 15 provided adequate data for meta-analysis. The quality of evidence ranged from low to high. PD-L1 expression was significantly associated with a reduced disease-free survival (DFS) (RR 1.63, CI 1.04–2.56,
p
= 0.03, I
2
68%, τ
2
0.19 and HR 1.90, CI 1.33–2.70,
p
< 0.001, I
2
0%, τ
2
0.00); however, no association was found with the overall survival (OS). Furthermore, a significant association was found with respect to underlying chronic lymphocytic thyroiditis and
BRAFV600E
mutation status in papillary thyroid carcinomas. In the subgroup analysis, the association of PD-L1 and DFS remained strong in papillary thyroid carcinoma when compared with dedifferentiated thyroid carcinomas (anaplastic and poorly differentiated thyroid carcinomas) that failed to demonstrate a significant association with respect to PD-L1. These findings underscore the role of PD-L1 immunohistochemistry as a potential prognostic biomarker of disease recurrence in patients with papillary thyroid carcinoma.
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