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Introduction: Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer in adults, presents significant challenges owing to its resistance to conventional therapies. Standard treatment primarily revolves around surgical methods, particularly nephrectomy, which is critical for managing localized diseases. Despite recent advancements, the metastatic potential of ccRCC necessitates ongoing vigilance in postoperative monitoring to manage and detect disease recurrence. Recent shifts in treatment paradigms, especially with the integration of molecular patterns in ccRCC, have enabled the development of targeted therapies. Immune checkpoint and tyrosine kinase inhibitors (TKIs) have become central to managing metastatic ccRCC, offering new hope through improved survival outcomes. Recent studies have corroborated this by demonstrating the benefits of combining these therapies. Case Presentation: This report discusses a case study of a patient with high-grade ccRCC and thyroid metastases initially deemed non-resectable. The combination of immunotherapy and TKIs reduced tumor size, transforming the thyroid metastasis to a resectable state. Conclusion: This case highlights significant advancements in treatment approaches and the critical in the management of ccRCC, underscoring the necessity for continuous adaptation of clinical practices to incorporate new therapeutic developments.

Abstract The clinical significance of thyroglobulin (Tg) expression in papillary thyroid cancer (PTC) has not been systematically explored in relation to the Ki-67 index, lymph node ratio (LNR), or other conventional prognostic predictors. In this retrospective study of 327 patients with PTC, we investigated the immunohistochemical expression of Tg in both primary tumors and their matching lymph node metastases in relation to the Ki-67 index, LNR, and clinical data. Tumoral Tg immunoreactivity was inversely correlated to the Ki-67 index and tumor recurrence. The Ki-67 index was higher in lymph node metastases (mean 4%) than in the primary tumors (mean 3%). Reduced Tg expression, estimated as 0–25% Tg positive tumor cells, was more common in lymph node metastases compared to primary tumors. In addition to advanced metastatic burden (defined as N1b stage and LNR ≥ 21%), low Tg expression (0–25% positive tumor cells) in lymph node metastases had a significant prognostic impact with shorter recurrence-free survival. These findings support the potential value of histopathological assessment of Tg expression and Ki-67 index in lymph node metastases as complementary predictors to anticipate the prognosis of PTC patients better.

Abstract Background Follicular thyroid carcinomas (FTCs) rarely metastasize to regional lymph nodes, and descriptions of synchronous lateral lymph node metastases of FTC and papillary thyroid carcinoma (PTC) are lacking. Case Presentation We describe a 43-year-old female with a preoperative cytology indicating a right-sided PTC with lateral lymph node metastases. She underwent a total thyroidectomy and central and lateral lymph node dissection, and histopathology confirmed a multifocal tall cell variant PTC together with a 12 mm minimally invasive FTC in the ipsilateral lobe. While the central compartment demonstrated metastatic PTC, the lateral compartment contained PTC metastases alongside a 15 mm large follicular-patterned mass in a separate lymph node. As the cells lacked PTC associated nuclear changes, the possibility of a lateral lymph node metastasis of FTC was considered, with the possibility of ectopic thyroid tissue as a differential diagnosis. By utilizing next-generation sequencing, a Q61R NRAS mutation was pinpointed, thus proving the tissue as tumorous. The patient underwent radioiodine treatment and is currently monitored following a negative whole-body scan. Conclusions This is probably the first case report of a patient with co-existing lateral lymph node PTC and FTC metastases. Consulting previous publications, there is currently a gap of knowledge in terms of how patients with regional FTC metastases should be followed-up and treated, especially when co-occurring with spread high-risk PTC subtypes. Moreover, what guides a seemingly indolent FTC to spread via the lymphatic system remains to be defined from a molecular standpoint.

Abstract Background Thyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed. Case presentation A 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion. Conclusions The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.

Adrenal incidentalomas are commonly detected via routine radiological procedures, and any sign of grossly invasive properties may alert the clinical team to suspect malignancy. Adreno-hepatic fusion (AHF) is a developmental disorder in which the parenchyma of the right adrenal gland is partly or wholly fused with the liver. The development of an adrenal cortical tumor in AHFs is a rare phenomenon that may mimic an invasive lesion. The index patient is a 74-year-old male with an incidental finding of a 25 mm lesion in segment VI of the liver. The lesion was deemed as fat-containing with magnetic resonance imaging (MRI) scans, and no signal was obtained on fluorodeoxyglucose-positron emission tomography (FDG-PET). A core needle biopsy was taken, and histology displayed adrenal cortical tumor lacking pleomorphism, mitoses and necrosis intermingled with hepatocytes. The favored diagnosis was adrenal cortical adenoma (ACA) arising in an AHF. Surgical resection was subsequently performed, thus verifying the diagnosis. A review of the current literature identified 10 cases with ACA development in AHF, predominantly detected as incidental masses in older female patients, and always positive for markers of adrenal differentiation when assessed. We conclude that radiological evidence of an adrenal tumor adherent to the liver capsule should not automatically imply adrenal cortical carcinoma, especially if the tumor is small and FDG-PET negative. Although exceedingly rare, adenoma formation in a pre-existing AHF should constitute a differential diagnosis in this specific clinical setting. Moreover, adrenal cortical immunohistochemical markers seem to correctly identify the tissue origin in these rare malformations.

Abstract Background Metastatic neuroendocrine carcinoma often presents as carcinoma of unknown primary. Although most cases display immunohistochemical positivity for neuroendocrine markers, subsets of cases display reduced or negative expression for some of these proteins. The identification of metastatic neuroendocrine carcinomas is even more complicated by the occurrence of unrelated tumor types with focal neuroendocrine differentiation. Case presentation Our patient was a 74-year-old man of Middle Eastern ethnicity. An initial biopsy of a soft tissue metastasis displayed a neuroendocrine profile indicative of a metastatic neuroendocrine carcinoma, positive for CD56 and synaptophysin, and focally for ISL LIM homeobox 1 and insulinoma-associated protein 1. The Ki-67 index was 50%. Chemotherapy was initiated, but our patient progressed. Scrapings from a pathological hip fracture 3 months later revealed focal synaptophysin immunoreactivity and widespread melanoma antigen, human melanoma black 45, and SOX10 positivity, which are indicative of metastatic malignant melanoma with focal neuroendocrine differentiation. Conclusions Malignant melanoma may display neuroendocrine differentiation, and the entity should be considered a rare differential diagnosis when assessing biopsies of suspected neuroendocrine carcinomas.

Parathyroid adenoma is a tumor composed of increased parenchymal tissue, often built-up by chief cells, transitional cells or oncocytic cells arranged in acinar or solid formations. Occasionally, rare histological patterns are reported, including cystic or trabecular arrangements. We present a 47 year-old male patient with primary hyperparathyroidism who underwent focused parathyroidectomy for a right inferior adenoma. Surgery was uneventful, but histologically, normal parathyroid tissue adjacent to a tumorous structure displaying a cystic growth pattern was detected. The cells lining the cyst walls appeared cylindrical and pseudo-stratified, vaguely reminiscent of a respiratory type of epithelium usually associated to branchial cleft cysts or thyroglossal cyst remnants, albeit with a tumorous appearance. The respiratory-like epithelium stained positive for parathyroid markers PTH and GATA3, thereby confirming them as parathyroid-derived. The patient was cured from surgery as he displayed normal calcium and PTH levels postoperatively, and is currently alive and well without signs of relapse 4 years after surgery. This is to our knowledge the first report of a parathyroid tumor displaying a respiratory-like epithelium. Experimentally, canine parathyroid glands can develop ciliated respiratory epithelium in response to inhalation of ozone. Our patient is a construction worker with a hypothetically increased risk of continuous ozone exposure. Although this association remains purely speculative, future investigations of this tumor phenotype could perhaps yield novel insights regarding the frequency of this histological variant, potential clinical associations, and clues regarding influencing factors.

Telomere maintenance is a critical requirement for enabling replicative immortality and tumour development. Here, telomerase expression and activity, telomere length (TL) and potential regulatory factors that can underlie telomerase machinery alterations in small intestinal neuroendocrine tumours (SI-NETs) were analyzed. Telomerase activity assessed by TRAP assay was increased in SI-NETs compared to normal ileum (P < 0.001). The telomerase reverse transcriptase gene (TERT) was over-expressed in SI-NETs vs. normal ileal samples (P = 0.01). Furthermore, relative TL assessed by qPCR was found shorter in tumours compared with normal ileum (P = 0.02) and in distant metastasis samples compared to primary tumours and local metastases (P= 0.02). TERT promoter hotspot mutations were not present and TERT copy number gain was only observed in 3/70 tumour samples. TERT or chromosome 18 copy number alterations were not associated with telomerase expression and activity or TL. However, hypermethylation of TERT promoter in Region B – in the proximity of the transcription start site – was inversely correlated with TERT expression and telomerase activity and positively correlated with TL. Global LINE1 methylation was positively correlated with TERT promoter Region B methylation and was inversely correlated with telomerase activity, TERT expression and the upstream Region A methylation. The results show that telomerase activation, TERT expression and shorter telomeres are commonly found in SI-NETs. Aberrant DNA methylation of TERT promoter and of LINE1 can be implicated in abnormal regulation of TERT in SI-NETs.

Abstract Background Follicular thyroid carcinoma (FTC) is a neoplasm that presents with a micro-follicular growth pattern and a neutrally stained cytoplasm. Seldom, FTCs display unusual morphological characteristics – but given the rarity of these histological subtypes, little is known regarding the underlying genetics and the coupling to patient outcome. Case presentation We present two extremely rare cases of minimally invasive FTC with signet ring cell morphology (SRC-FTC) and describe the cytological, microscopic, immunohistochemical and molecular features for both tumors. Both were male patients, age 71 and 51 respectively. The preoperative cytology for both cases could not pinpoint a clear-cut signet ring cell morphology, but a tendency towards nuclear marginalization was seen. The tumors were 38 mm and 22 mm respectively and displayed evident signet ring cell features in subsets of tumor cells as well as degenerative stromal changes. The tumor cells were positive for TTF1, PAX8 and thyroglobulin, and the proliferation indexes were 4% and 1,9% respectively. Both tumors displayed capsular invasion, but not lymphovascular invasion. The tumors were sequenced for mutations in the TERT promoter and 22 additional cancer-related genes, interestingly; one patient was shown to carry a deleterious intronic variant in PTEN, a tumor suppressor gene coupled to thyroid tumorigenesis and Cowden syndrome. Both patients are alive and well awaiting postoperative radioiodine treatment. Conclusions The SRC-FTCs described herein were small, TERT promoter wildtype tumors exhibiting low proliferation, thereby suggesting that these exceedingly rare lesions probably carry a favorable prognosis – although the scarce availability regarding descriptions of this tumor entity nevertheless might justify careful clinical monitoring and mandate investigations in larger case series.

Abstract Background Papillary thyroid carcinoma with pleomorphic tumor giant cells (PTC-PC) is characterized by the occurrence of bizarre, pleomorphic cells within a small area of a conventional PTC. The histologic distinction between PTC-PC and PTC’s with a focal anaplastic thyroid cancer (ATC) component (denoted in the 2004 WHO classification as “papillary thyroid carcinoma with spindle and giant cell carcinoma”, PTC-SGC) is debated, however the prognosis is thought to be different (excellent for PTC-PC, poor for PTC-SGC). Therefore, this diagnostic challenge is significant for any endocrine pathologist to recognize. Herein, we report the histological and clinical workup of a PTC-PC case, with particular focus on the molecular analyses that facilitated the establishment of the final diagnosis. Case presentation The patient was a pregnant, 28-year-old female presenting with a 30 mm conventional PTC, with focal areas with undifferentiated cells exhibiting exaggerated nuclear pleomorphism. No foci of extrathyroidal extension, angioinvasion or lymph node engagement were seen. Immunohistochemical analyses revealed the pleomorphic cells exhibiting retained differentiation. Molecular genetic analyses demonstrated a codon V600 missense mutation of the BRAF gene, but no TP53 or TERT promoter mutations. The absence of an aggressive phenotype in addition to the lack of mutations in two major ATC-related genes led to the diagnosis of a PTC-PC. Postoperative MRI showed no evidence of metastatic disease. Radioiodine ablation was performed seven months post-operatively, and a SPECT-CT imaging did not show signs of residual tissue. She is well and without signs of disease 16 months post-operatively. Conclusions PTC-PC is a differential diagnosis to PTC-SGC that mandates careful considerations. Taken together with previous publications, PTC-PC seems to be histologically similar to PTC-SGC, but clinically distinct. Even so, the distinction is not easily made given the different therapeutic consequences for each individual patient. This is the first report that includes molecular genetics to aid in finalizing the diagnosis. Exclusion of mutations in TP53 and the TERT promoter could be considered as an adjunct tool when assessing papillary thyroid cancer with focal pleomorphism.

Immunohistochemistry with antibodies targeting enzymes responsible for the final conversion steps of cortisol (CYP11B1) and aldosterone (CYP11B2) is gaining ground as an adjunct tool in the postoperative evaluation of adrenocortical nodules. The method allows the pathologist to visualize hormone production for each lesion, thereby permitting a more exact assessment regarding the distinction between adrenocortical adenomas and adrenocortical hyperplasia, with implications for patient follow-up. We describe how immunohistochemistry facilitated the histopathological diagnosis of twin adenoma (one cortisol- and one aldosterone-producing) from suspected hyperplasia in a patient with hypertension, mild autonomous cortisol secretion and concurrent adrenocorticotropic hormone–producing adrenomedullary hyperplasia. As the nodules were similar in size and displayed rather analogous histology, CYP11B1 and B2 immunohistochemistry was needed to exclude adrenocortical hyperplasia, allowing us to discharge the patient from further surveillance. We conclude that the application of functional immunohistochemistry has direct clinical consequences and advocates the prompt introduction of these markers in clinical routine.

Cystic papillary thyroid carcinoma (cPTC) is a subgroup of PTC presenting a diagnostic challenge at fine needle aspiration biopsy (FNAB). To further investigate this entity we aimed to characterize protein profiles of cyst fluids from cPTC and benign thyroid cystic lesions. In total, 20 cPTCs and 56 benign thyroid cystic lesions were studied. Profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on cyst fluids from a subset of cases after depletion, and selected proteins were further analyzed by Western blot (WB), immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). A total of 1,581 proteins were detected in cyst fluids, of which 841 were quantified in all samples using LC-MS/MS. Proteins with different expression levels between cPTCs and benign lesions were identified by univariate analysis (41 proteins) and multivariate analysis (59 proteins in an orthogonal partial least squares model). WB analyses of cyst fluid and IHC on corresponding tissue samples confirmed a significant up-regulation of cytokeratin 19 (CK-19/CYFRA 21-1) and S100A13 in cPTC vs. benign lesions. These findings were further confirmed by ELISA in an extended material of non-depleted cyst fluids from cPTCs (n = 17) and benign lesions (n = 55) (p55 ng/ml for CK-19 resulted in 82% specificity and sensitivity. For S100A13 a cut-off at >230 pg/ml revealed a 94% sensitivity, but only 35% specificity. This is the first comprehensive catalogue of the protein content in fluid from thyroid cysts. The up-regulations of CK-19 and S100A13 suggest their possible use in FNAB based preoperative diagnostics of cystic thyroid lesions.

Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p

Background:The accurate diagnosis of thyroid tumors is challenging. Proteomics has emerged as a promising approach for the discovery of molecular diagnostic markers as a potential complement to routine diagnostics.Methods:Protein fractions from 29 frozen thyroid tumor tissue samples (10 papillary carcinomas, 9 follicular carcinomas, and 10 follicular adenomas) as well as from normal thyroid tissue were analyzed by surface enhanced laser desorption/ionization time-of-flight mass spectrometry followed by validation by Western blotting and immunohistochemistry.Results:A Ca2+-binding protein belonging to the S100 family, S100A6, was differentially expressed between papillary and follicular thyroid tumors. Moreover, two posttranslationally modified forms of S100A6 were observed and verified by liquid chromatography-coupled tandem mass spectrometry. Validation by Western blotting displayed a significantly higher expression of S100A6 in papillary thyroid carcinoma (PTC) in comparison with the other tumor groups or normal tissue (p< 0.05). Immunohistochemical analysis on 98 tumors showed that PTC cases had a significantly stronger cytosolic staining and a larger proportion of stained nuclei than follicular tumors. BRAFgene mutation was not significantly associated with S100A6 protein levels.Conclusion:This study supports a role of S100A6 in thyroid tumorigenesis and as a potential aid in the discrimination between follicular thyroid tumors and PTC. [ABSTRACT FROM AUTHOR]

Papillary (PTC) and follicular (FTC) thyroid cancers are rare disorders but are, nevertheless, among the most common cancers in individuals below 40 years of age. From the population-based Swedish Cancer Registry we identified 3,588 individuals with PTC and 1,966 with FTC during 1958–87. Histopathology was determined by examining the original histopathology reports. The relative survival ratio (RSR) was used as the measure of patient survival. Incidence of both PTC and FTC was higher among women, especially for PTC and particularly during the fertile part of female life. Incidence of PTC increased significantly over time, a trend that was not observed for FTC. Five-year relative survival appeared to be higher for patients diagnosed with PTC compared to FTC, although this difference was almost completely explained by the confounding effect of age. Patients with PTC experience lower mortality during the period 7–20 years after diagnosis. Excess mortality was lower among women, although the magnitude of the difference varied with age and histopathology. In contrast to our perceptions based on clinical practice, we observed no difference in excess mortality between patients diagnosed with PTC and FTC during the years immediately after diagnosis (where the majority of deaths occur). Our data suggest that there may exist a subgroup of thyroid tumors with superior prognosis diagnosed in women during the fertile part of female life. Sex hormones may play a role in the etiology of these tumors. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]