DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbor somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behavior and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥50%) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (P < 0.0001) and lymph node metastases (P < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behavior. DLL3 expression in ≥50% of tumor cells virtually excludes MTC without stromal desmoplasia. DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.

[Pathology and molecular profile of differentiated thyroid carcinoma]. / Pathologie und molekulares Profil differenzierter Schilddrüsenkarzinome.

The clinical term of differentiated thyroid carcinoma (DTC) includes follicular (FTC) and papillary thyroid carcinomas (PTC). In diagnostic thyroid pathology, however, the term differentiated carcinoma (NOS) is used only very rarely for tumors with morphological features of both FTC and PTC. The current World Health Organization (WHO) classification of thyroid tumors introduced the entity of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). As a result, the diagnostic criteria for PTC had to be adjusted (compulsory histological demonstration of invasion and/or papillae), which also significantly limited the diagnostic potential of a fine needle biopsy (FNB) of the thyroid. The FTC is now divided into three distinct subgroups. Moreover, the WHO classification also established the diagnostic criteria of poorly differentiated thyroid carcinoma (PDTC), which has to be distinguished from both differentiated carcinomas and benign adenomas. This article also summarizes the current diagnostic status of molecular pathological analyses of thyroid tumors.

Immunohistochemical Profile and 47-Gene Next-Generation Sequencing (NGS) Solid Tumor Panel Analysis of a Series of 13 Strumal Carcinoids.

Strumal carcinoid is an extraordinary rare tumor of the ovary consisting of thyroid tissue intermixed with neuroendocrine tumor component. The cellular origin of strumal carcinoids has been an area of debate. There is also little data on detailed immunohistochemical and molecular characteristics of these neoplasms. For this reason, this series investigated the characteristics of a series of 13 strumal carcinoids using immunohistochemical markers and a 47-gene next-generation sequencing (NGS) solid tumor panel analysis. Both cellular components showed thyroglobulin expression in all tumors. TTF-1 expression was noted in both cellular components of 11 cases. Chromogranin A was positive in both components of most tumors (n = 12, 92.3% in the neuroendocrine component and n = 10, 76.9% in the thyroid follicular component). Synaptophysin stained the neuroendocrine component of all cases, and it was also identified in the follicular thyroid component of a single case. All tumors were negative for CDX2 and calcitonin. ISLET1 was positive in the neuroendocrine component of 8 cases (6.5%). With the exception of one case, all tumors were positive for SSTR2a. The tumors were associated with a low Ki67 labeling index. All cases were microsatellite stable and no pathogenic mutations were identified using a 47-gene NGS solid tumor analysis. This series underscored that strumal carcinoids are distinct neuroendocrine tumors. The synchronous expression for thyroid follicular epithelial and neuroendocrine differentiation biomarkers may suggest a precursor cell origin displaying mixed-amphicrine differentiation. While strumal carcinoids can be diagnosed by their typical morphology and immunohistochemical profile, frequent SSTR expression may serve as a potential theranostic biomarker in the management of affected patients. In addition, the absence of common driver mutations in the NGS solid tumor panel may suggest that these neoplasms seem to be genetically unrelated to follicular epithelial-derived thyroid tumors and potentially different than other commonly identified well-differentiated neuroendocrine neoplasms. Therefore, further studies focusing on molecular characteristics of this entity are still needed.

[Pheochromocytomatosis after adrenalectomy: metastasis or cell seeding?] / Phäochromozytomatose nach Adrenalektomie: Metastasierung oder Zellverschleppung?

Pheochromocytomatosis is defined as a multifocal cell dissemination limited to the operatively opened space with no signs of distant metastasis. After primary adrenalectomy due to a pheochromocytoma this is a rare and underrecognized manifestation of a tumor recurrence. Between 2010 and 2019 a total of 5 patients with the presentation of pheochromocytomatosis were treated in this center. Clinical and survival data were compared to 12 patients with a metastasized pheochromocytoma. Patients presenting with pheochromocytomatosis showed a better but not significant overall survival (136.8 vs. 107 months). Furthermore, patients with pheochromocytomatosis presented more often with a noradrenaline secretion type. Tumor recurrence in the pheochromocytomatosis group occurred on average 69.2 months after the initial diagnosis and was therefore much later than in patients with distant metastases from a pheochromocytoma (39 months, p = 0.13). This article outlines this special manifestation of recurrence of a pheochromocytoma based on this patient collective. Besides technical operative aspects there appears to be evidence for tumor-specific factors that promote the development of pheochromocytomatosis. Importantly, it seems that all patients with a pheochromocytoma should receive lifelong aftercare and that patients should be closely monitored during the first 5 years after surgery.

[Morphologic diagnostic criteria of noninvasive follicular neoplasia with papillary-like nuclear features (NIFTP) : A diagnostic challenge for the patient's benefit]. / Morphologische Diagnosekriterien der nichtinvasiven follikulären Neoplasie mit PTC-äquivalenten Kernmerkmalen (NIFTP) : Eine diagnostische Herausforderung zum Nutzen des Patienten.

The major goals of the introduction of the noninvasive follicular neoplasia with papillary-like nuclear features (NIFTP) are to spare patients with a biologically indolent subgroup of the follicular variant of papillary carcinoma (FV-PTC) both overtreatment and the psychologically burden of a cancer/carcinoma diagnosis. However, strict histological and molecular pathological criteria have been introduced for the diagnosis of NIFTP. NIFTP tumors may be a few millimeters in diameter, but may also measure more than 4 cm. Histologically, an encapsulated/clearly demarcated lesion with (>70%) follicular structure and the nuclear characteristics of PTC must be present as a prerequisite; invasion of capsule/vessels must be excluded as well as significant proportions (>30%) showing a solid/trabecular/insular growth pattern, psammoma bodies, tumor necrosis, an increased mitotic rate (>3/10 HPF), and/or a BRAF V600E mutation. The establishment of the NIFTP necessitated a redefinition of the diagnostic criteria of PTC and has implications on the evaluation of fine needle biopsy (FNB) of the thyroid gland. Although a prediction is difficult, the correct diagnosis of NIFTP could lead to a 10-20% reduction in thyroid carcinoma incidence.

Thyroxine promotes lung cancer growth in an orthotopic mouse model.

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvß3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvß3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvß3 inhibitor 3,5,3',5'-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvß3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvß3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

[Primary meningioma of the optical nerve sheet in infancy as initial presentation of neurofibromatosis type 2]. / Primäres Meningeom des Nervus opticus im Säuglingsalter als Erstmanifestation einer Neurofibromatose Typ 2.

Intraorbital meningiomas are rare tumors, making up less than 4% of all intraorbital tumors. Intraorbital meningiomas of childhood are curiosities with only few documented cases. We present the case of an 8­month-old male infant, presenting with strabismus and nystagmus. Magnetic resonance imaging showed a long segment thickening of the optical nerve and an intraocular tumor. The tumor was suspicious for retinal dysplasia and enucleation of the eye was performed to exclude malignancy. Histological examination revealed a meningothelial meningioma (WHO grade I), extending along the optical nerve and into the eye accompanied by retinal dysplasia and epiretinal membranes. Meningiomas of childhood, retinal dysplasia, and epiretinal membranes are regularly associated with neurofibromatosis type 2. Subsequent genetic analysis led to the final diagnosis. This case documents a very unusual early beginning of a neurofibromatosis type 2.

[Ectopic tissue of the thyroid gland and the parathyroid glands]. / Ektopes Gewebe der Schilddrüse und der Nebenschilddrüsen.

Ectopic thyroid tissue results from developmental defects of the early stages of thyroid embryogenesis, in which the median thyroid anlage descends from the floor of the mouth to its final pre-tracheal position. The most common sites of ectopic thyroid tissue are accordingly in the area of the floor of the mouth and in the course of the thyroglossal duct. Rare localizations are intrathoracic (mediastinal, cardiac, pulmonary) and sub-diaphragmatic (including the adrenals, liver, gall bladder, and gastrointestinal tract). The most important differential diagnosis of ectopic thyroid is metastasis of differentiated thyroid carcinoma.By contrast, the term parathyroidectopy is not uniformly defined. Usually, the cervical-central localizations are referred to as "positional variants" (with the exception of the maxillary sinus and high parapharyngeal), whereas the cervical-lateral localizations (carotid sheath, vagus nerve) and those below the brachiocephalic and mediastinal positions (extraligamentary, aortopulmonary window, paravagal) and other rare localizations are classified as "ectopic parathyroid tissue". Parathyroidectomy is very common (in autopsy studies in 28 to 42.8% of all humans). In the context of primary hyperparathyroidism (pHPT), there is a prevalence of 6.3 to 16% of ectopic hyperfunctional parathyroid tissue (predominantly adenomas), which play an important role in the surgical treatment of pHPT.