Papilläres Schilddrüsenkarzinom
- Häufiste Schilddrüsenkarzinom- Assoziiert mit RET/PTC Translokation and BRAF Mutationen (Onkogene), Exposition zu radioaktiven Strahlen während der Kindheit Histologie:- Wenig Protein, wenig DNA → "Orphan Annie eye nucleus", "Milchglaskerne"- Dachziegelartiges Überlappen der Kerne, Kerneinschüsse- Tumorinfiltration der Kapsel- Psammomkörperchen
Follikuläres Schilddrüsenkarzinom
- 2. häufiste Form von Schilddrüsenkarzinom- Assoziiert mit ↓ Jod, RAS Aktivation, Deaktivation von PTEN- Hämatogene Metastasierung Histologie:- Trabekulärer Bau- Kapselinvasion, Invasion in Blutgefässen
Medulläres Schilddrüsenkarzinom
- Von den parafollikulären C-Zellen abgeleitet, die meist im oberen Drittel der Schilddrüse lokalisiert sind- Produktion von Kalzitonin- Spontane Mutation in RET Onkogen (einzeln)- Hereditär: Familial medullary thyroid carcinoma; MEN2A oder MEN2B Syndrome (multiple) Histologie:- Infiltrativ-destruktives Wachstum, unscharfe Begrenzung, Gefässinvasion- Spindelzellig mit langgestreckten Kernen- Prokalzitonin lagert sich an und bildet Amyloid Kann sezernieren: Serotonin (→ Errötung) oder VIP (→ Diarrhö).
Anaplastisches Schilddrüsenkarzinom
∼1-2% aller Schilddrüsenkarzinome- Am meisten aggressiv Histologie:- Hochgradige Zell- und Kernpolymorphie- Spindelzellig, pleomorphische Riesenzellen- Infiltrativ-destruktiv wachsend- Nekrosen und Hämorrhagien
Phäochromozytom
- Aus den Chromaffinzellen- 25% hereditär: MEN2A, MEN2B, Neurofibromatose Typ 1, von Hippel Lindau (VHL) Histologie:- Pleomorphes Bild mit sehr grossen Zellen, Kernpolymorphie aber trotzdem benigne!- Stark vaskularisiert, häufig Hämorrhagien- Kaum Mitosen Immunhistochemie: S100 Therapie: 1. Nicht-selektiver α-Antagonist (Phenoxybenzamine), dann β-Blocker2. Laparaskopische Tumorresektion ("no touch technique")Wenn nicht resektable → MIBG-Therapie (Noradrenalin-Analog + radioaktives Iod)
Neuroendokrine Zellen
- Können überall vorkommen, insbesondere aus dem Epithel des Gastointestinaltrakts oder Lunge - Bekommen Signal von Nervenzellen und sezernieren Hormone Mögliche Hormone:- Amine (Serotonin, Histamin)- Polypeptide (Bradykinin)- Prostaglandin Grading basiert auf Ki67-Proliferationsindex.
Karzinoides Karzinom
- Entwirkeln meist im Gastrointestinaltrakt. Wird erst symptomatisch, wenn sich Lebermetastasen bilden und dem 1st Pass Metabolismus entgehen. Wenn Symptome vorhanden, dann heisse es Karzinoid Syndrom.Serotonin:- ↑ Motilität und Peristalisis → Diarrhö- Stimuliert Fibroblasten und Kollagenbildung → Klappenfibrose → Tricuspidalklappeninsuffizienz- Bronchokonstriktion → GiemenHistamine, Bradykinin → Vasodilatation → Errötung- ↓ Tryptophan → Pellagra (Niacin-Mangel) Histologie:- Kaum Mitosen (langsam wachsend) Diagnose:- CT- Ocreotid-Scan- Urinanalyse: ↑ 5-HIAA- Blutanalyse: Niacin-Mangel Therapie: Somatostatin
Thyroid nodule - Differential
Benign thyroid nodules (∼95% of cases):- Thyroid adenomas→ Follicular adenoma (most common)→ Hürthle cell adenoma→ Toxic adenoma→ Papillary adenoma (least common)- Thyroid cysts- Toxic multinodular goiters Malignant thyroid nodules (∼5% of cases)- Thyroid carcinoma- Thyroid lymphoma- Metastatic cancer from breast/renal carcinoma (rare) Risk factors for malignancy:- Male gender- Extremes in age (< 20 years and > 65 years)- History of radiation to the head or neck- Family history of thyroid cancer or polyposis- Solid nodule - Cold nodule
Follicular adenoma
Most common type of thyroid adenoma. Clinical features:- Often presents as a slow-growing solitary nodule- The nodule grows larger → develops autonomy → over the course of several years becomes a toxic adenoma Diagnostics: - FNA cannot distinguish between follicular adenoma and carcinoma. - Thyroid surgery is therefore always indicated both for treatment and definitive diagnosis. Treatment:- Lobectomy with histologic analysis of frozen-section specimen- Thyroidectomy in the case of follicular carcinoma
Toxic adenoma
Pathophysiology: - Gain-of-function mutations of TSH receptor gene in a single precursor cell → autonomous functioning of the follicular cells of a single nodule → focal hyperplasia of thyroid follicular cells → toxic adenoma- The autonomous nodule overproduces thyroid hormones → hyperthyroidism → decrease in pituitary TSH secretion → suppression of hormone production from the rest of the gland Clinical features: hyperthyroidism Diagnostics:- ↑ T3 and ↓ TSH- Thyroid scintigraphy: → Solitary, hot nodule→ Shows radioiodine uptake by the hyperfunctioning nodules with suppression of rest of the gland Treatment:- Control symptoms with beta-blockers and thioamides until euthyroidism is achieved, followed by tapering of beta-blockers- Definitive treatment: Radioactive iodine ablation or lobectomy or hemi-thyroidectomy
Toxic multinodular goiter
- Second most common cause of hyperthyroidism- More prevalent in iodine-deficient areas Pathophysiology: Chronic iodine deficiency/thyroid dysfunction → decreased hormone production → increased pituitary TSH secretion → persistent TSH stimulation of the thyroid gland → hyperplasia of thyroid nodules, some more active than others → multinodular goiter (non-toxic MNG) → autonomous functioning of some nodules (toxic MNG) → hyperthyroidism Clinical features: hyperthyroidism and multinodular goiter Diagnostics:- ↑ T3 with ↓ TSH- Thyroid scintigraphy: shows radioiodine uptake by the hyperfunctioning nodules with suppression of the rest of the gland Histopathology: patches of enlarged follicular cells distended with colloid and with flattened epithelium Treatment: same as for toxic adenoma; surgery, if required, involves a near-total or total thyroidectomy
Thyroid cysts
Classification- Simple cysts are exclusively fluid-filled nodules lined by benign epithelial cells.- Complex cysts are partly solid and partly cystic and carry a 5-10% risk of malignancy. Etiology:∼ 50% are due to cystic degeneration of thyroid tissue (colloid cyst)∼ 40% are due to involution of a follicular adenoma∼ 10% are due to thyroid cancer Clinical features:- Hemorrhage into a cyst → pain and rapid enlargement of the nodule- A large cyst or extensive hemorrhage can cause compression symptoms (e.g., hoarseness, dysphagia) Diagnostics:- Ultrasound to assess size and appearance→ If low suspicion of malignancy but size > 2 cm → FNA→ If high suspicion of malignancy and size > 1 cm → FNA Treatment:- Benign cyst: Aspiration may be curative in some cases- For malignant cysts, see thyroid cancer
Goiter - Differential
- Iodine deficiency (leading cause of goiter worldwide) - Inflammation (eg, Hashimoto's thyroiditis, subacute granulomatous thyroiditis) - Graves' disease - Ingestion of goitrogens (eg, lithium carbonate) - Elevated TSH production (eg, pituitary adenoma) - Congenital goiter
Graves disease
Most common cause of hyperthyroidism in the United States- F > M (8:1)- Typical age range: 20-40 years - 50% of patients with Graves disease have a family history of autoimmune disorders (eg, type 1 diabetes mellitus, Hashimoto's disease, pernicious anemia, myasthenia gravis) Pathophysiology:- TSH-receptor stimulating IgG immunoglobulin (TRAb; type II hypersensitivity reaction) → ↑ thyroid function and growth → hyperthyroidism and diffuse goiter- TRAb stimulate orbital fibroblasts → fibroblast proliferation, hyaluronic acid synthesis, and differentiation of fibroblasts to adipocytes (opthalmopathy with exophthalmus)- TRAb stimulate dermal fibroblasts and deposition of glycosaminoglycans in connective tissue (pretibial myxedema) Diagnostics:- Best initial test: ↓/undetectable TSH and ↑ T3/T4 - Measure thyroid antibodies: ↑ TRAbs (specific), ↑ anti-TPO and anti-Tg (nonspecific)- Thyroid scintigraphy: Indicated if TRAbs are low to establish a diagnosis→ Shows a diffuse uptake of radioactive iodine (123I)→ Contraindicated in pregnancy Pathology:- Enlarged thyroid gland (normal 12-24 g)- Scalloping- Small follicles- Less amount of colloid (faster turnover) Treatment:- β-blockers: rapid control of hyperthyroidism symptoms- Antithyroid drugs: methimazole, propylthiouracil- Radioactive iodine ablation: First-line therapy in nonpregnant patients with small goiters
Morbus Basedow
1. Hyperplastisches Follikelepithel- Hohe zylindrische Zellen mit prominenten, vesikulärem Kern- Neigt sich dazu, sich papillär in das Lumen vorzuwölben 2. Wenig Kolloid 3. Gut vaskularisiertes Stroma
Riedel's thyroiditis
Rare, special form of autoimmune thyroiditis. Etiology:- Component of IgG4-related disease (may also cause fibrosis of salivary glands, kidneys, pancreas and lungs)IgG4 attacks thyroid follicar cells → T cells release inflammatory cytokines → abnormal fibroblast activation → stromal fibrosis → gland enlarges and hardens → fibrosis spreads to neck structuresDifferential: Anaplastic carcinoma of the thyroid Clinical presentation:- Goiter: Hardened, fixed, painless and enlarged thyroid gland- Hypothyroidism- Symptoms of compression (dyspnea, dyspnea, hoarseness) Diagnosis:- Low T3, T4- Ultrasound, CT scan, MRI- Tissue biopsy: Fibrous tissue, many T-cells, IgG4 antibody-producing plasma cells Treatment: Corticosteroids, hormone replacement, surgery may be necessary because of compression.
Subacute granulomatous thyroiditis (De Quervain thyroiditis)
Transient patchy inflammation of the thyroid gland that is associated with granuloma formation. Etiology:- Viral infections: Mumps virus, Coxsackie virus, influenza virus, echovirus, adenovirus- Mycobacterial infections Stages:1. Thyrotoxic phase (lasts 4-6 weeks)2. Hypothyroid phase (lasts 4-6 months)3. Euthyroid phase Clinical presentation:- Possible history of upper respiratory tract infections a few weeks prior to the onset- Painful, diffuse, firm goiter- Fever and/or malaise may be present.- Features of hyperthyroidism followed by features of hypothyroidism Diagnostics:- Thyroid function tests- Confirmatory test: ↑ ESR, radioiodine uptake study: ↓ iodine uptake (< 5%)- Ultrasound- Histologic features: granulomatous inflammation, multinucleated giant cells Treatment:Thyrotoxic phase- Beta-blockers to control symptoms of hyperthyroidism - NSAIDs: pain control in the case of acute granulomatous thyroiditis- Occasionally corticosteroids (i.e. prednisolone)Antithyroid drugs (e.g., methimazole) should not be administered!Hypothyroid phase: levothyroxine
Hashimoto's thyroiditis
Most common form of autoimmune thyroiditis and the leading cause of hypothyroidism in the United States.- F:M = 7:1 - Associations with HLA-DR3 and DR5, non-Hodgkin's lymphoma or autoimmune diseases Diagnosis:- Thyroid function tests- Antibody detection: → Anti-TPO antibody (also positive in 70% of patients with Graves disease)→ Anti-Tg antibody positive → Anti-microsomal antibodies- Ultrasound- Fine-needle aspiration: To exclude malignancy or lymphoma Pathology:- Diffuse lymphocytic infiltration (cytotoxic T lymphocytes) with germinal centers- Follicular cells change into Hurthle cells (oncocytic-metaplastic cells with eosinophilic cytoplasm) - Follicles atrophy- Fibrotic tissue Treatment:- Levothyroxine (T4) replacement therapy- Life-long monitoring Complications:- Myxedema coma- Thyroid lymphoma
Hashimoto Thyreoiditis
- Leicht fibrosiertes, knotiges mikrofollikuläres Schilddrüsenparenchym. - Dichtes lymphoplasmazelluläres Entzündungsinfiltrat mit Sekundärfollikeln. - Herdförmige entzündliche Zerstörung des Follikelepithels. - Follikelepithel mit reichlich feingranulärem Zytoplasma (onkozytäre Epitheltransformation) und reaktiven Kernatypien (einzelne vergrösserte hyperchromatische Kerne) = Hürthle Zellen
Papillary carcinoma
Most common thyroid cancer. - Associated with RET/PTC rearrangements and BRAF mutations, childhood radiation. - Metastasizes to regional cervical lymph nodes.∼ 80% of cases- 30-50 years of age Pathology:- Psammoma bodies- “Orphan Annie” eyes nuclei: Empty-appearing large oval nuclei with central clearing- Tumor papillae: connective tissue centers with vessels surrounded by a columnar epithelium- Nuclear grooves: longitudinal invaginations of nuclear bilayer Treatment: Hemithyroidectomy Prognosis: Excellent
Follicular carcinoma
- Associated with PAX8-PPAR-γ rearrangement and RAS mutation.- Patients with iodine deficiency ∼10% of cases- 40-60 years of age - Hematogenous metastasis (lungs, bone) Pathology:- Uniform follicles- Vascular and/or capsular invasion Treatment: - Total/radical thyroidectomy with neck dissection - Radioiodine therapy: often conducted 4-6 weeks after surgery to destroy remaining thyroid tissue or metastases- Thyroid hormone therapy with L-thyroxine after thyroidectomy
Medullary thyroid cancer
Tissue of origin: Parafollicular cells (C cells) - Sometimes a genetic predisposition: multiple endocrine neoplasia type 2 (MEN2) (25% of medullary carcinomas)- Sporadic (75% of medullary carcinomas) Pathology:- Ovoid cells of C cell origin and therefore without follicle development- Amyloid in the stroma (stains with Congo red)- Zellballen with Granular Nuclear ChromatinMedullary thyroid cancer often presents with isomorphic cells with a light cytoplasm and granular chromatin (so-called 'salt and pepper nuclei.') There have been many diverse descriptions of these characteristics. The arrangement of the cells, here in Zellballen, can differ from sample to sample. Nuclear polymorphisms and mitotic figures are not characteristic per se, but they can be a common finding. For a more complete diagnosis, a special stain for calcitonin must be used. Considering the origin of the C-cells, calcitonin can be regularly detected not only in the sample but also in the blood. Treatment:- Thyroidectomy with hormone replacement- Combined radiotherapy and chemotherapy
Neuroblastoma
Malignant neuroendocrine tumor of the sympathetic nervous system that originates from neural crest cells.- 3rd most common childhood cancer overall, following leukemia and brain tumors- Mean age at diagnosis: 1-2 years- Associated with overexpression of N-myc oncogene Clinical presentation:- Abdomen: Palpable, irregular abdominal mass that can cross the midline, abdominal distension and pain, constipation- Paravertebral ganglia: Spinal cord compression, scoliosis, dyspnea, cough, Horner syndrome- Orbit of the eye: Periorbital ecchymoses (“raccoon eyes”)- Paraneoplastic syndromes→ Chronic diarrhea → electrolyte imbalances (Neuroblastomas may secrete VIP)→ Opsoclonus-myoclonus-ataxia: rapid and multi-directional eye movements, rhythmic jerks of the limbs, and ataxia Diagnostics:- ↑ Catecholamine metabolites HVA (homovanillic acid) and VMA (vanillymandelic acid) in 24-hour urine- ↑ Lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE)- Abdominal ultrasound- CT or MRI: to identify the primary site- Scintigraphy: MIBG scan (MIBG is similar in structure to norepinephrine, so it is taken up by sympathetic nerve cells, including neuroblastoma or pheochromocytomatumor cells, throughout the body.)- Biopsy→ Evaluation for MYCN gene amplification→ Homer Wright rosettes: Halo-like clusters of cells surrounding a central pale area containing neuropil→ Small round blue cells with hyperchromatic nuclei→ Bombesin positive
Pheochromocytoma
Tumor arising from chromaffin cells, which are derived from the neural crest. Locations include:∼ 90% adrenal medulla (physiologically activated by acetylcholine) ∼ 10% extra-adrenal in the sympathetic ganglia∼ 10% at multiple locations Etiology:- 25% of pheochromocytomas are hereditary. - Associations include: Multiple endocrine neoplasia type 2 (MEN 2A, MEN 2B), neurofibromatosis type 1 (NF1), von Hippel-Lindau (VHL) disease “10 percent rule” - roughly 10% of pheochromocytomas are: extra-adrenal, multiple, bilateral, malignant, pediatric cases, not associated with hypertension, show calcifications on imaging! Clinical presentation:- Episodic hypertension (or persistent hypertension in some cases)- Throbbing headache- Diaphoresis- Heart palpitations and tachycardia- Pallor- Abdominal pain and nausea- Anxiety- May also secrete EPO →? polycythemia Diagnosis:- Best initial test: metanephrines in plasma (high sensitivity)- Confirmatory test: metanephrines and catecholamines in 24-hour urine (high specificity)- Genetic testing- Adrenal/abdominal CT or MRI- Scintigraphy (MIBG) Pathology:- Tumor cells arranged in nests, Zellballen- Nuclei are isomorphic, round, and have large nucleoli- Sustentacular cells outline nests; S-100 immunohistochemistry stain is needed - Highly vascularized, hemorrhages Treatment:- Preoperative blood pressure management: Combined alpha and beta-adrenergic blockade- Treatment of choice: laparoscopic tumor resection (adrenalectomy); "No-touch" technique
