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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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While most carcinoids are asymptomatic through the natural lifetime and are discovered only upon surgery for unrelated reasons (so-called "coincidental carcinoids"), all carcinoids are considered to have malignant potential.
About 10% of carcinoids secrete excessive levels of a range of hormones, most notably serotonin (5-HT), causing:
- Flushing (serotonin itself does not cause flushing). Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes,[14] a serotonin-secreting carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes onto the valve.
- Diarrhea
- Wheezing
- Abdominal cramping
- Peripheral edema
The outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency. Niacin deficiency, also known as pellagra, is associated with dermatitis, dementia, and diarrhea.
This constellation of symptoms is called "carcinoid syndrome" or (if acute) "carcinoid crisis". Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. The most common originating sites of carcinoid is the small bowel, particularly the ileum; carcinoid tumors are the most common malignancy of the appendix. Carcinoid tumors may rarely arise from the ovary or thymus.
They are most commonly found in the midgut at the level of the ileum or in the appendix. The next most common affected area is the respiratory tract, with 28% of all cases — per PAN-SEER data (1973 – 1999). The rectum is also a common site.
Carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) are associated with carcinoid syndrome.
Carcinoid tumors are the most common malignant tumor of the appendix, but they are most commonly associated with the small intestine, and they can also be found in the rectum and stomach. They are known to grow in the liver, but this finding is usually a manifestation of metastatic disease from a primary carcinoid occurring elsewhere in the body. They have a very slow growth rate compared to most malignant tumors. The median age at diagnosis for all patients with neuroendocrine tumors is 63 years.
RMS can occur in almost any soft-tissue site in the body; the most common primary sites are genitourinary (24%), parameningeal (16%), extremity (19%), orbit (9%), other head and neck (10%), and miscellaneous other sites (22%). RMS often presents as a mass, but signs and symptoms can vary widely depending on the site of the primary tumor. Genitourinary tumors may present with hematuria, urinary tract obstruction, and/or a scrotal or vaginal mass. Tumors that arise in the retroperitoneum and mediastinum can become quite large before producing signs and symptoms. Parameningeal tumors may present with cranial nerve dysfunction, symptoms of sinusitis, ear discharge, headaches, and facial pain. Orbital tumors often present with orbital swelling and proptosis. Extremity tumors generally present as a rapidly enlarging, firm mass in the relevant tissue. The cancer's prevalence in the head, face, and neck will often allow for earlier signs of the disease simply due to the obvious nature of tumors in these locations. Despite the varying presentation and typically aggressive nature of the disease, RMS has the potential to be diagnosed and treated early. The fourth IRSG study found that 23% of patients were diagnosed in time for a complete resection of their cancer, and 15% had resection with only minimal remnants of the diseased cells.
Congenital mesoblastic nephroma typically (76% of cases) presents as an abdominal mass which is detected prenatally (16% of cases) by ultrasound or by clinical inspection (84% of cases) either at birth or by 3.8 years of age (median age ~1 month). The neoplasm shows a slight male preference. Concurrent findings include hypertension (19% of cases), polyhydramnios (i.e. excess of amniotic fluid in the amniotic sac) (15%), hematuria (11%), hypercalcemia (4%), and elevated serum levels of the kidney-secreted, hypertension-inducing enzyme, renin (1%). Congenital anomalies have been reported in 11 patients: 6 with genitourinary anomalies, 2 with gastrointestinal anomalies, 1 with hydrocephalus, and 1 with the Beckwith–Wiedemann syndrome. The vast majority of patients present with localized (i.e. non-metastatic) disease. Most patients' disease is classified at presentation as stage I or II (i.e. localized), few patients present with stage III (i.e. locally advanced/infiltrating), and virtually no patients present with stage IV (metastases present or V (i.e. tumors in both kidneys) disease (see staging of renal cancer).
There are few early warning signs that a patient has a DSRCT. Patients are often young and healthy as the tumors grow and spread uninhibited within the abdominal cavity. These are rare tumors and symptoms are often misdiagnosed by physicians. The abdominal masses can grow to enormous size before being noticed by the patient. The tumors can be felt as hard, round masses by palpating the abdomen.
First symptoms of the disease often include abdominal distention, abdominal mass, abdominal or back pain, gastrointestinal obstruction, lack of appetite, ascites, anemia, and/or cachexia.
Other reported symptoms include unknown lumps, thyroid conditions, hormonal conditions, blood clotting, kidney or urological problems, testicle, breast, uterine, vaginal, or ovarian masses.
AT/RT may be related to malignant rhabdoid tumor (MRT), which occurs outside the CNS, usually in the kidney. The finding that AT/RT and MRT both have deletions of the "INI1" gene indicates that rhabdoid tumors of the kidney and brain are at least closely related. AT/RT and MRT also have similar histology and similar clinical and demographic features. Moreover, 10–15% of MRT patients have simultaneous or subsequent brain tumors, many of which are secondary or primary MRT.
The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin:
- well-differentiated neuroendocrine tumours, further subdivided into tumors with benign and those with uncertain behavior
- well-differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior
- poorly differentiated (high grade) neuroendocrine carcinomas, which are the large cell neuroendocrine and small cell carcinomas.
Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer, a rare gastrointestinal tract tumor.
Placing a given tumor into one of categories depends on well-defined histological features: size, lymphovascular invasion, mitotic counts, Ki-67 labelling index, invasion of adjacent organs, presence of metastases and whether they produce hormones.
Diagnosis of mesoblastic nephroma and its particular type (i.e. classic, mixed, or cellular) is made by histological examination of tissues obtained at surgery. Besides its histological appearance, various features of this disease aid in making a differential diagnosis that distinguish it from the following childhood neoplasms:
- Wilm's tumor is the most common childhood kidney neoplasm, representing some 85% of cases. Unlike mesoblastic nephroma, 3 years of age. Bilateral kidney tumors, concurrent birth defects, and/or metastatic disease at presentation favor a diagnosis of Wilm's tumor.
- congenital infantile sarcoma is a rare aggressive sarcoma typically presenting in the lower extremities, head, or neck of infants during their first year of life. The histology, association with the "ETV6-NRTK3" fusion gene along with certain chromosome trisomies, and the distribution of markers for cell type (i.e. cyclin D1 and Beta-catenin) within this tumor are the same as those found in cellular mesoblastic nephroma. Mesoblastic nephroma and congenital infantile sarcoma appear to be the same diseases with mesoblastic lymphoma originating in the kidney and congenital infantile sarcoma originating in non-renal tissues.
- Rhabdoid tumor, which accounts for 5-510% of childhood kidney neoplasms, occurs predominantly in children from 1 to 2 years of age. Unlike mesoblastic nephroma, rhabdoid tumors may present with tumors in other tissues including in ~13% of cases, the brain. Rhabdoid tumors have a distinctive histology and abnormalities (i.e. loss of heterozygosity, single nucleotide polymorphism, and deletions) in chromosome 22.
- Clear cell sarcoma of the kidney, which is responsible for 5-10% of childhood pediatric tumors, occurs predominantly in children from 2 to 3 years of age. Unlike meoblastic nephorma, clear cell sarcoma of the kidney presents with metastasis, particularly to bone, in 5-6% of cases; it histology is diverse and has been mistaken for mesoblastic nephroma. One chromosomal translocations t,(10;17)(q22;p13), has been repeatedly reported to be associated with clear cell sarcoma of the kidney.
- Infantile myofibromatosis is a fibrous tumor of infancy and childhood most commonly presenting during the first 2 years of life as a single subcutaneous nodule of the head and neck region or less commonly as multiple lesions of skin, muscle, bone, and in ~33% of these latter cases, visceral organs. All of these lesions have an excellent prognosis and can regress spontaneously except for those in which there is visceral involvement where the prognosis is poor. While infantile myofibromatosis and classic mesoblastic nephroma have been suggested to be the same diseases because of their very similar histology, studies on the distribution of cell-type markers (i.e. cyclin D1 and Beta-catenin) indicate that they have different cellular origins.
GCCs have an aggressive course compared to other appendiceal neuroendocrine tumours.
Clinical signs and symptoms depend on the location of the tumor.
Since many of the tumors occur in the posterior fossa, they present like other posterior fossa tumors, often with headache, vomiting, lethargy, and ataxia (unsteady gait). A case of a seven-month-old child with a primarily spinal tumor that presented with progressive paraplegia and abnormal feeling in the legs was reported.
The strumal carcinoid is a type of monodermal teratoma with histomorphologic features of (1) the thyroid gland and (2) a neuroendocrine tumour (carcinoid).
Pulmonary neuroendocrine tumor are classified according to tumoral grade:
- Low grade pulmonary neuroendocrine tumor: Typical pulmonary carcinoid tumour (TC; low-grade);
- Intermediate-grade pulmonary neuroendocrine tumor: Atypical pulmonary carcinoid tumour (AC; intermediate-grade)
- High-grade pulmonary neuroendocrine tumor
- Small cell lung cancer (SCLC)
- Large cell neuroendocrine carcinoma (LCNEC of the lung)
Low-grade nodular neuroendocrine proliferations ≥ 0.5 cm are classified as carcinoid tumors and smaller ones are called pulmonary tumorlets.
When neuroendocrine cell hyperplasia and tumorlets are extensive, they represent the rare preinvasive lesion for carcinoids known as "diffuse idiopathic pulmonary neuroendocrine cell hyperplasia".
Both LCNEC and SCLC can demonstrate histologic heterogeneity with other major histologic types of lung carcinoma, such as pulmonary adenocarcinoma or pulmonary squamous cell carcinoma, but is not characteristic of TC or AC.
Atypical pulmonary carcinoid tumour is a subtype of pulmonary carcinoid tumor. It is an uncommon low-grade malignant lung mass that is most often in the central airways of the lung. It is also known as "atypical lung carcinoid tumour", " atypical lung carcinoid" or "moderately differentiated neuroendocrine carcinoma".
It is a more aggressive than typical carcinoid tumors: nodal metastases in 70% vs. 5%. The 5 year survival is 49-69%.
Atypical carcinoid tumors have increased mitotic activity (2-10 per 10 HPF), nuclear pleomorphism or foci of necrosis.
Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose. Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a metastasis. About 40% of PanNETS have symptoms related to excessive secretion of hormones or active polypeptides and are accordingly labeled as "functional"; the symptoms reflect the type of hormone secreted, as discussed below. Up to 60% of PanNETs are nonsecretory or nonfunctional, in which there is no secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin, do not cause a clinical syndrome although blood levels may be elevated. In total, 85% of PanNETs have an elevated blood marker.
Functional tumors are often classified by the hormone most strongly secreted, for example:
- gastrinoma: the excessive gastrin causes Zollinger–Ellison syndrome (ZES) with peptic ulcers and diarrhea
- insulinoma: hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C peptide
- glucagonoma: the symptoms are not all due to glucagon elevations, and include a rash, sore mouth, altered bowel habits, venous thrombosis, and high blood glucose levels
- VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or pancreatic cholera syndrome)
- somatostatinoma: these rare tumors are associated with elevated blood glucose levels, achlorhydria, cholelithiasis, and diarrhea
- less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma, and parathyroid hormone–related peptide tumor
In these various types of functional tumors, the frequency of malignancy and the survival prognosis have been estimated dissimilarly, but a pertinent accessible summary is available.
PanNETs are sometimes abbreviated as PETs or PNETs: such use should not to be confused with the primitive neuroectodermal tumor (PNET).
The majority of PanNETs are benign, while some are malignant. The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin. In practice, those tumors termed well or intermediately differentiated PanNETs in the WHO scheme are sometimes called "islet cell tumors." The high grade subtype, termed neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with "islet cell carcinoma".
Conceptually, there are two main types of NET within this category: those which arise from the gastrointestinal (GI) system and those that arise from the pancreas. In usage, the term "carcinoid" has often been applied to both, although sometimes it is restrictively applied to NETs of GI origin (as herein), or alternatively to those tumors which secrete functional hormones or polypeptides associated with clinical symptoms, as discussed.
Given the difficulty in diagnosing rhabdomyosarcoma, definitive classification of subsets has proven difficult. As a result, classification systems vary by institute and organization. However, rhabdomyosarcoma can be generally divided into three histological subsets:
- "Embryonal rhabdomyosarcoma" (ERMS) is the most common histological variant, comprising approximately 60–70% of childhood cases. It is most common in children 0–4 years old, with a maximum reported incidence of 4 cases per 1 million children. ERMS is characterized by spindle-shaped cells with a stromal-rich appearance, and the morphology is similar to the developing muscle cells of a 6–8 week old embryo. Tumors often present in the head and neck as well as the genitourinary tract. ERMS also has two defined subtypes, botryoid and spindle cell ERMS, and these subtypes are associated with a favorable prognosis.
- Subtypes of ERMS
- Botryoid ERMS is almost always found in mucosal lined organs including the vagina, bladder, and nasopharynx (although presentation in the nasopharynx typically affects older children). It often presents in patients <1 year old as a round, grape-like mass on the affected organ. Histologically, cells of the botryoid variant are defined by a dense tumor layer under an epithelium (cambium layer).
- Spindle cell rhabdomyosarcoma comprises about 3% of all RMS cases. This subtype is very similar to that of leiomyosarcoma (cancer of the smooth muscle tissue), and it has a fascicular, spindled, and leiomyomatous growth pattern with notable rhabdomyoblastic differentiation . It occurs most commonly in the paratesticular region, and the prognosis for this particular form of RMS is excellent with a reported 5 year survival rate of 95%.
- "Alveolar rhabdomyosarcoma" (ARMS) is the second most common type. ARMS comprises approximately 20–25% of RMS-related tumors, and it is equally distributed among all age groups with an incidence of about 1 case per 1 million people ages 0 to 19. For this reason, it is the most common form of RMS observed in young adults and teenagers, who are less prone to the embryonal variant. This type of RMS is characterized by densely-packed, round cells that arrange around spaces similar in shape to pulmonary alveoli, although variants have been discovered without these characteristic alveolar spacings. ARMS tends to form more often in the extremities, trunk, and peritoneum. It is also typically more aggressive than ERMS.
- "Anaplastic (undifferentiated) rhabdomyosarcoma", also known as "pleomorphic rhabdomyosarcoma", is the final variant of RMS recognized in most classification systems. Anaplastic rhabdomyosarcoma is defined by the presence of anaplastic cells with large, lobate hyperchromatic nuclei and multipolar mitotic figures. These tumors display high heterogeneity and extremely poor differentiation. The anaplastic cells may be diffuse or localized, with the diffuse variation correlating to a worse prognosis. It occurs most often in adults, rarely in children, and is often discovered in the extremities. Due to the lack of discernible separation among cancers of this type, clinicians will often label undiagnosed sarcomas with little to no discernible features as anaplastic RMS. It is the most aggressive type of RMS, and will often require intensive treatment.
There is also an extremely rare subtype of RMS that has been described as "sclerosing rhabdomyosarcoma" by "Folpe, et al", but it is not a currently recognized subtype by the NCI or WHO. This subtype has characteristic histology involving hyaline sclerosis and pseudovascular development. Its origins are unclear, but some studies have pointed to an association with embryonal RMS.
Multiple classification systems have been proposed for guiding management and treatment, and the most recent and widely used classification system is the "International Classification of Rhabdomyosarcoma" or ICR. It was created by the IRSG in 1995 after their series of four multi-institutional trials aimed at studying the presentation, histology, epidemiology, and treatment of RMS (IRSG I–IV). The ICR system is based on prognostic indicators identified in IRSG I–IV. Pleomorphic rhabdomyosarcoma usually occurs in adults rather than children, and is therefor not included in this system. Sclerosing rhabdomyosarcoma is also not included in this system due to its rare presentation and weak classification schema.
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- severe headache
- visual loss (due to papilledema)
- vomiting
- bilateral Babinski sign
- drowsiness (after several hours of the above symptoms)
- gait change (rotation of feet when walking)
- impaction/constipation
- back flexibility
Most paragangliomas are either asymptomatic or present as a painless mass. While all contain neurosecretory granules, only in 1–3% of cases is secretion of hormones such as catecholamines abundant enough to be clinically significant; in that case manifestations often resemble those of pheochromocytomas (intra-medullary paraganglioma).
"Lung tumors" are neoplastic tumors of the lung These include:
Primary tumors of the lung/pulmonary system:
- Bronchial leiomyoma, a rare, benign tumor
- Lung cancer, the term commonly used to refer to "carcinoma of the lung"
- Pulmonary carcinoid tumor
- Pleuropulmonary blastoma
- Neuroendocrine tumors of the lung
- Lymphomas of the lung.
- Sarcomas of the lung.
- Some rare vascular tumors of the lung
Non-lung tumors which may grow into the lungs:
- Mediastinal tumors
- Pleural tumors
Metastasis or secondary tumors/neoplasms with other origin:
- Metastasis to the lung
Children with pancreatoblastoma rarely present with early-stage disease, instead, most present with locally advanced or metastatic disease. Common presenting symptoms include abdominal pain, emesis, and jaundice. A multidisciplinary approach including good clinical history, state of the art imaging, and careful pathology is often needed to establish the correct diagnosis.
Desmoplastic small-round-cell tumor is an aggressive and rare cancer that primarily occurs as masses in the abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen, liver, chest wall, skull, spinal cord, large intestine, small intestine, bladder, brain, lungs, testicles, ovaries, and the pelvis. Reported sites of metastatic spread include the liver, lungs, lymph nodes, brain, skull, and bones.
The tumor is classified as a soft tissue sarcoma. It is considered a childhood cancer that predominantly strikes boys and young adults. The disease rarely occurs in females, but when it does the tumors can be mistaken for ovarian cancer.
In dogs, mast cell tumors are the most frequent round cell tumor.
Symptoms may include coughing, an upper respiratory tract infection, shortness of breath, and chest pain. These symptoms are very non-specific, and can be caused by other types of tumor in the lung or mediastinum more generally, and by other conditions. Imaging (X-ray, CT, MRI) may be used to determine the presence and precise location of a tumor, but not a specific diagnosis of PPB or other tumor.
Doctors are unable to tell if a child has PPB right away, and not upper respiratory tract infection, until more test are taken and they show that there is no infection. Another symptom is pneumothorax.
GCCs are diagnosed by pathology. They have a characteristic biphasic appearance which includes (1) goblet cell-like cells, and (2) neuroendocrine-type nuclear chromatin (stippled chromatin).
About 85% of paragangliomas develop in the abdomen; only 12% develop in the chest and 3% in the head and neck region (the latter are the most likely to be symptomatic). While most are single, rare multiple cases occur (usually in a hereditary syndrome). Paragangliomas are described by their site of origin and are often given special names:
- Carotid paraganglioma (carotid body tumor): Is the most common of the head and neck paragangliomas. It usually presents as a painless neck mass, but larger tumors may cause cranial nerve palsies, usually of the vagus nerve and hypoglossal nerve.
- Organ of Zuckerkandl: A collection of paraganglia near the bifurcation of the aorta, comprising a small mass of neural crest-derived chromaffin cells. Serves as a common origin of abdominal paragangliomas.
- Glomus tympanicum and Glomus jugulare: Both commonly present as a middle ear mass resulting in tinnitus (in 80%) and hearing loss (in 60%). The cranial nerves of the jugular foramen may be compressed, resulting swallowing difficulty, or ipsilateral weakness of the upper trapezius and sternocleiodomastoid muscles (from compression of the spinal accessory nerve). These patients present with a reddish bulge behind an intact ear drum. This condition is also known as the "Red drum". On application of pressure to the external ear canal with the help of a pneumatic ear speculum the mass could be seen to blanch. This sign is known as "Brown's sign". A deficient bony plate along the tympanic portion of the internal carotid artery (aberrant ICA) is a normal variant and can be mistaken with glomus jugulare.
- Vagal paraganglioma: These are the least common of the head and neck paragangliomas. They usually present as a painless neck mass, but may result in dysphagia and hoarseness.
- Pulmonary paraganglioma: These occur in the lung and may be either single or multiple.
- Other sites: Rare sites of involvement are the larynx, nasal cavity, paranasal sinuses, thyroid gland, and the thoracic inlet, as well as the bladder in extremely rare cases.