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By: M. Shawn, M.B. B.CH. B.A.O., M.B.B.Ch., Ph.D.

Clinical Director, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine

Gastric dysplasia is usually a disease of later life; the diagnosis is made most commonly after the sixth decade and usually occurs against a background of long-standing chronic gastritis acne 9dpo purchase cheapest betnovate and betnovate. Obviously acne on chin cheap betnovate 20gm on-line, its main clinical significance is its association with gastric cancer; whenever a diagnosis of dysplasia is made acne era coat buy cheap betnovate on-line, it is prudent to reexamine the patient endoscopically for an occult established gastric cancer in the vicinity of the original biopsy acne 3 days purchase betnovate online from canada. For high-grade dysplasia the association with concurrent gastric cancer is so strong (up to 85%) that complete 8 Tumors of the Esophagus and Stomach 395 excision is necessary. Meticulous pathologic examination of such resection specimens is required to confirm completeness of excision and to identify adverse prognostic indicators if an invasive tumor is found. It may be entirely inconspicuous or may take the form of a slightly raised, thickened, congested mucosa, an ill-defined nodularity, or a slightly depressed lesion surrounded by radiating mucosal folds. The use of chromoendoscopy, magnifying endoscopy, and narrow-band imaging can highlight the mucosal irregularity. A tendency exists for high-grade dysplasia to be a depressed lesion and for low-grade dysplasia to be slightly raised. Some lesions, especially those with highgrade dysplasia, may show superficial erosions or even overt ulceration. Mucosa of the antrum, especially the lesser curve, is more commonly affected than that of the corpus. Microscopic Appearances the essential characteristics of gastric dysplasia, comprising abnormalities of cytology, differentiation, and architecture, have already been described in the previous section on adenomas. Conversely, highgrade dysplasia shows more cytologic atypia with large irregular nucleoli and an increasingly complex architecture, including back-to-back glands, that merges with carcinoma in situ. These have included mucin histochemistry, immunocytochemistry for markers of differentiation or cell proliferation, oncogene products, and morphometric analysis. Unfortunately none, so far, has shown a clear advantage over conventional morphologic assessment. Differential Diagnosis the principal differential diagnosis of dysplasia is regenerative epithelial hyperplasia or atypia related to gastritis, erosion, or ulceration. Foveolar hyperplasia is almost inevitable in gastritis, but the degree of accompanying atypia reaches worrying proportions only in a limited number of situations. The second is reactive (chemical or reflux) gastritis, a condition characterized by edema, vascular ectasia, fibrosis, smooth muscle proliferation, and foveolar hyperplasia of the mucosa, but relatively few inflammatory cells. In both of these types of gastritis, useful pointers to a regenerative rather than dysplastic change are relative preservation of the glandular architecture and the presence of some degree of maturation of the proliferating epithelium toward the mucosal surface. Furthermore, the nuclei of regenerative hyperplasia, though hyperchromatic, are usually rounder and basally oriented, and their nucleoli, though prominent, are small and regular. Though marked epithelial cytonuclear atypia is seen in the central part of the field, it is accompanied by cellular maturation in the upper zone of the pit and at the luminal surface-this is not dysplasia. Here, the degree of atypia may be particularly marked but differs from true dysplasia in that it affects both the foveolar and the deeper, specialized zones of the mucosa and is accompanied by cytoplasmic eosinophilia or vacuolation and sometimes microcystic change of the glands. Unlike true dysplasia, proliferative activity is confined to the deep foveolar zone, atypical mitoses are uncommon, and cellular maturation is seen toward the luminal surface. Men are affected more frequently than women, with the male to female ratio varying from 1 in young adults to 2 or more at the age of 60 years. A higher incidence is seen in Korea, Central and South America, and some parts of northern and eastern Europe,196 but second-generation immigrants take on the incidence of the host country. B, Bizarre, cytologically atypical gland lying within granulation tissue from the margin of a benign peptic ulcer. Similarly, a progressive decrease has occurred in intestinal-type tumors, whereas the diffuse type is increasing. An increasing proportion of adenocarcinomas of the proximal stomach (28%) have been noted in recent years, mirroring the increase in esophageal adenocarcinoma arising from Barrett esophagus. Clinical symptoms or signs include dyspepsia, anorexia, weight loss, hemorrhage, or obstruction of the gastric inlet or outlet, but these are rarely striking until the tumor is advanced, hence the overall poor prognosis. Nevertheless, early tumors are diagnosed more frequently, usually in individuals with symptoms suggestive of peptic ulcer disease, or by mass screening of asymptomatic populations, as has been pioneered in Japan. Macroscopic Appearances Advanced gastric cancer may take the form of polypoid. Ulcerated tumors are most common in the antrum on the lesser curve and classically differ from peptic ulcers by virtue of having more irregular contours with raised, rolled edges. However, it is impossible to make this distinction with certainty, and it is essential that multiple biopsies of the margins of all gastric ulcers be taken before embarking on clinical management. Polypoid and fungating carcinomas are more common in the corpus, often on the greater curve, whereas the diffusely infiltrating variety may occur as an ill-defined, superficially ulcerating plaque accompanied by conspicuous thickening of the underlying gastric wall or, less commonly, as a diffuse thickening of the entire stomach-the "leather bottle stomach. Microscopic Appearances In general terms, gastric adenocarcinomas may consist of tubular, acinar, or papillary structures or of poorly cohesive single cells that are widely infiltrative and dissect through the layers of the gastric wall in an insidious way. Cytologically, the tumor cells may show gastric or intestinal-type features, including differentiation toward parietal cells,210 argyrophil endocrine cells,211,212 or even chief cells213 or Paneth cells. Carcinoma of the stomach frequently shows considerable variation in histologic pattern and degree of differentiation. Grading (well, moderately, or poorly differentiated) applies primarily to papillary and tubular types. Papillary adenocarcinoma is characterized by numerous papillary processes with fibrovascular cores; a micropapillary variant is also recognized. Signet ring cell carcinoma consists predominantly of single cells or small clusters of cells containing intracytoplasmic mucus vacuoles and accounting for more than 50% of the tumor. Signet ring cell carcinoma tends to infiltrate the wall of the stomach diffusely and is often accompanied by marked fibrosis, giving rise to the linitis plastica macroscopic appearance. Other discohesive tumors may be composed of small cells resembling lymphocytes and others mimicking histiocytes or a mixture of cells, some with deeply eosinophilic cytoplasm. The tubular, papillary, and mucinous patterns are more commonly seen in the localized gastric carcinomas of polypoid, fungating, or ulcerated macroscopic types.

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B acne prevention cheap betnovate 20gm fast delivery, the two lobules in the peripheral portion of the tumor are not surrounded by fibrous stroma acne 4 dpo purchase 20 gm betnovate otc, lying naked in the adipose tissue acne xlr betnovate 20gm visa, and thus constitute invasive buds acne back discount betnovate 20gm fast delivery. Left, In some cases, the epithelial cells are ovoid, with few delicate cytoplasmic processes. Right, In some cases, especially type B1 thymoma, a striking dendritic pattern of staining is observed. That is, little perinuclear cytoplasm is present, but prominent anastomosing cytoplasmic processes are seen. The lymphoid component comprises predominantly immature T lymphocytes, which have been shown by genotypic studies to be nonclonal. B cells are usually present in small numbers, and they are found in particular in areas of medullary differentiation and in lymphoid follicles. Electron Microscopy the neoplastic cells of thymoma possess multiple interdigitating elongated cell processes connected by desmosomes. The top pathways associated with metastases are amino acid metabolism, biosynthesis of steroids and glycosphingolipids, cell cycle checkpoint proteins, and Notch signaling. According to Regnard and colleagues,36 this is the sole prognostic factor on multivariate analysis. In type A thymoma, the interspersed glandular structures typically show stronger staining than the spindled tumor cells. The various types of thymoma exhibit some differences in cytokeratin subtype expression. B, the lymphocytes associated with thymoma are typically immature T cells, as confirmed by terminal deoxynucleotidyl transferase immunostain. Tumor size greater than 11 cm has been shown to be an unfavorable prognostic factor on multivariate analysis. Poor performance status has been shown on multivariate analysis to be an unfavorable prognostic factor for overall survival. Although previous studies have found myasthenia gravis to be an adverse prognostic factor,89 recent studies have reported this feature to have no substantive effect on prognosis, probably because of improvements in the management of myasthenia gravis and earlier discovery of the thymic tumor as a result of presentation as myasthenia gravis. If a thymic epithelial tumor shows any significant degree of squamous differentiation, squamous cell carcinoma should be strongly suspected. On the other hand, the residual thymic epithelial cells found in a variety of nonepithelial tumors of the thymus may potentially lead to confusion with thymoma, but they can be recognized by their patchy distribution. Thymic Carcinoma Definition Thymic carcinoma (previously known as type C thymoma) is a primary epithelial neoplasm of the thymus showing cytologic features of malignancy and lacking thymic organotypic features. Clinical Features Thymic carcinomas account for approximately 15% of all primary thymic epithelial tumors. There is no association with myasthenia gravis or other paraneoplastic syndromes, except for the rare cases that evolve from a preexisting thymoma. Very rarely, squamous cell carcinoma may be associated with paraneoplastic hypercalcemia. The yellow color seen on the right side represents dye painted on the resection margin. A, the tumor infiltrates within a desmoplastic stroma in irregular islands but still with some vague resemblance to the lobulation seen in thymoma. Clinical Behavior and Treatment Thymic carcinomas are aggressive and commonly metastasize to regional lymph nodes and distant sites, particularly bone, lung, and liver. Squamous cell carcinoma, the most common type of thymic carcinoma, can be difficult to distinguish from pulmonary squamous cell carcinoma invading or metastasizing to the mediastinum. The distinction is important because thymic squamous cell carcinoma has a better prognosis (survival >50%). In the better differentiated tumors, keratinization and intercellular bridges are often evident. A case with prominent cystic change, simulating thymic cyst, has also been reported. Lymphoepithelioma-like carcinoma is histologically identical to nasopharyngeal carcinoma. Islands and sheets of tumor are intermingled with small lymphocytes and plasma cells. This tumor occurs more commonly in men, and a bimodal age distribution exists with peaks at 14 years and 48 years. Irregular islands of syncytial-appearing cells have vesicular nuclei and distinct nucleoli. In some cases, the tumor appears to arise in close association with the epithelial lining of multilocular cysts. In the latter group, nuclear atypia is significant, mitotic figures are easily found, and necrosis is present; most patients die of disease. Basaloid carcinoma is a rare thymic carcinoma characterized by sheets, nests, and trabeculae of small basaloid cells with peripheral palisading and frequent mitoses. Cystic degeneration is common, with the cysts being lined by tumor cells and with a cystic-papillary architecture being produced in some cases.

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Prussian blue staining frequently shows normal or increased iron stores but only occasional (<15%) ring sideroblasts acne hyperpigmentation treatment buy betnovate australia. Approximately 50% of patients have an abnormal karyotype acne keloidalis nuchae home treatment purchase 20gm betnovate mastercard, the majority of which (80%-85%) fall into low-risk prognostic categories (see later discussion) acne medication purchase generic betnovate line. The dysplasia noted is predominantly in the form of cytoplasmic hypogranulation or nuclear hypolobation acne keloid treatment cheap 20 gm betnovate overnight delivery. Internal controls of normally granulated neutrophils are important to recognize so as to avoid misinterpretation of a poorly stained specimen. Refractory Thrombocytopenia A diagnosis of refractory thrombocytopenia can be rendered when at least 30 megakaryocytes can be evaluated and dysplasia is noted in more than 10% of the megakaryocytes. Most commonly, the dysplasia takes the form of abnormal nuclear lobation (hypolobate, bilobate, and multilobate) or the presence of micromegakaryocytes. Specific cytogenetic abnormalities are not well established at this time; however, del(20q) has been reported in this entity. Sometimes the peripheral smear reveals dimorphic populations of normochromic and hypochromic cells; alternatively, normochromic, macrocytic, or normocytic anemia can be seen. Dysgranulopoiesis is considered present if cytoplasmic hypogranulation, or hyposegmented or hypersegmented nuclei, are observed in 10% or more of this lineage. Dysmegakaryopoiesis is diagnosed if more than 10% of a minimum of 30 megakaryocytes are micromegakaryocytes or have multiple, widely separated nuclei or a single, nonlobulated nucleus. Dysplastic features tend to be prominent and often involve all three myeloid lineages. This syndrome commonly, but not exclusively, occurs in middle-aged women (median 66 years; male to female ratio 1: 1. The bone marrow is usually hypercellular and characteristically contains conspicuously increased numbers of megakarocytes, which are characteristically small and hypolobated. Variable degrees of erythroid and myeloid dysplasia are noted, and erythroid hypoplasia is common. Other, less frequent recurrent chromosomal aberrations include balanced chromosomal translocations, unbalanced structural abnormalities (deletions and duplications), and numeric abnormalities. In this system, a normal karyotype, isolated del(5q), del(20q), or -Y, is considered a low-risk abnormality and carries a favorable prognosis. Patients with any one or two other chromosomal abnormalities, except those involving chromosome 7, are considered at intermediate risk. Poor risk is conferred to those individuals with complex (more than three) rearrangements or any abnormality that involves chromosome 7. Complex cytogenetic abnormalities also correlate with a higher risk of progression to acute leukemia and shortened survival. These common causes of morphologic dysplasia must be excluded for a diagnosis to be made. These myeloid precursor forms include cells destined to contribute to mature neutrophilic, eosinophilic, and basophilic granulocytic lineages, as well as the monocytic, erythroid, and megakaryocytic lineages. Therefore the increase in immature myeloid elements occurs at the expense of residual normal hematopoiesis and frequently results in hematopoietic insufficiency. The term acute denotes the rapidly progressive clinical course of the disease in the absence of any treatment. Careful inspection of cellular morphology for dysplastic nuclear features (typically absent in aplastic anemia) and accurate blast counts can aid in this differential. Bones (particularly the skull and facial bones), breast, testis, ovary, and brain are favored sites. General Morphologic Features in Acute Myeloid Leukemia In the majority of cases, marrow cellularity is increased and mainly comprises blasts or immature granulocytic or monocytic forms. A corresponding decrease occurs in maturing granulocytic forms and megakaryocytes (with a few notable exceptions). Erythroblasts are not included in the blast count except for the rare "pure" acute erythroblastic leukemias. In all other subtypes, once a blast count greater than 20% has been established, cytochemistry, immunophenotyping, and clinical history are all used in final subclassification. The nucleus is surrounded by moderate amounts of basophilic cytoplasm, which often contains several azurophilic granules. In some cases, numerous cytoplasmic granules or fused granules forming rod-like structures (Auer rods) (median 60 years). For both sexes, the incidence rises between the ages of 25 and 65 years over 10-fold (1. The most common consequence in the marrow is the replacement of normal hematopoietic elements, which results in cytopenias. Fatigue, pallor and dyspnea on exertion, infection and fever, and bleeding can occur as a result of anemia, neutropenia, and thrombocytopenia, respectively. Bone marrow aspirate smear showing myeloblasts with readily discernible Auer rods. Promonocytes have irregular or lobulated nuclei, with delicate folds or creases but fine chromatin, inconspicuous nucleoli, and abundant blue-gray, finely granulated, often vacuolated cytoplasm.

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Syndromes

Probably most cases represent type B3 thymoma (with typical architectural features of thymoma) in which the cytologic atypia exceeds that seen in the typical examples (so-called B3 thymoma with anaplasia) acne 7 months postpartum buy generic betnovate on line. It is unclear whether these tumors are still biologically B3 thymomas or represent progressed B3 thymomas with superimposed dysplastic or in situ carcinoma changes acne topical medications order betnovate 20gm amex. In other cases skin care 4men wendy generic betnovate 20 gm fast delivery, the tumor lacks the lobulation and perivascular spaces characteristic of thymoma acneorg buy betnovate us, but cellular atypia is not significant. Immunohistochemical studies can sometimes provide further information as to whether the tumor is biologically closer to thymoma or thymic carcinoma. If many TdT+ lymphocytes are present, the tumor is probably biologically closer to thymoma. This tumor shows lobulation and perivascular spaces, but the tumor cells show an extreme degree of nuclear hyperchromasia and pleomorphism. At the more benign end of the spectrum are the carcinoid tumors, and at the most malignant end are the small cell and large cell neuroendocrine carcinomas. The terminology and criteria for diagnosis are the same as those applied in the lung. The prognosis is generally poor, probably because of late detection of the tumor and lack of effective treatment. Microscopic Appearances Carcinoids are characterized by organoid clusters, sheets, and ribbons of polygonal cells separated by delicate fibrovascular stroma. True rosettes, pseudorosettes, perivascular rosettes, and spherical masses (often with comedo necrosis) can be present. The tumor cells possess round or oval nuclei with finely dispersed chromatin and inconspicuous nucleoli. Typical carcinoid is defined by a mitotic count of less than 2/10 hpf (2 mm2) and lack of necrosis. Atypical carcinoid is defined by (1) a mitotic count of 2 to 10/10 hpf (2 mm2) or (2) presence ## Carcinoid Tumor (Typical and Atypical) Clinical Features Carcinoid tumors of the thymus are uncommon. The patients have no symptoms, are initially seen with symptoms referable to the mediastinal mass, or have endocrine symptoms. A, Sheets of polygonal cells are traversed by delicate fibrovascular septa, characteristic of endocrine neoplasm. Pigmented variant, with ceroid pigment or melanin pigment being present in some tumor cells. This may mimic spindle cell thymoma, but the neuroendocrine nature of the tumor is suggested by the granular chromatin, granular cytoplasm, and delicate fibrovascular septa. The right field shows the component of atypical carcinoid, with eosinophilic granular cytoplasm. Thymic carcinoid with divergent sarcomatoid differentiation, with intermingling of the carcinoid with a sarcomatous component, which may even exhibit osseous or cartilaginous differentiation. Most tumor cells are positive for panneuroendocrine markers such as chromogranin and synaptophysin, in contrast to the patchy staining commonly observed in thymic carcinoma. The cytoplasm contains mitochondria, welldeveloped rough endoplasmic reticulum, and dense-core neurosecretory granules. Large cell lymphoma may simulate carcinoid tumor because of compartmentalization by a sclerotic stroma. In general, the tumor cells are more dispersed in at least some areas, and they commonly exhibit irregular nuclear folding. The diffuse subtype of carcinoid may simulate seminoma, but the latter often features prominent nucleoli, a sprinkling of lymphocytes, and lack of, or only focal dot-like staining for, cytokeratin. Paraganglioma shows a characteristic Zellballen pattern without formation of trabeculae. Lack of staining for cytokeratin and presence of S100-positive sustentacular cells around the tumor packets help to distinguish this tumor from carcinoid. Rare examples show focal squamous differentiation or adenosquamous differentiation. Teratomas are the most common, accounting for 44% of all cases and an even higher percentage in children (70%). The histologic features are indistinguishable from small cell carcinoma of the lung. In the prepubertal age group, teratoma and yolk sac tumor account for practically all cases, whereas in the postpubertal age group all the various types of germ cell tumor can occur. A rare but diagnostic presentation of teratoma is trichophysis (coughing up of hair). Supervening or Associated Second Neoplasms Some mediastinal germ cell tumors are associated with the development of hematologic neoplasia. The hematologic malignancies occur synchronously or subsequently (usually within 1 year) and include megakaryocytic disease, acute myeloid leukemia, myelodysplastic syndrome, "malignant histiocytosis," histiocytic neoplasm, and systemic mastocytosis. Some such cases have been demonstrated to show the same chromosomal aberration as the mediastinal tumor (isochromosome 12p), suggesting a common origin for both tumors. For teratomas with somatic-type sarcoma component, 80% of patients die within 2 years. Various types of germ cell tumor can be associated with the presence of multiple cysts, which result from metaplastic changes in the remnant thymic epithelium.

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