Jonathan A Clare, M.D.

• Assistant Professor of Emergency Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/10004261/jonathan-clare

The lymphoid cells in the cortex (right field) strongly express TdT medications nurses cheap solian 50 mg with mastercard, whereas those in the medulla (left field) are negative medicine 360 discount solian online mastercard. B-cell lymphoma medicine shoppe locations solian 50mg without a prescription, unclassifiable treatment 02 bournemouth order 100mg solian overnight delivery, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma (mediastinal gray zone lymphoma) 6 medications bad for your liver buy discount solian online. Diffuse thymic fibrosis Metastatic Tumors Unclassified Tumors Epithelial Tumors 1 medicine images order solian cheap online. Thymic epithelial tumor with features borderline between thymoma and thymic carcinoma Neuroendocrine Tumors 1. Approximately one third to one half of patients present initially with an asymptomatic anterior mediastinal mass on chest radiograph. One third present with paraneoplastic manifestations, such as myasthenia gravis, red cell aplasia, acquired hypogammaglobulinemia, thyroiditis, and systemic lupus erythematosus (Table 21C-3). The peripheral blood T lymphocytes exhibit an immunophenotype of medullary thymocytes or peripheral T lymphocytes, and are shown on molecular analysis to be polyclonal. The postulated mechanisms include (1) a reactive process due to disturbed immunoregulation that accompanies the thymoma and (2) spillover of the more mature T lymphocytes from the thymoma. Bland cytologic features, but mild cytologic atypia or occasional large atypical nuclei are acceptable. They are much less likely to be associated with myasthenia gravis,52 and the prognosis is favorable. Some of the thymomas in this age group show unusual stromal changes, such as cellular fibrous stroma within and around the lobules, and infiltration by eosinophils, histiocytes, and mast cells. Macroscopic invasion into thymus or surrounding fatty tissue, or grossly adherent to but not breaking through mediastinal pleura or pericardium Macroscopic invasion into adjacent organs. The position paper from the International Thymic Malignancy Interest Group provides further details on the application of the staging system. Chemotherapy, usually cisplatinum-based, is often given, sometimes with good responses. The invasive lobules (right upper field) are directly in contact with the fat without surrounding fibrous tissue. The Muller-Hermelink Classification of Thymomas In the mid-1980s, on the basis of histologic and immunophenotypic resemblance of thymomas to cortical or medullary areas in the thymus, Muller-Hermelink proposed a "functional" classification of thymomas (Table 21C-5). Although many studies have confirmed the correlation of histologic type with tumor stage and clinical outcome (Table 21C-6),54,90,95,100-107 some studies have failed to show prognostic significance of this classification on multivariate analysis and instead have found that the presence or absence of invasion is the single most important prognostic factor. Early recurrences, defined as those occurring within 3 years of surgery, often prove fatal. This is being rectified by acknowledging that these are tumors of low malignant potential. Adequate sampling is essential: at least one block per centimeter of tumor, with a minimum of five representative blocks irrespective of tumor size. In the report, the following features should be stated besides the diagnosis: (1) capsular integrity and invasion (with minimal invasion being defined as infiltration into adjacent fat to an extent of less than 3 mm), (2) status of the various margins, and (3) distance to closest margin. Macroscopic Appearances Thymomas vary in size from microscopic to large (weighing several kilograms). The cut surface typically shows tan-colored fleshy lobules delineated by fibrous septa, although rare thymomas may lack obvious lobulation. Invasive thymomas may manifest by obvious breaching of the fibrous capsule or invasion of adjacent structures and organs. The external surface of a resected thymoma typically has a smooth bosselated appearance. An invasive tumor bud has penetrated the capsule, and it lacks a fibrous clothing. The cellular composition and pattern of growth can vary greatly from case to case and even from lobule to lobule within the same tumor. The epithelial cells are usually large and appear "syncytial," ovoid, or polygonal. Their epithelial nature may be difficult to appreciate except when cellular groups are present, at the edges of the lobules, and around perivascular spaces. Isolated cells showing nuclear atypia or pleomorphism are acceptable, but mitotic figures should be sparse. The epithelial cells can also be spindle shaped, with elongated nuclei, fairly dense chromatin, and inconspicuous nucleoli. The epithelial cells are arranged in sheets, clusters, pseudorosettes, anastomosing networks, or ribbons. Spindle cells often show a fascicular, storiform, or hemangiopericytoma-like growth pattern. Microcystic spaces, small round glands, narrow cleft-like glandular spaces, mucinous glands, pseudopapillary formations, and abortive Hassall corpuscles are sometimes found. Rarely, multiple large blood-filled cystic spaces are found, so-called peliosis thymomis. Type B1 thymoma has the most dense population of lymphocytes among the various thymoma types. A, A highly characteristic feature is the presence of interspersed pale-staining foci representing medullary differentiation. Note the superficial resemblance to lymph node involved by B-cell chronic lymphocytic leukemia, which is characterized by pale-staining proliferation centers scattered in a dark-staining small lymphocyte background. B, the epithelial cells can be recognized by their larger nuclei with pale chromatin and small nucleoli. C, the perivascular space contains a blood vessel in the center and is filled with proteinaceous fluid and some lymphocytes. The lymphocytes are usually intimately intermingled with the epithelial cells but are sometimes segregated from them. Tingible-body macrophages may be scattered throughout, imparting a starry-sky appearance. A, In the focus of medullary differentiation (right field), the lymphocytes are less closely packed. B, Immunostaining for terminal deoxynucleotidyl transferase is negative in the focus, contrasting with strong staining in the surrounding lymphocytes. B, the epithelial cells can form discrete groups, and thus it is relatively easy to recognize the epithelial nature of this neoplasm. The lobules are often large and thus may be difficult to discern by examining an individual histologic section. The epithelial cells are commonly spindle shaped and arranged in a fascicular, storiform, or pericytomatous pattern. They possess bland-looking nuclei with fairly dense chromatin and indistinct nucleoli. At least focal glandular differentiation is seen, in the form of well-formed glands, abortive glands, signet ring cells, microcysts, cysts, papillae, and pseudopapillae, especially at the periphery of the lobules. A rare adenomatoid variant, characterized by a reticular, microvesicular, or microcystic growth pattern, has also been described. A, Palisading of epithelial cells is seen around a perivascular space, which is filled with lymphocytes. B, Immunostaining shows that the perivascular space is surrounded by cytokeratin-positive epithelial cells. A, Interspersed among the spindle cells are true glandular spaces, some of which contain secretion. Note that the glandular cells have fairly dense chromatin and inconspicuous nucleoli, as characteristic of tumor cells of type A thymoma. In this example, many signet ring cells are interspersed among the spindled tumor cells. They represent abortive attempts at glandular differentiation (intracytoplasmic lumens). In some cases, the tumor comprises uniform cuboidal cells with pale cytoplasm (right field). Note similarity of the chromatin pattern with that of the spindle cells (left field). At the peripheral portions and fibrous septa of the tumor, narrow tubular glands are lined by relatively flat cells. Glandular structures are characteristic of type A thymoma and are not seen in pure type B thymoma. Lymphocytes are typically sparse, and most of them are negative for TdT, that is, T cells at medullary thymocyte or mature stage. Uncommonly, abundant stroma is present, consisting of plaque-like fibrocollagen or stromal cells forming loose lattice-like networks. The diagnosis of type A thymoma used to be restricted to tumors with mitotically inactive and bland-looking spindled cells. The newly characterized atypical type A thymoma exhibits the same architectural features as conventional type A thymoma but shows increased mitotic activity (4 per 10 highpower fields [hpf]) and/or coagulative necrosis (to be distinguished from lobular type of necrosis). A lymphocyte-poor type A thymoma component is admixed with a lymphocyte-rich type B thymoma component, with the two components being present in highly variable proportions-in some areas, one type may predominate or occurs as the sole component. Sometimes the type A component apparently forms "cellular septa" coursing among the type B lobules. The neoplastic epithelial cells of the type B component are oval to plump spindled and often have smaller nuclei and less distinct nucleoli compared with those seen in type B1 or B2 thymoma. The lymphocytes occurring in the type B component are mostly immature T cells (TdT positive), whereas those in the type A component are mostly mature T cells (TdT negative). A, In this example, the two components are discrete, with a type A thymoma lobule (right) juxtaposed sharply with a type B thymoma lobule (left). The former comprises spindle cells associated with few lymphocytes, and the latter comprises plump ovoid cells admixed with numerous lymphocytes. Immunostaining for terminal deoxynucleotidyl transferase shows that most lymphocytes associated with the type B component are positive, whereas those associated with the type A component are negative. This example shows transition from B2 thymoma (right field) to B3 thymoma (left field). The epithelial component is relatively inconspicuous, manifesting as isolated ovoid cells with pale round nuclei and small nucleoli, although some cells may have larger nuclei and distinct nucleoli. This tumor has the richest component of lymphocytes among the various thymoma types. Commonly interspersed palestaining round foci representing medullary differentiation are present, composed of more loosely packed T lymphocytes that express a more mature phenotype (TdT negative). The neoplastic cells take the form of isolated or clustered large ovoid cells with vesicular nuclei and distinct nucleoli. They often exhibit a palisaded appearance around perivascular spaces and adjacent to the fibrous septa. In approximately 20% of cases, focal epithelialrich areas compatible with B3 thymoma are seen; such cases should be diagnosed as thymoma with B2 and B3 components (with estimation of the percentage of area occupied by the respective components). The tumor comprises lobules of polygonal epithelial cells separated by thick sclerotic septa. The epithelial cells often exhibit a squamoid quality, but intercellular bridges are lacking. Cellular palisading around perivascular spaces and along fibrous septa is often striking. Note resemblance of some of the cells to koilocytes, because of the presence of nuclear crenation and perinuclear cytoplasmic clearing. B, the tumor comprises lobules of polygonal epithelial cells with few admixed lymphocytes. Note the palisading of cells around the narrow perivascular space in the center field. This is distinguishable from type A thymoma by the atypia of the cells and the lack of A thymoma architecture such as glands, rosettes, and pericytomatous vascular pattern. However, in other cases, the cells have large vesicular nuclei and distinct nucleoli, resembling those seen in type B2 thymoma. Mild to moderate nuclear atypia is present, and some mitotic figures are commonly found. In some cases, the tumor cells are spindle shaped and form fascicles, resembling type A thymoma (atypical type A), but the cells are more atypical, and the distinctive growth patterns of type A thymoma are lacking. In this variant, multiple small discrete or coalescent nodules of bland-looking spindled epithelial cells are separated by abundant lymphoid cells with or without prominent germinal centers. Immunohistochemical analysis of the lymphoid component shows the presence of some immature T cells (TdT+) immediately around or within the epithelial nodules. The lymphoid cells between the epithelial nodules are predominantly B cells, which are admixed with some mature T cells. Staining for cytokeratin remarkably highlights the segregation between the epithelial and lymphoid components, in that no cytokeratin-positive cells are observed in the lymphoid stroma.

Mitotically Active Leiomyoma the mitotically active leiomyoma14-17 variant corresponds to leiomyomas with mitotic activity greater than 5 mitotic figures per 10 hpf but otherwise exhibits features typical of usual leiomyoma medications prednisone buy solian 50mg visa, particularly bland cytomorphologic features treatment herniated disc cheap solian amex, circumscribed margins symptoms of strep discount solian 100 mg online, and the absence of (coagulative tumor cell) necrosis symptoms 8 days post 5 day transfer solian 50 mg discount. These tumors may occur over a wide age range but symptoms xanax is prescribed for order discount solian, in contrast to leiomyosarcoma symptoms 6 days after iui 100 mg solian overnight delivery, are typically seen during the reproductive years, with a mean age in the fifth decade. The increased mitotic activity may be secondary to hormonal influences because these tumors are commonly seen in association with pregnancy, the secretory phase of the menstrual cycle, or hormonal therapy. Mitotic activity may be variable and is often increased during the secretory phase of the menstrual cycle, but usually fewer than 5 mitotic figures are present per 10 high-power fields (hpf). Those tumors with a higher mitotic count that are otherwise morphologically benign are discussed in the section on Mitotically Active Leiomyoma (see later discussion). Cellular Leiomyoma the threshold for considering a leiomyoma to be cellular is not precisely defined and is rather subjective. Similar to leiomyomas of the usual type, cellular leiomyomas are well circumscribed; however, they may appear tan, brown, or yellow on gross examination and have a softer consistency. A greater degree of cellu larity is apparent in comparison with the usual type of leiomyoma. Fascicular architec ture, cleftlike spaces, and large thickwalled blood vessels are characteristic. The size of the original tumor in their series was not known, and only four hematoxylin and eosin (H&E)-stained slides were evaluated, which, in this instance, raises the possibility of an undersampled leiomyosarcoma but more importantly underscores the requirement for extensive sampling in all tumors with nuclear atypia. After adequate sampling (minimum of one section per centimeter, including the interface with normal myometrium), atypical leiomyomas, particularly those with diffuse nuclear atypia, are distinguished from leiomyosarcoma by the absence of coagulative tumor cell necrosis and a mitotic count of fewer than 7 figures per 10 hpf; those tumors with mitotic counts between 7 and 10 mitotic figures per 10 hpf are best considered tumors of uncertain malignant potential. For practical purposes, after a diagnosis of atypical leiomyoma in patients treated by myomectomy alone, careful follow-up or hysterectomy should be considered. Leiomyoma with Hydropic Degeneration Accumulation of edema fluid (hydropic change) may occur focally or more diffusely within an otherwise banal leiomyoma. Histologically, the intercellular accumulation of edema fluid often has a paler, more eosinophilic appearance than myxoid change and usually results in a characteristic perinodular distribution of fluid deposition. In some instances the degree of hydropic change is so extensive as to obscure the smooth muscle nature of the tumor (requiring confirmatory immunohistochemistry with smooth muscle markers). The hydropic change may extend beyond the perimeter of the leiomyoma, suggesting infiltration by a myxoid neoplasm; however, these areas typically do not stain for acidic mucins. The generally well-circumscribed nature and absence of smooth muscle bundle protrusion into endotheliallined spaces (which may require confirmation by mitotic figures per 10 hpf, and the biologic behavior of histologically banal tumors that cross this mitotic threshold is not clear. Most atypical leiomyomas have a similar gross appearance to leiomyomas of the usual type, but a subset may have a more yellow appearance and a softer consistency. In addition to the presence of significant nuclear atypia, a defining histologic feature is a mitotic count that numbers fewer than 7 mitotic figures per 10 hpf, particularly in tumors with diffuse nuclear atypia. This threshold is based on the series of Downes and Hart,18 in which tumors that met these criteria had a benign follow-up (mean 11 years), with most patients in this series being treated by hysterectomy. It is important to note that very few patients who have been treated by myomectomy alone have had long-term follow-up; therefore these tumors, particularly those with diffuse nuclear atypia treated by myomectomy alone, should be diagnosed with care. As a case in point, one example of such a tumor (with <2 mitotic figures per 10 hpf), treated by myomectomy alone, recurred at the surgical site within the myometrium 3 years after initial excision (personal observation). Separation of muscle bundles by accumulation of edema fluid produces a multinodu lar appearance. Deposition of abundant extracellular matrix separates the tumor cells and imparts an epithelioid appearance. Plexiform Leiomyoma Considered a variant of epithelioid leiomyoma because of its pseudoepithelioid appearance on histologic examination, this benign smooth muscle tumor, also known as a plexiform tumorlet, is most commonly an incidental finding in hysterectomy specimens at the time of histologic examination. Accumulation of the latter causes loss of the typical spindled appearance to the cells and imparts an epithelioid appearance. Immunohistochemical and ultrastructural analysis have shown that these tumors have features of smooth muscle rather than epithelial differentiation. Patients with the epithelioid variant of leiomyoma do not differ in their clinical presentation from those with the usual type of leiomyoma, being most often affected during the reproductive years. On gross examination, some tumors may appear different from the usual type of leiomyoma, having a softer consistency or a tan or yellow appearance. Microscopically, these tumors are characterized by a proliferation of rounded cells with abundant clear or eosinophilic cytoplasm arranged in sheets but also sometimes in nests and cords. The nuclei may be located centrally within the cytoplasm or at the periphery, which may impart a signet ring cell appearance. The validation of diagnostic criteria for reliable prediction of the behavior of smooth muscle tumors with epithelioid differentiation is limited by the rarity of this tumor subtype. Only a limited number of series have been published and, even with these studies, classification and prognostication continue to be problematic. Other features that have correlated with benign behavior include a well-circumscribed margin and tumor size less than 6 cm. Only a few epithelioid leiomyomas have been analyzed cytogenetically, and most have shown abnormalities similar to that seen in conventional leiomyomas, including del(7)(q21. Myxoid Leiomyoma this extraordinarily uncommon variant of leiomyoma is characterized by the presence of extracellular matrix deposition composed of acid mucin. Histologically, an abundant pale-blue myxoid matrix, that is typically positive for Alcian blue, separates the muscle bundle fibers. The presence of a prominent adipocytic component often results in yellow coloration of the leiomyoma on gross examination. For practical purposes, based on limited experience, lack of tumor cell necrosis, minimal to no nuclear atypia, lack of infiltration, and a mitotic count of fewer than 2 per 10 hpf favor a benign myxoid leiomyoma. Lipoleiomyoma this unusual variant of leiomyoma40-42 is characterized by the presence of variable numbers of adipocytes admixed with the smooth muscle cells, which, when numerous, will result in a yellow coloration discernible on gross examination. Vascular Leiomyoma Also termed angiomyoma or angioleiomyoma, this unusual and somewhat subjective morphologic variant of benign leiomyoma43 is characterized by a prominent component of blood vessels. Extramedullary hematopoiesis in the form of clusters of nucle ated red blood cells. Leiomyoma with Hematopoietic Elements Occasionally, otherwise morphologically ordinary leiomyomas may be infiltrated by variable, sometimes extensive amounts of hematopoietic cells,44-50 including lymphocytes, mast cells, eosinophils, or histiocytes. Neurilemmoma (Schwannoma)like Leiomyoma the neurilemmoma histologic variant of leiomyoma51,52 is characterized by palisading of tumor cell nuclei such that the lesion resembles a benign nerve sheath tumor. Although the resemblance may be uncanny, these tumors do not show ultrastructural evidence of schwannian differentiation. Other Benign Lesions Adenomyoma Although considered here as a variant of leiomyoma, whether adenomyomas53 represent a tumorous mass as opposed to a circumscribed variant of adenomyosis is not clear and this has not been studied pathogenetically. Similar to leiomyomas, these lesions typically occur during the reproductive years and patients usually present with abnormal uterine bleeding. Increased number of blood vessels characterizes this unusual variant of leiomyoma. Pseudovascular spaces lined by bland cuboidal to attenuated epithelium are surrounded by a proliferation of smooth muscle. On gross examination, the lesions are typically well demarcated from the surrounding myometrium and often contain small cysts that may appear hemorrhagic. When located submucosally, they may mimic an endometrial polyp but usually have a firmer consistency and a myomatous appearance on the cut surface. Histologically, these lesions are composed of nests and islands of endometrial stroma and well-spaced, sometimes cystic, benign-appearing endometrioid glands that are surrounded by a proliferation of smooth muscle, with the latter component typically predominating. Distinction from adenomyosis may sometimes be arbitrary but, in general, adenomyosis tends to be a diffuse process that has indistinct borders with the myometrium. More important is the distinction from atypical polypoid adenomyoma (see Chapter 13B), which, similar to adenomyoma, is characterized by a myomatous stroma but differs in having a more complex proliferation of glands (that in some instances is indistinguishable from well-differentiated endometrioid adenocarcinoma) and commonly shows squamous morular metaplasia. Adenomatoid Tumor these tumors,54-57 which are usually incidental findings in hysterectomy or myomectomy specimens from reproductive-aged women, are not variants of leiomyoma per se but represent a benign tumorous mass of presumed mesothelial origin with a prominent smooth muscle component that may mimic a leiomyoma on gross and histologic examination. They are most commonly located in the subserosal area; may appear tan, white, or yellow; and are generally more poorly demarcated from the surrounding myometrium than leiomyomas. Most tumors measure less than 5 cm; however, occasionally they may be larger, with many such cases having a prominent cystic component. Histologically, pseudovascular spaces lined by cuboidal to attenuated epithelial cells with bland nuclei are separated by bands of smooth muscle. If the tumor does not involve the endometrial cavity, preoperative endometrial sampling may not be informative; nevertheless, in a postmenopausal patient, the clinical impression of a large or rapidly enlarging fibroid should raise the suspicion for malignancy. Uterine leiomyosarcoma is an aggressive tumor that has a tendency to recur locally and/or metastasize, most commonly to the liver and lung. Regional lymph node involvement is not common and is typically seen only in patients with advanced-stage disease; therefore lymph node dissection is usually performed only in patients with 13 Tumors of the Female Genital Tract 803 clinically suspicious nodes. A more homogeneous, "fish flesh" appearance with geographic areas of hemorrhage and necrosis is typical. Pathologic Features Leiomyosarcoma is typically a solitary or dominant mass within the uterus, is most commonly intramural but may be submucosal or subserosal, and has a mean diameter of 9 cm. Although any of these unusual gross features may raise the possibility of malignancy (and should prompt extensive sampling), the diagnosis of leiomyosarcoma is based solely on the histologic appearance of the tumor. The vast majority of leiomyosarcomas are of the spindle cell type; however, epithelioid and myxoid variants occur, with each of these variants having different criteria for the diagnosis of malignancy (Table 13D-1). Spindle Cell Leiomyosarcoma the spindle cell variant of leiomyosarcoma is so called because it morphologically mimics benign leiomyomas, being composed of fascicles of spindled cells with varying amounts of eosinophilic cytoplasm. Over time it has become apparent that no single histologic feature, perhaps with the exception of tumor cell necrosis (which may be difficult to recognize in isolation), is diagnostic of malignancy. Rather, the diagnosis of leiomyosarcoma is based on data from a landmark study by Bell and colleagues,16 in which a combination of histologic features is assessed. These features include (1) the presence and extent of significant nuclear atypia (practically defined as atypia notable at low power [i. Myxoid Leiomyosarcoma Similar to the spindle cell variant, myxoid leiomyosarcoma39,81-83 also typically occurs in women in their sixth decade who present with abnormal bleeding, pelvic pain, or a pelvic mass. In contrast, however, the gross appearance will have a more gelatinous appearance, with a glistening cut surface, which may vary in extent depending on the amount of extracellular myxoid matrix deposition. Histologically, these tumors are characterized by abundant, pale blue, extracellular myxoid matrix that is Alcian blue positive. This latter scenario is very uncommon and raises the important diagnostic problem of what constitutes proper tumor cell necrosis versus benign degenerative changes. Coagulative tumor cell necrosis is characterized by (1) an irregular, angulated border (geographic appearance); (2) a sharp interface between the viable and necrotic cells (as opposed to a transition zone composed of granulation or hyalinized tissue characteristic of ischemia); (3) the presence of apoptotic or nuclear debris at the interface; and (4) atypical ghost cells (for tumors with nuclear atypia) within the necrotic areas. A sharp interface between viable and necrotic cells with nuclear debris is characteristic. Tumor cells typically exhibit at least focal moderate atypia, although much of the tumor may have a bland cytomorphologic appearance. Because of the rarity of this tumor, diagnostic criteria separating myxoid leiomyosarcoma from myxoid leiomyoma are not well established. Atkins and colleagues39 suggested that a rate in excess of 2 mitotic figures per 10 hpf, regardless of the presence or absence of either atypia or necrosis, will separate benign from malignant myxoid tumors. For practical purposes, the diagnosis of myxoid leiomyosarcoma should be considered if any of the following are present: (1) moderate to marked cytologic atypia; (2) coagulative tumor cell necrosis; (3) mitotic activity exceeding 2 mitotic figures per 10 hpf; or (4) destructive infiltration of the surrounding myometrium. Epithelioid Leiomyosarcoma A predominance of rounded tumor cells with abundant eosinophilic or clear cytoplasm characterizes this subtype of leiomyosarcoma30,35,37,38. Similar to myxoid leiomyosarcoma, the validation of diagnostic criteria used to predict reliably the behavior of epithelioid smooth muscle tumors is limited by the rarity of this tumor subtype and the limited number of series that have been published. In the largest published series of epithelioid smooth muscle tumors (80 cases; in abstract form38), malignant behavior was associated with the presence of tumor cell necrosis, vascular invasion, moderate to severe nuclear atypia, and a mitotic count greater than 3 per 10 hpf. Although many of the tumor cells may appear bland, most cases exhibit at least a moderate degree of nuclear atypia. Most leiomyosarcomas will show some degree of positivity for smooth muscle markers, the most commonly employed being smooth muscle actin, desmin, and h-caldesmon. It is important to note that loss of staining for these markers can occur (correlating with downregulation by gene expression profiling). For some, such as epithelioid and myxoid smooth muscle tumors, uncertainty remains because of their rarity and thus inherent difficulty in establishing and validating diagnostic criteria that would predict malignant behavior. Other tumors are best considered in this category because they approach, but fall short of, the diagnostic threshold for malignancy or the presence of tumor cell necrosis is ambiguous and cannot be distinguished from a benign process with certainty. In addition, features defined by Bell and colleagues16 as indicating a tumor with uncertain or low malignant potential are outlined in Table 13D-1. In practice, only a minority of smooth muscle tumors falls within this category, and some would even question whether low-grade uterine leiomyosarcoma exists. Immunohistochemical markers such as p53, p16, and Ki-67 have not been proved to be of diagnostic use and should be interpreted with caution on a case-by-case basis. Patients typically present with abnormal uterine bleeding, pelvic pain, or a pelvic mass, and clinical examination usually reveals an enlarged uterus. Gross examination, in which multiple myometrial masses are typically present, may also show worm-like plugs of tumor within parametrial vessels. On rare occasions, extension into the inferior vena cava and its tributaries may occur, including involvement of the heart. Usually a component of conventional leiomyoma is also present within the uterus; however, in some cases the entire tumor is present within vascular spaces, which may not be appreciated initially on gross examination. Histologically, the intravascular tumor, which often has a lobulated or clefted contour, resembles a typical uterine leiomyoma, although in many cases it may also exhibit extensive hydropic or hyaline change. Other histologic variants may occur, including cases in which the intravascular component is cellular, myxoid, or epithelioid or contains a component of adipocytes (lipoleiomyoma-like). Although there are no reported series of these tumors with long-term follow-up, they are generally considered benign without risk of recurrence.

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Prediction of the Primary Site for Metastatic Carcinoma About 3% to 4% of carcinomas present with metastases from an occult primary neoplasm treatment 7th march bournemouth purchase solian 100mg line. For example treatment 001 - b purchase cheapest solian, a breast or lung primary has to be seriously considered for axillary lymph nodes medications similar to xanax buy solian without a prescription, and a breast medications given for adhd cheap solian 50mg otc, lung treatment mastitis order discount solian on-line, or genital organ origin has to be considered for supraclavicular nodes symptoms 5-6 weeks pregnant buy solian 100 mg overnight delivery. Morphologic assessment can provide important diagnostic clues and help in the selection of special studies. Undifferentiated carcinoma of the nasopharynx can often be suspected on the basis of the presence of sheets of cells with indistinct cellular outlines, crowded vesicular nuclei, and prominent nucleoli. Immunohistochemical studies are particularly helpful in selected situations, as listed in Table 21A-21. In general, they are more likely to yield fruitful information for adenocarcinoma than squamous cell carcinoma. The tumor is well circumscribed, with compressed lymph node tissue at the periphery. It consists of intersecting fascicles of bland-looking spindle cells that are probably myofibroblasts. The interfollicular infiltration and intermingling of tumor cells with lymphocytes may prompt a diagnosis of lymphoma. The epithelial nature of this tumor is suggested by the presence of vague cellular groupings, such as in the right field. In nasopharyngeal carcinoma, the cell borders are typically indistinct and the nuclei are vesicular. Hemorrhagic spindle cell tumor with amianthoid fibers (palisaded myofibroblastoma) 2. Nevus cell aggregates and blue nevus formation of stellate collagen nodules (amianthoid fibers). Interstitial hemorrhage is often prominent, and a hemorrhagic zone may be present in the periphery. Angiomyomatous Hamartoma this lesion occurs almost exclusively in inguinal lymph nodes and may be accompanied by ipsilateral lymphedema. Proliferation of thick-walled blood vessels in the nodal hilum extends into the nodal parenchyma in the form of haphazardly disposed smooth muscle cells in a sclerotic stroma. Sometimes, the lesion occurs as an incidental finding in pelvic lymph nodes (nodal lymphangiomyoma). That is, these lesions belong to the family of perivascular epithelioid cell tumors. Lymph node can also be very rarely involved by angiomyolipoma, usually in association with a renal tumor. Deciduosis of Lymph Node In pregnant women, compact masses of decidual cells may be found in intra-abdominal lymph nodes. The absence of desmoplastic reaction, mitotic figures, and keratinization distinguishes this lesion from metastatic squamous cell carcinoma. Short fascicles of spindle cells are interspersed with narrow, branching vascular spaces. Kaposi Sarcoma of Lymph Node Clinical Features and Epidemiology Kaposi sarcoma is a distinctive vascular tumor of lymphatic origin, frequently showing multicentric growth (see Chapter 3). It occurs in several clinical settings, associated with different prognosis1,1703-1711: 1. Cutaneous lesions occurring in young adults; the disease can be indolent or progressive. Lymphadenopathic form, occurring mainly in children; the disease is rapidly progressive. The disease is often fulminant and disseminated, involving mucocutaneous sites, lymph nodes, and visceral organs. Associated with immunosuppression: the risk of development of Kaposi sarcoma is increased in organ transplant recipients and immunosuppressed subjects. Established Kaposi sarcoma is characterized by curved intersecting fascicles of spindle cells, resulting in longitudinally sectioned fascicles juxtaposed side by side with transversely sectioned cells showing a sieve-like pattern. The small vascular spaces and clefts containing extravasated erythrocytes are often more evident in the latter. The spindle cells are usually but not invariably bland looking and mitotically inactive. Plump ovoid cells can also occur, and they often merge into some barely canalized vascular channels. In the hilar region (right field), proliferation of thick-walled blood vessels is seen. Right, In the parenchyma, smooth muscle cells are haphazardly disposed in a sclerotic stroma. Inflammatory Pseudotumor of Lymph Node this is a rare, benign lymphadenopathy occurring in young adults who usually present with fever. The process predominantly involves the connective tissue framework of the node and is characterized by proliferation of spindle cells (mostly activated histiocytes and fibroblasts), thin-walled blood vessels, and mononuclear cells. Lymph node inflammatory pseudotumor is clinically and morphologically different from inflammatory pseudotumor of the lung and miscellaneous sites, and at least some cases may be related to the family of idiopathic fibrosclerotic disorders. The mild increase in spindle cells, thin-walled vessels, and plasma cells suggests the diagnosis, which can be rendered more definitively because of the presence of hyaline globules in the cell in the center. Diagnosis of early lesions of Kaposi sarcoma in the nodal capsule can be very difficult; there may be merely a subtle increase in some irregular vascular channels mixed with plasma cells and rare spindle cells. In contrast to benign vascular tumors, no or very few actin-positive pericytes are present in Kaposi sarcoma. Primary Vascular Tumors of Lymph Node Primary vascular tumors of lymph node other than Kaposi sarcoma are very rare. A diagnosis of nodal epithelioid hemangioendothelioma should prompt careful exclusion of a primary elsewhere. Vasoproliferative Lesions Complicating Hyaline-Vascular Castleman Disease A variety of vasoproliferative lesions can supervene in hyaline-vascular Castleman disease. Vascular neoplasms, which span a spectrum from benign to malignant, have been reported. A, Intersecting curved fascicles of spindle cells, with longitudinally sectioned cells juxtaposed with transversely sectioned cells. B, Many cells in this field exhibit the eosinophilic hyaline globules characteristic of Kaposi sarcoma. This uncommon tumor is characterized by solid "organoid" growth of bland-looking cells (right field), which merge into irregular vascular clefts (upper field) and into cavernous vascular spaces (left field). The cellular area comprises spindle cells interspersed with some branching vascular slits. Vascular Transformation of Lymph Node Sinuses this is a reactive condition often associated with lymphovascular obstruction. The nodal sinuses are expanded by complex anastomosing vascular channels with a flat endothelial lining, often accompanied by a sclerotic stroma. Cellular spindle or plump cell areas may be seen, but there is maturation into better formed vascular channels toward the capsular aspect. Very rarely, the vascular channels form plexuses or form vague or discrete nodules. B, the lesion comprises spindle cells with pale nuclei and blood vessels, which are intermingled with small lymphocytes. Immunostaining is required to distinguish it from follicular dendritic cell proliferative lesion. The skin is the most common site of involvement (in the form of multiple skin nodules), but lymph node and spleen can also be involved. The disease is potentially lethal but shows an excellent response to antibiotics such as erythromycin. Bacillary angiomatosis of lymph node is characterized by multiple coalescent nodules of barely canalized or ectatic vessels lined by pale-staining plump endothelial cells that may exhibit some degree of nuclear pleomorphism. It has been postulated that they reach the lymph nodes by embolization into lymphatics. Blue nevi can also rarely occur in nodal capsules, sometimes associated with similar lesions in the skin. Epithelial or Mesothelial Inclusions in Lymph Node Epithelial elements may sometimes be found in lymph nodes, mimicking metastatic carcinoma. Thyroid follicle inclusions in cervical lymph nodes are very rare and have to be diagnosed with use of strict criteria, including microscopic size, lack of cytologic atypia, and lack of stromal reaction, because thyroid follicles found in lymph nodes are much more likely to represent metastasis from an occult papillary thyroid carcinoma. The mesothelial cells are found mostly in the sinuses, forming isolated cells or clusters, and can potentially be mistaken for metastatic carcinoma. They are polygonal and possess bland nuclei and abundant eosinophilic cytoplasm, associated with intercellular "windows. The nodules are not genuine follicles but are large collections of neoplastic cells with fibrous framework or blood vessels stretched around them. The cytologic composition is also not in keeping with follicular center cell lymphoma. How to Distinguish Between Reactive Follicular Hyperplasia and Follicular Lymphoma The follicles in reactive follicular hyperplasia are discrete and well separated by at least some interfollicular lymphoid tissue; these follicles are often variable in size and shape and are not uncommonly dumbbell shaped or serpentine. They have well-defined mantles, although mantles may be deficient in some reactive conditions. The follicles exhibit a heterogeneous population of follicular center cells, with large cells often outnumbering small cells. Tingible-body macrophages are typically interspersed, and cellular polarization into light and dark zones is present. The germinal centers are characteristically mottled because of the presence of tingible-body macrophages. B, Part of the germinal center is light staining (light zone), and part of it is dark staining and rich in tingible-body macrophages. The most important criterion for diagnosis of follicular lymphoma is the arrangement of the follicles as seen at low magnification. A pattern of back-to-back follicles disposed throughout the entire nodal parenchyma, with little interfollicular tissue, is diagnostic of follicular lymphoma. This pattern is observed in approximately 80% of all cases of follicular lymphomas. A diagnosis of follicular lymphoma should be made with utmost caution in children and young adults. Bone marrow biopsy can also be very helpful, because the presence of paratrabecular lymphoid infiltrates would provide strong support for a diagnosis of follicular lymphoma. Caveats in Morphologic Assessment There can be many exceptions to the previously listed criteria. Reactive follicle centers heavily infiltrated by reactive T lymphocytes may impart an impression of small cell predominance or cellular monotony. When preexisting reactive follicles are partially involved by follicular lymphoma, the histologic appearances can be highly confusing. The lymphoid follicle lacks a discrete mantle and shows follicle lysis, as evidenced by hemorrhage and presence of patches of disintegrated cells. In such a situation, other immunostains are required to provide the supportive evidence. One caveat is that in rare cases of reactive lymphadenopathy, some of the germinal centers may show light chain restriction. In reactive follicles, polarity can often be visualized by immunostaining for Ki67, because a substantial proportion of the follicle center cells in the dark zone are stained positively. A low Ki67 (proliferation) index in the follicles strongly favors a diagnosis of follicular lymphoma over reactive follicular hyperplasia (mean Ki67 index 15. It should be seriously considered if the cytologic composition is monotonous or the irregularly folded nuclei have an overall rounded contour. Marginal zone lymphoma with prominent follicular colonization can be difficult to distinguish from follicular lymphoma. In follicular lymphoma, the nodules are often closely packed and spill over into the perinodal tissue. Thus it is prudent to perform immunohistochemical studies to confirm the diagnosis in all cases. The large follicles are three to four times the diameter of the reactive follicles and are rich in small lymphocytes but may contain isolated or small aggregates of residual follicular center cells. L&H cells are lacking, and few or no T-cell rosettes are found around large lymphoid cells within the large follicles. Morphologic Evaluation First, the topography and architecture of the large lymphoid nodules are assessed at scanning magnification. Lymphoblastic lymphoma with a pseudolobular pattern can be readily ruled out, because the nodules are delineated by delicate pink-staining fibrous septa or blood vessels and do not represent true follicles. If most cells within the nodules show the morphologic features of germinal center cells, follicular lymphoma has to be considered. Is the Diffuse Small Cell or Mixed Cell Lymphoid Infiltrate Reactive or Neoplastic The peripheral portion of the germinal center is also partly replaced by the lymphoid proliferation.

Not surprisingly symptoms 6 year molars generic 100 mg solian amex, aneuploidy correlates strongly with a poor prognosis treatment kidney stones generic solian 100mg free shipping, despite the fact that a few malignant tumors are diploid medications kidney infection discount solian 100mg mastercard. These include gastric inflammatory myofibroblastic tumor treatment action group purchase 50 mg solian, a lesion that occurs almost exclusively in children338 and young adults administering medications 7th edition ebook purchase solian 50mg without prescription, solitary fibrous tumor arising from the gastric serosa medications for ptsd order solian once a day,339 so-called calcifying fibrous tumor of the gastric wall,340 and involvement of the Schwannomas Some 2% of mesenchymal neoplasms of the stomach are benign schwannomas. Verocay bodies, vascular hyalinization, and Antoni A and B areas are rarely seen, and the appearance is different from that of soft tissue schwannomas. Histologically and immunophenotypically they are identical to their cutaneous counterparts. Gastroblastoma Gastroblastoma is a rare gastric epitheliomesenchymal biphasic tumor composed of spindle and epithelial cells. The mesenchymal component, formed of sheets of uniform, oval or spindled cells, is admixed with epithelial clusters or cords of varying maturity and occasionally forming glands. Ultrastructurally, desmosomes and microvilli have been noted, supporting a truly epithelial lesion. Other Connective Tissue Tumors Many benign and malignant connective tissue tumors of the stomach have been recorded. However, this distinction is somewhat artificial in that it fails to recognize occasional cases of disseminated lymphoma with a cellular phenotype that strongly suggests origin from the gastrointestinal tract. Immunophenotyping shows that the great majority of primary gastric lymphomas are of B-cell lineage. With regard to lymphomas that characteristically involve the small intestine, enteropathy-associated T-cell lymphoma does not occur as a primary gastric tumor, and gastric involvement by immunoproliferative small intestinal disease (Mediterranean lymphoma, -chain disease) is very rare; an invasive gastric signet ring cell lymphoma occurred in one case. Most patients are middle-aged or older and present with features suggesting peptic ulcer or gastric cancer, depending on the extent of the disease. This, coupled with careful morphologic, immunohistochemical, and molecular biologic studies of cell lineage, has allowed a reappraisal of lymphoid neoplasms of the stomach to be made with the appreciation of distinctive tumor types. Because the disease is frequently multifocal within the stomach, treated patients require endoscopic follow-up to identify local recurrence. Many gastric B-cell lymphomas simulate gastric carcinomas grossly, being polypoid, fungating, or ulcerating tumors. Some appear as giant folds reflecting the presence of a diffusely infiltrative lesion. Florid destruction of such glands often leads to the appearance of isolated, residual eosinophilic epithelial cells in a sea of medium-sized lymphoid cells. Sheets of small and intermediate-sized lymphoid cells infiltrate the mucosa and submucosa, enveloping reactive mucosal lymphoid follicles and wiping out the specialized mucosal glands. The centrocyte-like cells in the lamina propria of this case have clear cytoplasm and resemble monocytoid B cells. The centrocyte-like cells may invade and "overrun" the reactive B-cell follicles or selectively "colonize" their centers, sparing the mantle zone. When regional lymph nodes are involved they first show the same infiltration around the margin of follicles, resembling so-called monocytoid B-cell lymphoma and causing potential confusion with parafollicular infiltration by the entirely different T-zone lymphoma. Prominent benign lymphoid infiltration of the gastric wall may occasionally be found in inflammatory conditions of the stomach, such as peptic ulcer or Crohn disease, but, in such situations, it usually takes the form of lymphoid aggregates rather than the sheet-like infiltration of centrocyte-like cells in lymphoma. Indeed, this may be impossible, especially in small biopsies, and repeated sampling or careful endoscopic follow-up may be required to clarify the situation. If the lymphoid infiltrate is heavy and diffuse with wipeout of the gastric glands, then the diagnosis of lymphoma is straightforward. On the other hand, if the infiltrate is patchy and does not push the glands apart, it is likely to be reactive. Specialized glands have been virtually destroyed by neoplastic lymphoid cells, leaving only occasional clusters of eosinophilic epithelial cells. The neoplastic infiltrate is pleomorphic with large numbers of mitotically active blast cells that, in contrast to centrocyte-like cells of low-grade lymphoma, do not form lymphoepithelial lesions. However, B-cell monoclonality has been found in 1% to 4% of biopsies with chronic Helicobacter gastritis but appears to be related to the presence of lymphoid follicles in the biopsy specimen. Other sources of confusion include myeloid leukemic infiltration (chloroma), gastric sarcomas, and metastatic malignant melanoma; one case report394 has highlighted epithelial infiltration by melanoma cells that closely mimicked lymphoepithelial lesions. Mucin histochemistry and immunocytochemistry are invaluable in reaching the correct diagnosis. Malignant Lymphomatous Polyposis Widespread involvement of the gastric mucosa and submucosa sometimes takes the form of multiple polyps or, more frequently, a generalized thickening and pallor of the rugal folds to produce a cerebriform gross appearance. Microscopy shows diffuse infiltration by a monotonous population of small lymphoid cells with irregularly folded nuclei that surround, but do not colonize, residual nonneoplastic germinal centers, sometimes interspersed by bands of hyaline collagen. T-cell tumors of the stomach are rare, aggressive lymphomas that are reported mostly from the Far East where they are frequently (but not invariably) associated with human T-lymphotropic virus 1 infection. Rare examples show evidence of an intraepithelial T-cell phenotype, similar to those seen in the intestine (see Chapter 9). Langerhans Cell Histiocytosis the stomach may be involved as part of systemic Langerhans cell histiocytosis (see Chapter 21) or may be the site of a localized lesion, sometimes in the form of mucosal nodules or polyposis. Macroscopically, they appear as glassy, transparent, sessile polyps, less than 1 cm in diameter, confined to the body-fundic mucosa. Histologically, they are composed of cystically dilated glands lined by proliferating fundic epithelium, including parietal cells and chief cells, admixed with normal glands. Most are asymptomatic, although some cause gastric obstruction, bleeding, or perforation. Malignant melanoma appears to have the highest propensity to metastasize to the stomach with gastric metastases developing in up to 25% of patients. Lesions measuring 2 cm or larger should be completely excised for histologic exclusion of neoplasia. Macroscopic Appearances Hyperplastic polyps are sessile or pedunculated, smoothsurfaced or lobulated, and usually measure less than 2 cm in diameter. Microscopic Appearances Histologically, hyperplastic polyps show hyperplasia of the gastric foveolae, leading to elongated tortuous glands showing cystic changes and irregular branching. The surface of the polyp may be ulcerated and acutely inflamed, showing degenerative and regenerative atypia in the epithelial and stromal cells; this can cause major diagnostic confusion because both true carcinoma. The stroma of the polyp is edematous, infiltrated by plasma cells, lymphocytes (including follicles with germinal centers), and eosinophils, and contains wisps of smooth muscle fibers that extend from the muscularis mucosae. A recently described variant, named gastric mucosal prolapse polyp, is distinguished by basal glandular elements, hypertrophic muscle fibers ascending perpendicularly from the muscularis mucosae, and thick-walled blood vessels. These polyps are more commonly sessile than typical hyperplastic polyps, predominantly located in the antrum, and believed to result from mucosal prolapse. Consideration of the clinical, endoscopic, and macroscopic appearances is usually helpful. Inflammatory Fibroid Polyp this uncommon benign lesion, of unknown etiology, is found in male and female adults of all ages and is associated, in some cases, with hypochlorhydria or achlorhydria. Grossly, it is a small, well-circumscribed, solitary, sessile or pedunculated lesion that is often ulcerated. Histologically, it is usually centered in the submucosa (though purely mucosal lesions are described) and resembles edematous granulation tissue. Sometimes "floret"-like multinucleate giant cells with hyperchromatic nuclei are included. A chronic inflammatory cell infiltrate is seen that is often dominated by eosinophils but, in contrast to eosinophilic gastritis, which presents with a diffusely thickened and deformed antrum narrowing the pylorus in children and young adults, inflammatory fibroid polyp is not associated with circulating eosinophilia or a history of atopy. Inflammatory fibroid polyps should also be distinguished from rare eosinophilic granulomas associated with parasitic infections, eosinophilic gastroenteritis, inflammatory pseudotumor, hemangioendothelioma, and hemangiopericytoma. These hamartomatous polyps are composed of hyperplastic glands lined by foveolar-type epithelium, separated by branching cores of smooth muscle, with atrophy of the deep glandular components. Rare reports of gastric carcinoma in association with Peutz-Jeghers polyposis are described,427 but it is far from clear how often this has arisen within a preexisting polyp. The appearances are indistinguishable from lesions of Cronkhite-Canada syndrome and may mimic hyperplastic polyps closely. They may present at any age, usually with anemia or hypoproteinemia, and are most common in the antrum. Juvenile polyposis is associated with an increased risk of gastrointestinal cancer, particularly in the colorectum, but the stomach may also be at risk-dysplasia and carcinoma have been described in gastric juvenile polyps. They do not show the smooth muscle fibers of Peutz-Jeghers polyps, but they can be confused with hyperplastic polyps. Gastric polyps may also occur in Cowden disease and may comprise epithelial and/or connective tissue (smooth muscle or neural) components. Published histologic descriptions are sparse, but in one case report the polyps consisted of enlarged, elongated foveolar glands along with more basal, cystically dilated glands that contained papillary infoldings. Smooth muscle fibers were intermingled within the mucosal components, and the cystic structures sometimes extended into the submucosa. They are indistinguishable histologically from juvenile polyps, and the diagnosis can only be made in the presence of clinical evidence of alopecia, nail atrophy, or hyperpigmentation. It is usually found in the pylorus or antrum as an intramural hemispherical, conical, or short cylindrical mass. The most characteristic feature is a central depression on the mucosal surface, which represents the opening of one or more rudimentary pancreatic ducts. Both pancreatic acini and ducts are seen in the submucosa, extending deeply into the muscle coat. We also know of a single case report of "squamous cell papillomatosis" involving the whole of the posterior wall and lesser curvature of the stomach,443 in which the gastric mucosa was replaced by mature hyperkeratotic squamous epithelium with no evidence of atypia. Large squamous inclusions were present in the submucosa, and papillomatous squamous epithelium protruded from the serosal surface. When smooth muscle and duct-like structures (with or without Brunner glands) are the only components. Focal pancreatic-type acinar cells confined to the mucosa can be seen in the cardia and, in autoimmune gastritis, in the noncardia mucosa. The disease may regress spontaneously or may progress to chronic atrophic gastritis. It may be localized to the proximal greater curve or generalized in the body and fundus of the stomach. The antrum is rarely involved grossly (although it may show histologic changes), and usually an abrupt transition is seen between normal and diseased mucosa. The lamina propria is markedly edematous and may be infiltrated by smooth muscle fibers from the muscularis mucosae. Inflammation is typically sparse but when present may include prominent eosinophils. Histologically, they resemble hyperplastic polyps with florid cystic dilatation of the glands, but, in contrast to hyperplastic polyps, these dilated glands extend through a thickened and frayed muscularis mucosae into the submucosa. The submucosal glands arise by misplacement, due to ischemia and chronic inflammation related to previous surgery, and are bland without cellular atypia, allowing distinction from well-differentiated adenocarcinoma. Xanthoma or Xanthelasma these clinically insignificant lesions are found with increasing age, in men more than women, and are often associated with chronic gastritis and intestinal metaplasia of the gastric mucosa, as well as with bile reflux gastropathy. Grossly, they are single or multiple, 1 to 2 mm in diameter, round or oval, well circumscribed, yellow, macular or nodular. Histologically, they consist of accumulations of mature lipid-laden macrophages, containing cholesterol and neutral fat, within the lamina propria. 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