Co-Director, Stony Brook University School of Medicine
The endometrial stroma is composed of spindle cells with scant cytoplasm that are also actively proliferating chi royal treatment 250 mg depakote free shipping. Secretory activity is most prominent during the third week of the menstrual cycle medicine dictionary buy 500mg depakote free shipping, when the basal vacuoles progressively move to the apical surface treatment 3rd degree burns buy depakote 250mg lowest price. This serrated or "sawtooth" appearance is accentuated by secretory exhaustion and shrinkage of the glands medications kidney infection purchase generic depakote line. The ovary is influenced by hormones produced by the pituitary gland due to signals from the hypothalamus. Together, hypothalamic, pituitary, and ovarian factors and their interactions regulate maturation of ovarian follicles, ovulation, and menstruation. The histologic appearance of the endometrium may be used to assess hormonal status, document ovulation, and determine causes of endometrial bleeding and infertility. Progression through a normal menstrual cycle is correlated with the following histologic features: 1002 C H A P T E R 22 the Female Genital Tract A B C D Figure 22. Predecidual changes spread throughout the functionalis and are accompanied by a sparse infiltrate of neutrophils and lymphocytes, which in this context are considered normal. The action of the ovarian hormones on the endometrium primarily occurs through their cognate nuclear receptors. During the proliferative phase, estrogen drives the proliferation of both glands and stroma, sometimes by promoting "cross-talk" between these two cell types. For example, much of the effect of estrogen on glandular proliferation occurs via stromal cells, which in response to estrogen produce growth factors. During the secretory phase, progesterone down-regulates the expression of estrogen receptor in both the glands and the stroma, and as a result endometrial proliferation is suppressed. Progesterone also promotes the differentiation of the glands and causes functional changes in the stromal cells. Endometrial stem cells have been identified that likely have a central role in the regeneration of the endometrium after menses. They may also contribute to the development of ectopic endometrial tissue and endometrial cancer. This is a clinical term for uterine bleeding that lacks an underlying structural abnormality. As discussed earlier, the normal Body of uterus and endometrium 1003 A B C D Figure 22. Any disturbance of this finely tuned system may result in dysfunctional uterine bleeding, the most Table 22. Anovulatory Cycle the most frequent cause of dysfunctional bleeding is anovulation (failure to ovulate). Anovulatory cycles result from hormonal imbalances and are most common at menarche and in the perimenopausal period. Less commonly, anovulation is the result of the following: Endocrine disorders, such as thyroid disease, adrenal disease, or pituitary tumors Ovarian lesions, such as a functioning ovarian tumor (granulosa cell tumors) or polycystic ovaries (see the Ovaries section later in this chapter) Generalized metabolic disturbances, such as obesity, malnutrition, or other chronic systemic diseases Failure of ovulation results in excessive endometrial stimulation by estrogens that is unopposed by progesterone. Under these circumstances, the endometrial glands undergo mild architectural changes, including cystic dilation, that usually resolve due to a subsequent ovulatory cycle. However, repeated anovulation may result in bleeding that, in certain clinical situations, may prompt an endometrial biopsy. In this setting, biopsies reveal stromal condensation and eosinophilic Age Group Prepuberty Adolescence Reproductive age Causes Precocious puberty (hypothalamic, pituitary, or ovarian origin) Anovulatory cycle, coagulation disorders Complications of pregnancy (abortion, trophoblastic disease, ectopic pregnancy) Anatomic lesions (leiomyoma, adenomyosis, polyps, endometrial hyperplasia, carcinoma) Dysfunctional uterine bleeding Anovulatory cycle Ovulatory dysfunctional bleeding. However, unlike menstrual endometrium, progesterone-dependent morphologic features. Most commonly, the endometrium is composed of pseudostratified glands and contains scattered mitotic figures. More severe consequences of repeated anovulation are discussed in the Endometrial Hyperplasia section later in this chapter. The diagnosis of chronic endometritis rests on the identification of plasma cells in the stroma. Some women with this socalled "nonspecific" chronic endometritis have gynecologic complaints such as abnormal bleeding, pain, discharge, and infertility. If infection is suspected on clinical grounds, antibiotic therapy is indicated, even in the face of negative cultures, as it may prevent other sequelae. Thus, although chronic inflammation in the cervix is common and usually insignificant, it is of concern in the endometrium. The abnormal tissue most commonly includes both endometrial glands and stroma, but may consist only of stroma in some cases. It occurs in the following sites, in descending order of frequency: (1) ovaries, (2) uterine ligaments, (3) rectovaginal septum, (4) cul de sac, (5) pelvic peritoneum, (6) serosa of the large and small bowel and appendix, (7) mucosa of the cervix, vagina, and fallopian tubes, and (8) laparotomy scars. Endometriosis can have significant clinical consequences; it often causes infertility, dysmenorrhea (painful menstruation), pelvic pain, and other problems. The disorder is principally a disease of women in active reproductive life, most often in the third and fourth decades, and affects approximately 10% of women. There are three types of endometriosis: superficial peritoneal endometriosis, ovarian endometriosis, and deep infiltrating endometriosis. The superficial and ovarian forms of endometriosis are uncommonly associated with the development of malignancy, whereas it is extremely rare for the deep infiltrating form to undergo malignant transformation. Acute Endometritis Acute endometritis is uncommon and limited to bacterial infections that arise after delivery or miscarriage. Retained products of conception are the usual predisposing factors; the causative agents include group A hemolytic streptococci, staphylococci, and other bacteria.
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In chronic liver disease symptoms you are pregnant buy genuine depakote, the earliest morphologic alterations that appear to correlate with the presence of "at-risk" hepatocytes are called "large cell change" and "small cell change" symptoms 6 days before period order depakote 500 mg with visa. Large cell change refers to hepatocytes that are larger than normal and often have enlarged symptoms 4dp3dt purchase discount depakote on line, multiple treatment xerosis buy discount depakote on-line, pleomorphic nuclei, without an increase in nuclear-to-cytoplasmic ratio. In small cell change, the hepatocytes have a high nuclear-tocytoplasmic ratio and mild nuclear hyperchromasia and/or pleomorphism. A such as hereditary hemochromatosis and 1-antitrypsin deficiency, and alcoholic liver disease. Nonalcoholic fatty liver disease also increases the risk of HCC, even in the absence of cirrhosis. Although details are not clearly worked out, it is believed that the chronic injury, inflammation, and hepatocyte regeneration that are seen in these disorders contribute to the acquisition of driver mutations that lead to HCC development (described later). Part of the risk in Africa and Asia appears to be related to contamination of crops by aflatoxin, a mycotoxin produced by Aspergillus species that acts synergistically with alcohol and hepatitis B. The risk for HCC in cirrhosis related to other etiologies, like Wilson disease and chronic biliary diseases, is somewhat lower but still elevated above the population average. As with other cancers, HCC is associated with complementary sets of driver mutations that lead to the acquisition of cancer hallmarks (Chapter 7). Among the most common are activating mutations in the -catenin gene (40% of tumors), mutations in the TERT (telomerase transcriptase) gene promoter that up-regulate telomerase activity (50% to B Figure 18. Large hepatocytes with large, often atypical nuclei are scattered among normal-size hepatocytes with round, typical nuclei. The abnormal cells have a high nuclear-to-cytoplasmic ratio and are separated by thickened plates. Dysplastic nodules differ from adjacent cirrhotic nodules in size, color, and vascularization, show varying degrees of dysplasia, and have clonal aberrations associated with full-blown HCC. Small areas of HCC may sometimes be seen in high-grade dysplastic nodules ("nodule in nodule appearance"). HCC may form a single mass or multiple discrete masses, or it may diffusely infiltrate the liver. Tumors larger than 2 cm are more likely to be associated with vascular invasion and intrahepatic metastases. Invasion of veins with extension into the portal vein, inferior vena cava, and even the right side of the heart may occur. A Microscopically, well and moderately differentiated HCC are composed of cells that resemble normal hepatocytes, while poorly differentiated tumors show marked cytologic atypia. The tumor cells grow in thick plates or trabeculae, pseudoglandular structures with bile plugs, or sheets. The distinctive fibrolamellar variant shows a characteristic triad of features: large polygonal cells with granular (oncocytic) cytoplasm due to abundant mitochondria; vesicular nuclei with a prominent nucleolus; and parallel lamellae of dense collagen bundles. Clinical Features the clinical manifestations of HCC are nonspecific and include abdominal pain, malaise, fatigue, weight loss, and hepatomegaly. Elevated levels of serum -fetoprotein is a frequent finding in advanced disease, but it is not sensitive as a screening test for early tumors and is not associated with the fibrolamellar variant. Ultrasonography is used for screening high-risk patients such as those with cirrhosis. Computed tomography and magnetic resonance imaging with contrast studies yield highly characteristic findings. Early enhancement of the tumor due to contrast uptake in the arterial phase, followed by rapid venous washout, is considered diagnostic of HCC. Surgical resection when possible is the treatment of choice for tumors in noncirrhotic livers and in cirrhotic livers with B Figure 18. Image-guided tumor ablation with alcohol or radiofrequency waves can be done for unresectable tumors or those that do not meet criteria for transplantation. Hematogenous metastases, especially to the lung, tend to occur late in the disease. Overall outcomes in HCC are poor due to underlying liver disease and the intrinsic resistance of HCC to conventional chemotherapy. The overall 5-year survival rate is 30% for tumor confined to the liver and only 5% to 10% for cases with extrahepatic spread. Outcomes are better for the unusual fibrolamellar variant, with up to 40% of patients surviving 10 years or longer. This is in large part because, in the absence of underlying liver disease, extensive surgical resection is possible thanks to the regenerative capacity of the remaining liver. Intrahepatic cholangiocarcinoma is the most common primary malignant tumor of the liver after HCC. It is very common in Southeast Asian countries such as Thailand, Laos, and Cambodia, where liver fluke infestation is endemic. Pathogenesis Developmental disorders, like fibropolycystic liver disease, and chronic inflammatory conditions involving the bile ducts, including primary sclerosing cholangitis, infestation by liver flukes (particularly Opisthorchis and Clonorchis species), and hepatolithiasis are risk factors for biliary tract neoplasms. Chronic liver diseases that predispose to HCC, such as hepatitis B, hepatitis C, and nonalcoholic fatty liver disease, also increase the risk for intrahepatic cholangiocarcinoma. As with HCC, chronic injury, inflammation, and regeneration of biliary epithelium in these conditions may set the stage for acquisition of driver mutations leading to cancer.
This section focuses on mycosis fungoides symptoms juvenile diabetes buy genuine depakote, a lymphoma of skin-homing CD4+ T-helper cells that presents in the skin medicine 906 buy depakote with a visa. In most affected individuals medicine to reduce swelling buy cheap depakote line, the disease remains localized to the skin for many years medications bipolar best depakote 500mg, but it may eventually evolve into a systemic lymphoma. This tumor may occur at any age, but most commonly afflicts persons older than age 40. Mastocytosis the term mastocytosis encompasses a spectrum of rare disorders characterized by increased numbers of mast cells in the skin and, in some instances, in other organs as well. A cutaneous form of the disease that affects predominantly children and accounts for more than 50% of all cases is termed urticaria pigmentosa. The cutaneous lesions are usually multiple, although solitary mastocytomas may also occur in very young children. About 10% of individuals with mast cell disease have systemic disease, with mast cell infiltration of many organs. These individuals are often adults, and unlike those with localized cutaneous disease, the prognosis in individuals with systemic disease is more guarded. Many of the signs and symptoms of mastocytosis are due to the release of histamine, heparin, and other substances when mast cells degranulate. Darier sign refers to a localized area of dermal edema and erythema (wheal) that occurs when lesional skin is rubbed. Dermatographism refers to an area of dermal edema resembling a hive that occurs as a result of localized stroking of apparently normal skin with a pointed instrument. In systemic disease, all of the following may be seen: pruritus and flushing, triggered by certain foods, temperature changes, alcohol, and certain drugs (morphine, codeine, aspirin); watery nasal discharge (rhinorrhea); rarely, gastrointestinal or nasal bleeding, possibly due to the anticoagulant effects of heparin; and bone pain, which may be caused by mast cell infiltration or by pathologic fractures stemming from osteoporosis. Osteoporosis is caused by excessive histamine release in the marrow microenvironment and can be a clue to the diagnosis, particularly in premenopausal women and in men. In urticaria pigmentosa, lesions are multiple and widely distributed, consisting of round to oval, red-brown, nonscaling papules and small plaques. Solitary mastocytoma presents as a pink to tan-brown nodule that may be pruritic or show blister formation. The histologic picture in urticaria pigmentosa or solitary mastocytoma varies from a subtle increase in mast cells around superficial dermal blood vessels to large numbers of tightly packed mast cells in the upper to mid-dermis. Even with these stains, extensive degranulation may result in failure to recognize these cells by light microscopy, but their identity can be readily confirmed with immunohistochemical stains for mast cell markers, such as mast cell tryptase and KIT. The term is derived from the Greek root ichthy, meaning "fishy," and accordingly, this group of inherited disorders is associated with chronic, excessive keratin buildup (hyperkeratosis) that results in fish-like scaliness. Ichthyosis is subtyped according to the mode of inheritance, histology, and clinical features; the primary categories include ichthyosis vulgaris (autosomal dominant or acquired), congenital ichthyosiform erythroderma (autosomal recessive), lamellar ichthyosis (autosomal recessive), and X-linked ichthyosis. This insight has led to the clinical development of KIT kinase inhibitors, which often produce dramatic tumor regression, even in patients with advanced aggressive systemic disease. Variations in the thickness of the epidermis and the stratum granulosum and the gross appearance and distribution of lesions are used to subclassify these disorders. Pathogenesis the primary abnormality in ichthyosis is defective desquamation, leading to retention of abnormally formed scales. For example, X-linked ichthyosis is caused by a deficiency of steroid sulfatase, an enzyme that helps to remove proadhesive cholesterol sulfate from intercellular spaces. In its absence, cholesterol sulfate accumulates, resulting in persistent cell-to-cell adhesion within the stratum corneum and a failure of desquamation. Innumerable inflammatory dermatoses have been described and can be broadly classified as acute and chronic. Acute lesions last from days to weeks and are characterized by inflammatory infiltrates (usually composed of lymphocytes and macrophages rather than neutrophils), edema, and variable degrees of epidermal, vascular, or subcutaneous injury. Chronic lesions, on the other hand, persist for months to years and are often associated with changes in epidermal growth (atrophy or hyperplasia) or dermal fibrosis. Urticaria Urticaria (hives) is a common disorder of the skin that is usually caused by localized mast cell degranulation and is uniformly associated with dermal microvascular hyperpermeability. Urticaria most often occurs between ages 20 and 40, but all age groups are susceptible. Individual lesions develop and fade within hours (usually less than 24 hours), and episodes may last for days or persist for months. Sites of predilection for urticarial eruptions include any area exposed to pressure, such as the trunk, distal extremities, and ears. Individual lesions may coalesce to form annular, linear, or arciform configurations. There is usually a sparse superficial perivenular infiltrate consisting of mononuclear cells and rare neutrophils. Collagen bundles are more widely spaced than in normal skin, a result of dermal edema. Dermal lymphatic channels may also be dilated due to increased absorption of edema fluid. Pathogenesis Urticaria is most commonly the result of antigen-induced release of vasoactive mediators from mast cells. Urticaria of this type follows exposure to many different antigens (pollens, foods, drugs, insect venom) and is an example of a localized immediate hypersensitivity (type I) reaction triggered by the binding of antigen to IgE antibodies that are attached to mast cells through Fc receptors (Chapter 6).
Diseases
Buruli ulcer
Dissecting cellulitis of the scalp
Dysostosis Stanescu type
T-cell lymphoma
Juberg Marsidi syndrome
Papilloma of choroid plexus
Lafora disease
In immune thrombocytopenia medicine cups buy depakote paypal, destruction is caused by the deposition of antibodies or immune complexes on platelets symptoms whiplash order depakote with a mastercard. Alloimmune thrombocytopenia can arise when platelets are transfused or when platelets cross the placenta from the fetus into the pregnant mother treatment 4 high blood pressure purchase discount depakote online. In the latter case symptoms of the flu best purchase depakote, IgG antibodies 664 C H A P T E R 14 Red Blood Cell and Bleeding Disorders Table 14. In the overwhelming majority of cases, the antiplatelet antibodies are of the IgG class. As in autoimmune hemolytic anemias, antiplatelet antibodies act as opsonins that are recognized by IgG Fc receptors expressed on phagocytes (Chapter 6), leading to increased platelet destruction. The thrombocytopenia is usually markedly improved by splenectomy, indicating that the spleen is the major site of removal of opsonized platelets. The splenic red pulp also is rich in plasma cells, and part of the benefit of splenectomy may stem from the removal of a source of autoantibodies. In some instances the autoantibodies may also bind to and damage megakaryocytes, leading to decreases in platelet production that further exacerbate the thrombocytopenia. Secondary changes related to the bleeding diathesis may be found anywhere in the body. Typically, there is congestion of the sinusoids and enlargement of the splenic follicles, often associated with prominent reactive germinal centers. In many instances scattered megakaryocytes are found within the sinuses, possibly representing a mild form of extramedullary hematopoiesis driven by elevated levels of thrombopoietin. These findings are not specific but merely reflect accelerated thrombopoiesis, being found in most forms of thrombocytopenia resulting from increased platelet destruction. The importance of bone marrow examination is to rule out thrombocytopenias resulting from marrow failure or other primary marrow disorders. The secondary changes relate to hemorrhage, often in the form of petechial bleeds into the skin and mucous membranes. The peripheral blood often reveals abnormally large platelets (megathrombocytes), which are a sign of accelerated thrombopoiesis. Sequestration Hypersplenism Dilution Transfusions made in the mother may cause clinically significant thrombocytopenia in the fetus. This is reminiscent of hemolytic disease of the newborn, in which red cells are the target (Chapter 10). The most important nonimmunologic causes are disseminated intravascular coagulation (DIC) and the thrombotic microangiopathies, in which unbridled, often systemic, platelet activation reduces platelet life span. Nonimmunologic destruction of platelets may also be caused by mechanical injury, such as in individuals with prosthetic heart valves. Clinical Features Chronic ITP occurs most commonly in adult women younger than 40 years of age. It is often insidious in onset and is characterized by bleeding into the skin and mucosal surfaces. Pinpoint hemorrhages (petechiae) are especially prominent in the dependent areas where the capillary pressure is higher. Often there is a history of easy bruising, nosebleeds, gingival bleeding, and hemorrhages into soft tissues from relatively minor trauma. The disease may manifest first with melena, hematuria, or excessive menstrual flow. Subarachnoid hemorrhage and intracerebral hemorrhage are serious and sometimes fatal complications, but fortunately are rare in treated patients. Splenomegaly and lymphadenopathy are not seen in primary disease, and their presence should lead one to consider other diagnoses, such as ITP secondary to a B-cell neoplasm. A low platelet count, normal or increased megakaryocytes in the bone marrow, and large platelets in the peripheral blood are taken as presumptive evidence of Chronic Immune Thrombocytopenic Purpura Chronic immune thrombocytopenic purpura (ITP) is caused by autoantibody-mediated destruction of platelets. It can occur in the setting of a variety of predisposing conditions and exposures (secondary) or in the absence of any known risk factors (primary or idiopathic). The contexts in which chronic ITP occurs secondarily are numerous and include individuals with systemic lupus erythematosus (Chapter 6), HIV infection, and B-cell neoplasms such as chronic lymphocytic leukemia (Chapter 13). The diagnosis of primary chronic ITP is made only after secondary causes are excluded. Tests for platelet autoantibodies suffer from low sensitivity and specificity and are not clinically useful. Therefore, the diagnosis is one of exclusion and can be made only after other causes of thrombocytopenia (such as those listed in Table 14. Almost all patients respond to glucocorticoids (which inhibit phagocyte function), but many relapse following withdrawal of steroids. Those with moderately severe thrombocytopenia (platelet counts >30,000/mL) can be followed carefully, and in some of these individuals ITP may spontaneously remit. In individuals with severe thrombocytopenia, splenectomy normalizes the platelet count in about two-thirds of patients, but with the attendant increased risk of bacterial sepsis. Immunomodulatory agents such as intravenous immunoglobulin or anti-CD20 antibody (rituximab) are often effective in patients who relapse after splenectomy or for whom splenectomy is contraindicated. Peptides that mimic the effects of thrombopoietin (so-called TPO-mimetics) also may be effective in improving platelet counts in individuals with disease that is refractory to other treatments.
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