PCB 422 Pathology: Tropical Splenomegaly PDF

PCB 422 PATHOLOGY TROPICAL SPLENOMAGALY The spleen is part of the hepatoportal system and is the largest organ of the lymphatic system. It is a slender elongated secondary lymphoid organ located in the upper left quadrant of the abdomen that receives blood from the splenic artery. Although it is no...

PCB 422 PATHOLOGY TROPICAL SPLENOMAGALY The spleen is part of the hepatoportal system and is the largest organ of the lymphatic system. It is a slender elongated secondary lymphoid organ located in the upper left quadrant of the abdomen that receives blood from the splenic artery. Although it is not a vital organ, it functions as an immunological filter of the blood and destroys defective and old erythrocytes, storing platelets and producing and distributing immune cells and antibodies. The spleen is a major site of blood production outside of the bone marrow, especially during times of stress. The spleen sequesters many cellular elements (leukocytes, erythrocytes, and platelets) and can become dangerously congested during a strong inflammatory response to result in a condition termed splenomegaly. Several general pathophysiologic mechanisms cause splenic enlargement. Hyperplasia and hypertrophy cause splenomegaly due to increased function of the spleen. Others are congestion due to blockage of venous overflow, blood loss, infection, and pregnancy, but in these cases the spleen returns to normal size after the condition resolves. The most common etiologies of splenomegaly are chronic liver disease, malignancies, and infections. Malignancies—usually leukemia or lymphoma—are common causes of splenomegaly, seen in close to one-third of affected patients. As many as one-third of patients with splenomegaly have cirrhosis, where abnormal liver parenchyma leads to congestive splenomegaly. Several infections can lead to splenomegaly. Splenomegaly is common in patients with HIV, as a response to the virus or because of secondary infections. People who are born in tropical regions, global travelers, and military personnel deployed to tropical regions are at risk for parasitic infections that can lead to splenomegaly, most commonly schistosomiasis and chronic malaria. Tropical splenomegaly syndrome or Hyperreactive malarial splenomegaly (HMS) represents one of the leading causes of massive splenomegaly in malaria-endemic countries. The disease is well known in Nigeria, Uganda, New Guinea, and Congo, and there are also reports from South Arabia, Zambia, and the Sudan. Only a small proportion of people exposed to malaria get tropical splenomegaly syndrome. The tropical splenomegaly syndrome most commonly presents in young adults, though it has appeared as early as four years of age. Anti-malarial treatment has been shown to reduce the size of the spleen, indicating a response to treatment. However, premature discontinuation of treatment may lead to a relapse of TSS. Individuals with sickle cell trait are relatively protected from TSS, as with malaria. Etiology/Pathogenesis Exact mechanism of TSS remains unclear, evidence suggests that chronic malaria infection, in combination with unknown host factors, may trigger an overactive immune response that leads to the formation of macromolecular aggregates, deposition in the liver and spleen, and subsequent development of TSS. It is caused by an aberrant immune response to a chronic antigenic stimulation in subjects long exposed to malaria parasites. Previously defined as tropical splenomegaly syndrome (TSS), HMS has long been considered distinct from a splenomegaly directly resulting from malarial parasitaemia. The syndrome is characterized by macro-globulinaemia with overproduction of immunoglobulin, 1|Page especially of the IgM class, which aggregate into high molecular immune complexes and cause persistent splenomegaly because of prolonged clearance from the reticuloendothelial tissue. This IgM then forms clumps with other proteins in the body and gets deposited in certain cells in the liver and spleen. This can cause those organs to become larger than normal and lead to anemia (low red blood cells). Cryoglobulins and autoantibodies, such as, for instance, rheumatoid factor, contribute to the macro- globulinaemia. A direct correlation between the spleen size and the IgM titre has been described. Genetic factors are likely to be involved in the development of HMS. Signs and symptoms The most common symptom is an enlarged spleen, which can cause abdominal discomfort or pain in the left upper abdomen. The patient usually has anaemia, leucopenia, and thrombocytopenia, but spontaneous bleeding is unusual. The anaemia is the combined result of an increased plasma volume, a reduced red cell survival time, and an increased proportion (up to 40%) of the red cell mass in the spleen. The liver is also usually enlarged, and portal hypertension is a feature of gross splenomegaly. Serum albumin is reduced and serum globulin raised. The IgM level is high, and this is almost invariably associated with a high malarial antibody titre. While leucopenia is usual, a number of cases show absolute lymphocytosis, which may reach leukaemoid proportions Other symptoms may include: occasional fever. fatigue weight loss night sweats and chills. malaise. joint pain. nausea and vomiting. Diagnosis: Diagnosis of TSS can be challenging as the symptoms may resemble those of other diseases, particularly malaria. The initial stage of diagnosis involves excluding other potential factors that can cause an enlarged spleen, such as liver disease, lymphoma, or leukemia. Where the disease is endemic, as much as two thirds of gross splenomegaly may be of uncertain origin. Typhoid, chronic brucellosis, acute malaria in young persons, schistosomiasis, hepatic cirrhosis with portal hypertension, kala-azar, and sickle-cell anaemia must all be included on most tropical lists. Chronic lymphatic leukaemia and malignant lymphoma are among the most likely diseases of the lymphoreticular system with which it might be confused. Major criteria for diagnosis are: 1. Persistent gross splenomegaly extending more than 10 cm below the costal margin, for which no cause can be found 2. High antibody levels of Plasmodium species (≥1:800) without any other apparent cause. 3. IgM titre >2 standard deviations (SD) above the local mean value 2|Page 4. Favorable clinical immunologic responses to antimalarial therapy/immunological response to long-term malaria prophylaxis. 5. Regression of splenomegaly by 40% by six months after the start of therapy. Minor Criteria: Hepatic sinusoidal lymphocytosis. Normal cellular and humoral responses to antigenic challenge, including a normal Phyto hemagglutination response. Hypersplenism. Lymphocytic proliferation. Familial occurrence. Other laboratory findings related to hypersplenism, such as variable degrees of pancytopaenia, especially anaemia. The underlying mechanism causing anaemia is the plasma volume expansion and the spleen sequestration along with an increased haemolysis. Reticulocytes and indirect bilirubin are often increased. Sinusoidal lymphocytosis may be revealed by histologic examination of liver biopsy, but it is not specific. The peripheral blood smear in HMS subjects is most often negative. However, using more sensitive diagnostic methods, such as polymerase chain reaction (PCR), the proportion of positive cases increases. COMPLICATIONS The main, severe complications of TSS are acute infectious illnesses, haemolytic anaemia (especially during pregnancy) and splenic rupture. According to historical data, the syndrome is often fatal if left untreated. Some authors have hypothesized that HMS could be considered as a pre-malignant state that could evolve to chronic lymphocytic or hairy cell leukaemia or splenic lymphoma with villous lymphocytes, because of a multi-step process with a single clone selection in a set of deregulated polyclonal expansion of lymphocytes. Actually, TSS and lymphoproliferative disorders are often clinically indistinguishable. Spleen reduction after a prolonged anti-malarial treatment is one of the main criteria used to diagnose TSS. Failure to respond makes an alternative diagnosis more likely. LYMPHOMA Lymph Nodes are normally small BB-sized lymphoid organs widely distributed between the groin and the neck. While the spleen filters blood, lymph nodes act as immunological filters for interstitial lymphatic fluid from the body’s tissues. Lymph nodes provide an environment for the interaction of debris with APCs and other immune cells (T cells and B cells). Lymph nodes may sequester activated immune cells (or tumor cells) and become inflamed and engorged causing lymphadenopathy. Lymphoma is cancer of the lymphatic system. They are a heterogeneous group of malignancies that arise from malignant transformation of immune cells. The primary cancerous cell of origin is the lymphocyte; as a result, there is often considerable overlap between lymphomas and lymphoid leukaemias. They most commonly present as a solid tumor but can sometimes present as circulating tumor cells in peripheral blood. Histologically, lymphomas are subdivided into two main categories: Hodgkin lymphoma (Reed– Sternberg cells) and non-Hodgkin lymphoma (NHL) (B- or T-cell lymphocyte markers). Both Hodgkin’s and non-Hodgkin’s lymphoma NHL are further classified into distinct clinical entities 3|Page based on histology. The most common site of malignancy is the lymph node. Extranodal disease, can be found in the stomach, skin, oral cavity and pharynx, small intestine and CNS commonly in non- Hodgkin’s lymphoma. Hodgkin’s Lymphoma Hodgkin lymphoma is named after Thomas Hodgkin, who first described seven cases of a mysterious disease of the lymph system in 1832. Although Hodgkin lymphoma was not the first cancer to be described, it was one of the first cancers to have methodical investigational treatments that ultimately lead to successful outcomes. It is predominantly a disease of young adults, with a peak incidence between the ages of 15 and 35 years. However, in industrialized countries, it exhibits bimodal distribution; the first peak occurs in young adults and the second smaller peak occurs after age 50. Hodgkin lymphoma occurs slightly more frequently in males than in females. The 5-year overall survival for all stages of Hodgkin lymphoma is about 85%. Etiology The etiology of Hodgkin lymphoma is currently unknown, but laboratory and epidemiologic evidence support infectious exposure as a potential cause. Epstein-Barr’s virus (EBV) is found in about 40-50% of all classical Hodgkin lymphoma cases, and it is frequently observed in cases of mixed cellularity and lymphocyte-depleted Hodgkin lymphoma. Individuals who are immunosuppressed, such as patients with congenital immunosuppression, solid- organ transplant recipients, and human immunodeficiency virus (HIV)-infection, are also at much higher risk to develop Hodgkin lymphoma. Genetic factors are also associated with an increased risk of Hodgkin lymphoma. The strongest evidence comes from identical twin studies, which show that the unaffected identical twin has almost a 100-fold increase in risk. Pathophysiology Hodgkin lymphoma is a clonal malignant lymphoid disease of transformed B-lymphocytes. The diagnosis is made by histological examination of an excised lymph node biopsy. The characteristic pathological finding in HL is the Reed–Sternberg cell named after Dorothy Reed and Carl Sternberg, who first gave definitive microscopic description of Hodgkin lymphoma. Hodgkin’s lymphoma is divided into two major groups: classical Hodgkin’s lymphoma and nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL), which constitute about 95% and 5% of cases, respectively. Classic Hodgkin lymphoma is further divided into four histological subtypes: nodular sclerosis, mixed cellularity, lymphocyte-depleted, and lymphocyte-rich. The subtypes in these classifications are based on characteristics of the Reed–Sternberg cell, the surrounding cells, and the tissue. Signs and Symptoms About 25% of all patients present with fever (greater than 38°C (100.4°F), night sweats, and/or weight loss (loss greater than 10% within 6 months of diagnosis); and up to 50% of patients with advanced disease present. These have prognostic significance and are known as B symptoms. Patients may also experience other nonspecific symptoms including malaise, pruritus, fatigue, and development of pain after alcohol consumption at sites where nodes are involved 4|Page  Most patients with Hodgkin lymphoma present with a painless, rubbery, enlarged lymph node in the supradiaphragmatic area and commonly have mediastinal nodal involvement. Lymphadenopathy may come and go, but persistence of lymphadenopathy more than 2 months warrants evaluation. If lymph nodes in the chests are involved, patients may present with breathlessness. Bone pain may result from skeletal involvement Extranodal manifestations, such as bowel and hepatic involvements, are much less common in Hodgkin lymphoma than NHL. Diagnosis, Staging, and Prognostic Factors Diagnostic and staging procedures are based on recommendations made at the Ann Arbor and Cotswolds conferences and new scientific advances, as described in the National Comprehensive Cancer Network (NCCN) guideline. The diagnosis and pathologic classification of Hodgkin lymphoma can only be made by review of a biopsy (preferably an excisional biopsy) of the enlarged node by an expert hematopathologist. In addition to a careful physical examination, routine laboratory tests including a complete blood count, complete metabolic panel to assess renal and hepatic function, lactate dehydrogenase (LDH), and erythrocyte sedimentation rate (ESR) will be helpful in treatment planning and aid in prognosis. Pregnancy tests and HIV status should be assessed. Computed tomography (CT) scans of the chest, abdomen, and pelvis are routinely performed. Furthermore, positron emission tomography (PET) plays an important role in the initial staging of Hodgkin lymphoma, as it has shown high sensitivity and specificity in the staging of the disease. The NCCN guideline recommends diagnostic CT and integrated PET-CT scan (preferred) for initial staging. Bone marrow biopsy is now only recommended in patients with cytopenias and a negative PET. Staging can be based on clinical or pathologic findings. The clinical stage is based on all noninvasive procedures (history, physical examination, laboratory tests, and radiologic findings), whereas the pathologic stage is based on the biopsy findings of strategic sites (bone marrow, spleen, and abdominal nodes). It is important to note that Hodgkin lymphoma appears to follow a predictable pattern of nodal spread that is not seen with the NHLs. The Ann Arbor Staging Classification of Hodgkin Lymphoma Stage I = Involvement of a single lymph node region or structure (I) or of a single extralymphatic organ or site (IE) Stage II = Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extra-lymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE). The number of nodal regions involved should be indicated by a subscript (eg, II2) Stage III = Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE). III1: with or without splenic, hilar, celiac, or portal node involvement. III2: with paraaortic, iliac, or mesenteric node involvement Stage IV= Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement A—No symptoms 5|Page B—Fever, night sweats, weight loss (>10%) X—Bulky disease >One-third the width of the mediastinum >10 cm maximal dimension of nodal mass E—Involvement of extralymphatic tissue on one side of the diaphragm by limited direct extension from an adjacent, involved lymph node region S—Involvement of the spleen CS—Clinical stage PS—Pathologic stage Stage is a dominant factor in predicting survival; patients with limited-stage disease (stages I to II) have a 90% to 95% cure rate, while those with advanced disease (stages III to IV) have only a 60% to 80% cure rate. NON-HODGKIN LYMPHOMA NHL The NHLs are a heterogeneous group of lymphoproliferative disorders that affect individuals from early childhood to late adulthood. NHLs are classified into distinct clinical entities that are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. These differences influence the natural history, and approach and response to treatment. The use of extensive combination chemotherapeutic regimens shows dramatic improvement in survival and cure in patients with a disease that was once considered incurable. Epidemiology and Etiology Non-Hodgkin lymphoma is the fifth most common cause of newly diagnosed cancer in the United States and accounts for about 4% of all cancers. Although the average age of patients at the time of diagnosis is about 67 years, NHL can occur at any age. The incidence rate generally increases with age and is higher in men than in women and in whites than in blacks. There is increased incidence of NHL over the past three decades is second only to melanoma. Although the increase has been noted particularly among the elderly and patients with acquired immune deficiency syndrome (AIDS), much of it cannot be explained by known risk factors. The etiology of NHL is unknown, although several genetics, environmental agents, occupational exposure; exposure to herbicides, particularly phenoxyl herbicides, is associated with the development of NHL. These observations may explain why certain occupations, such as farmers, forestry workers, and agricultural workers, are associated with a higher risk of NHL. A higher risk of NHL is also associated with exposure to other chemical solvents and dyes, exposure to radiation from nuclear explosions infectious agents – Viral diseases EBV was discovered in cell lines from tumors of patients with African (endemic) Burkitt lymphoma, and sporadic Burkitt lymphoma in 15% to 85% of cases. EBV is also associated with posttransplant lymphoproliferative. Burkitt’s lymphoma, an aggressive B-cell lymphoma observed in West African children, is linked to malaria. Burkitt’s lymphoma is also one of the most common neoplasms to develop in HIV-related immunosuppressed patients. 6|Page  congenital immunodeficiency disorders or immune suppression, those receiving chronic pharmacologic immunosuppression in the setting of solid-organ transplantation acquired immunodeficiency disorders such as AIDS, Autoimmune diseases (Hashimoto’s thyroiditis and Sjögren’s syndrome) cause chronic inflammation in the mucosa-associated lymphoid tissue (MALT), which predisposes patients to subsequent lymphoid malignancies. Other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The Human T-cell lymphotropic virus type 1 HTLV-1, human herpes virus 8 (also referred as Kaposi sarcoma–associated herpes virus [KSHV]) was the first human retrovirus associated with a malignancy. Infection with human T-cell lymphotropic virus type 1, especially in early childhood, is strongly associated with an aggressive form of T-cell lymphoma, known as adult T-cell leukemia/lymphoma. Gastric infection with Helicobacter pylori, a gram-negative bacteria that leads to chronic gastritis, is associated with gastric MALT lymphomas. Finally, hepatitis C virus has been associated with splenic and nodal marginal zone lymphomas. A number of physical agents, and high intake of meats and dietary fats. Smoking or alcohol consumption is not strongly associated with an increased risk of NHL. Pathology and Classification Non-Hodgkin lymphomas are neoplasms derived from the monoclonal proliferation of malignant B or T lymphocytes and their precursors. About 85% to 90% of NHLs in the United States are of B-cell origin. Proliferation of malignant cells results in the replacement of the normal cells and architecture of lymph nodes or bone marrow with a relatively uniform population of lymphoid cells. The classification of NHLs has evolved over the past five decades, as advances in immunology and genetics have allowed scientists to recognize a number of previously unrecognized subtypes of NHLs. The current classification schemes characterize the NHLs according to the cell of origin (B cell vs T cell), clinical features, and morphologic features. Additional immunohistochemical markers, cytogenetic features, and genotypic characteristics may help to further classify NHL into subtypes. WHO classification categorizes lymphoid malignancies into two major categories: B-cell lymphomas - represent about 85% to 90% of all NHLs and T-cell (and natural killer cell) World Health Organization Classification of Non–Hodgkin’s Lymphoma 1. Precursor B- and T-Cell Neoplasms Precursor B-lymphoblastic leukemia/lymphoma represent about 85% to 90% of all NHLs. Precursor T-lymphoblastic leukemia/lymphoma 2. Mature B-Cell Neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma Extranodal marginal zone B-cell lymphoma (MALT lymphoma) Diffuse large B-cell lymphoma (DLBCL) Burkitt lymphoma/leukemia 3. Mature T-Cell and NK Cell Neoplasms 4. Immunodeficiency-Associated Lymphoproliferative Disorders 7|Page NHL is further categorized as indolent or aggressive. Indolent NHLs generally carry a good prognosis, with a median survival of 10 years; however, it is not curable in advanced stages. Aggressive NHL has a much shorter natural history than indolent NHL, but it is cured in 30% to 60% of patients. More than 80% of NHLs are B-cell neoplasms, with follicular and DLBC lymphoma as the most common subtypes, accounting for 31% and 22%, respectively. CLINICAL PRESENTATION General Patients with NHL present with a wide variety of symptoms, depending on the site of involvement and whether tumor involvement is nodal or extranodal. The most common presentation is painless lymphadenopathy, frequently in the neck area in the supraclavicular and cervical regions. The lymphadenopathy may be either localized or generalized, and the involved nodes are often painless, rubbery, and discrete. Massive lymphadenopathy can sometimes lead to organ dysfunction. For example, patients with NHL may present with acute renal failure from retroperitoneal adenopathy causing ureteral obstruction or from metabolic abnormalities such as hyperuricemia with uric acid nephropathy. About 40% of patients with NHL present with fever (temperature >380C [100.4°F]), weight loss (unexplained weight loss of 10% of body weight over the past 6 months), or drenching night sweats. If one or more of these symptoms is present, the patient is noted to have B symptoms, and a B is added to the stage of disease. B symptoms are more commonly observed in patients with aggressive NHLs. Patients with Hodgkin lymphoma rarely present with extranodal (ie, extralymphatic) disease, but 10% to 35% of patients with NHL have primary extranodal disease at the time of diagnosis. Presentation of fast-growing, aggressive NHL, such as diffuse large B-cell (DLBC) lymphoma is variable; most patients present with lymphadenopathy and extranodal involvement. Presentation can involve one or more lymph nodes and, sometimes, extralymphatic organs Laboratory Tests A complete blood count, tests of renal and liver function, and serum electrolytes should be obtained. Serum β2-microglobulin and LDH levels may be useful as prognostic factors and for monitoring response to therapy. Sites of involvement and dissemination of the malignant cells can sometimes be predicted based on the cell of origin and the tendency of tumors to frequently disseminate to areas where the normal counterparts of the lymphoma cells are located. For example, B-cell lymphomas involve areas of the lymphoid system normally populated by B-lymphocytes such as lymph nodes, spleen, and bone marrow. T-cell lymphomas commonly disseminate to various extranodal sites such as the skin and lungs The most common extranodal sites: gastrointestinal tract, with signs and symptoms of nausea, vomiting, obstruction, abdominal pain, a palpable abdominal mass, or gastrointestinal bleeding skin liver or spleen. bone marrow, with symptoms related to anemia, neutropenia, or thrombocytopenia. testes and bone. 8|Page  brain lymphoma, especially in patients with AIDS Diagnosis Excisional or incisional lymph node biopsy, bone marrow biopsy, morphology, and immunophenotyping are used to confirmand classify an NHL diagnosis. Individuals with HL will also present with lymphadenopathy typically in a contiguous pattern, whereas lymph nodes are more likely to present in a noncontiguous pattern in NHL. Extranodal lymphoid involvement in HL is less common than in NHL. In more than 90% of individuals the disease is located above the diaphragm at the time of initial diagnosis. They may also complain of B symptoms, fatigue, pruritus, cough, loss of appetite, and abdominal discomfort. Non-Hodgkin Lymphoma in Acquired Immune Deficiency Syndrome The risk of NHL for patients with AIDS is increased more than 100-fold as compared with the general population. AIDS-related lymphoma arises because of long-term stimulation and proliferation of B lymphocytes from HIV and the reactivation of prior EBV infection as a consequence of HIV-induced immunosuppression. AIDS-related lymphoma usually occurs late during HIV infection and is the cause of death in about 15% of HIV-infected individuals. Although HIV infects T cells, more than 95% of AIDS-related lymphomas are B-cell neoplasms. Most cases of AIDS-related lymphomas are classified as Burkitt or DLBCL. The growth pattern of lymphoma is described as follicular when malignant B cells take over normal germinal centers of lymph follicles. When the normal architecture of the lymph node is replaced by a uniform population of neoplastic lymphocytes, the growth pattern is described as diffuse. Morphologic features of the lymph node, such as cell type, size, and appearance, are important because they establish the specific subtype of lymphoma and are helpful in determining the best treatment. 9|Page