LRS

University of Neniveh. Dr. Radhwan Al-Jammas

College of Medicine
Department of pathology and forensic medicine.

PATHOLOGY OF THE LYMPHO-RETICULAR SYSTEM

LYMPH NODE PATHOLOGY

NON-NEOPLASTIC CONDITIONS

Reactive Lymphadenitis
Any immune response against foreign antigens (infectious & noninfectious inflammatory stimuli) is often associated with lymph node enlargement (lymphadenopathy). The infections that cause lymphadenitis are numerous and varied and may be acute or chronic. In most instances, the histological appearance of the nodes is entirely nonspecific i.e. different etiologies are associated with similar microscopic changes.
Acute Nonspecific Lymphadenitis
Grossly, inflamed nodes are swollen & congested i.e. gray-red.
Microscopically, there are large germinal centers containing numerous mitotic figures. When the cause is a pyogenic organism, a neutrophilic infiltrate is seen about the follicles and within the lymphoid sinuses. With severe infections, the centers of follicles can undergo suppurative necrosis.
Clinically, affected nodes are tender, and become fluctuant when abscess is formed. The overlying skin is frequently red, and penetration of the infection to the skin can produce draining sinuses. With control of the infection, the lymph nodes can revert to their normal appearance or, if damaged undergo fibrosis.
Chronic Nonspecific Lymphadenitis
This condition can assume one of three patterns, depending on the causative agent:
1. Follicular hyperplasia
2. Paracortical hyperplasia
3. Sinus histiocytosis
Morphology
Follicular Hyperplasia is associated with infections or inflammatory processes that activate B cells in the B-cell areas i.e. the follicles, & thus create the follicular (or germinal center) reaction. The cells in the reactive follicles include the activated B cells (centrocytes & centroblasts also called follicular center cells), scattered phagocytic macrophages containing nuclear debris (tingible body macrophages), and the not easily seen meshwork of follicular dendritic cells (function in antigen display to the B cells).
Causes of follicular hyperplasia include rheumatoid arthritis, toxoplasmosis, and the early stages of HIV infection. This form of lymphadenitis can be confused microscopically with follicular lymphomas .
Paracortical Hyperplasia
The paracortex is the zone situated between the cortex and the medulla, which contains the mobile pool of T lymphocytes responsible for cell-mediated immune responses. Paracortical hyperplasia is characterized by reactive changes within the T-cell regions of the lymph node, which is reflected microscopically as expanded zones between the cortical follicles. On immune activation parafollicular T cells transform into large proliferating immunoblasts that can efface the B-cell follicles. Paracortical hyperplasia is encountered in
1. Viral infections (such as EBV)
2. Following certain vaccinations (e.g., smallpox), and in immune
3. Reactions induced by certain drugs (especially the antiepileptic drug phenytoin ).
Sinus Histiocytosis is characterized by distention and prominence of the lymphatic sinusoids, owing to a marked hypertrophy of lining endothelial cells and an infiltrate of macrophages. Sinus histiocytosis is often encountered in lymph nodes draining cancers and may represent an immune response to the tumor or its products.


Granulomatous lymphadenitis
There is a large number of diseases that can result in granuloma formations in lymph nodes. However, the mere presence of granulomas in a lymph node biopsy will definitely shorten the list of the differential diagnosis in a case of lymphadenopathy. The causes of granulomatous lymphadenitis include
Infections
Foreign body reactions
Malignancy
Among the infectious causes are
Tuberculosis
Atypical mycobacteriosis
Sarcoidosis (although of still of unknown etiology; evidences suggest an infectious cause).
Fungal infections
Toxoplasmosis
Syphilis & Leprosy
Mesenteric lymphadenitis
Cat-scratch disease
Brucellosis
Malignancy related granulomatous lymphadenitis occurs whether the neoplasm is primary (Hodgkin & non-Hodgkin lymphomas), or secondary (metastatic carcinoma). It occurs whether the node is involved by the malignancy or not.
Sometimes the appearance of the granulomas is such that a specific diagnosis can be strongly suggested e.g. presence of caseation necrosis. In most cases, however, a combination of clinical, morphologic, & bacteriologic data (sometimes with the help of more sophisticated techniques) is necessary to determine the etiology of the granulomas.

LYMPHOID NEOPLASMS encompass a group of entities that vary widely in their clinical presentation and behavior. These include leukemias, lymphomas, and plasma cell dyscrasias. All these have the potential to spread to lymph nodes and various tissues throughout the body, especially the liver, spleen, and bone marrow. In some cases lymphomas spill over into the peripheral blood, creating a leukemia-like picture. Conversely, leukemias of lymphoid cells, originating in the bone marrow, can infiltrate lymph nodes and other tissues, creating the histologic picture of lymphoma. Because of the overlap in clinical presentations, the diagnosis and prognosis of various lymphoid neoplasms can only be established through the microscopic appearance and molecular characteristics of the tumor cells.
Two groups of lymphomas are recognized:
1. Hodgkin lymphoma and (HL)
2. Non-Hodgkin lymphomas (NHL)
According to the most recent issue of the Iraqi Cancer Registry (2002), malignant lymphoma represents 9% of all cancers in Iraq.
The behavior and treatment of Hodgkin lymphoma differ from those of most NHLs, thus making the distinction between the two of practical importance.
The WHO has established a widely accepted classification that depends on a combination of clinical, microscopic, immunophenotypic, and genotypic features (e.g., karyotype, presence of viral genomes, etc.)). B- and T-cell tumors are composed of cells derived from specific stages of their normal differentiation pathways. The diagnosis and classification of these tumors relies heavily on tests (e.g. immunohistochemistry) that detect specific antigens (e.g., B-cell, T-cell markers). Many such markers are identified according to their cluster of differentiation (CD) number. All lymphomas are derived from a single transformed cell and thus are by definition monoclonal. During the differentiation of precursor B and T cells there is a somatic rearrangement of their antigen receptor genes. This process ensures that each lymphocyte makes a single, unique antigen receptor. This rearrangement occurs before malignant transformation, thus the daughter cells derived from a given malignant ancestor share the same antigen receptor gene configuration and thus synthesize identical antigen receptor proteins (either immunoglobulins or T-cell receptors). For this reason, analysis of antigen receptor genes and their protein products is frequently used to differentiate monoclonal neoplasms from polyclonal, reactive processes. It has been shown that NHLs is often widely disseminated at the time of diagnosis, even when the disease appears clinically localized, that is why only systemic therapies are curative. In contrast, Hodgkin lymphoma often presents at a single site and spreads in a predictable fashion to neighboring lymph node groups. For this reason, early in the disease, local therapy may be effective.


The WHO classification embraces all lymphoid neoplasms, including leukemias and multiple myeloma, and separates them on the basis of origin into three major categories:
A. Tumors of B cells
B. Tumors of T cells and NK cells
C. Hodgkin lymphoma.

Some neoplasms are common and collectively make up the vast majority of lymphoid neoplasms (more than 90%), these include
1. Precursor B- and T-cell lymphoblastic leukemia/lymphoma
2. Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL)
3. Follicular lymphoma
4. Diffuse large B-cell lymphomas
5. Burkitt lymphoma
6. Multiple myeloma and related plasma cell dyscrasias
7. Mantle cell lymphoma
8. Hodgkin lymphoma
Precursor B- and T-Cell Lymphoblastic Leukemia/Lymphoma
These are aggressive tumors, composed of immature lymphocytes (lymphoblasts), which occur predominantly in children and young adults. They are microscopically indistinguishable.
Both pre-B- and pre-T-lymphoblastic lymphomas usually take on the clinical appearance of an acute lymphoblastic leukemia (ALL) at some time during their course. As a group, ALLs constitute 80% of childhood leukemia, peaking in incidence at age of 4 years, with most of the cases being of pre-B-cell origin. The pre-T-cell tumors, which initially present as thymic tumors, are most common in adolescent males of between 15 and 20 years of age.

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (CLL/SLL)

These two disorders differ only in the extent of peripheral blood involvement. If the peripheral blood lymphocytosis exceeds 4000 cells/mm3, the patient is diagnosed with chronic lymphocytic leukemia (CLL); if not, a diagnosis of small lymphocytic lymphoma (SLL) is made.
Microscopic features
There is diffuse effacement of the lymph node architecture by lymphoid cells.
The predominant cells are compact, monomorphic, small, resting lymphocytes with dark-staining round nuclei & scanty cytoplasm.
There are, in addition, foci of mitotically active larger cells; these aggregated to form proliferation centers. The latter are pathognomonic for CLL/SLL.
CLL/SLL is a neoplasm of mature B cells expressing pan-B-cell markers such as CD19, CD20, and surface immunoglobulin heavy and light chains.
In addition to the lymph nodes, the bone marrow, spleen, and liver are involved in almost all cases; this is associated with peripheral absolute lymphocytosis. Generalized lymphadenopathy and hepatosplenomegaly are present in 50% of cases. The median survival is about 5 years. CLL/SLL tends to transform to more aggressive lymphoid malignancies. Once transformation occurs, the median survival drops to less than one year.


Follicular Lymphomas are common adult NHLs in the United States, but (Like CLL/SLL), they occur much less frequently in Asian populations.
Microscopic features.
The native lymph node architecture is effaced by nodular (follicular) aggregates of proliferating lymphoid cells
Most commonly, the predominant neoplastic cells are "centrocyte-like" cells; these are slightly larger than resting lymphocytes & have "cleaved" nuclei due to prominent indentations and linear infoldings of the nuclear membrane.
The small, cleaved cells are mixed with variable numbers of larger "centroblast-like" cells that have vesicular nuclei, several nucleoli, and moderate amounts of cytoplasm. In most tumors, centroblast-like cells are a minor component of the overall cellularity.
These tumors express the pan-B-cell markers (CD19 and CD20).
The majority of tumors have a characteristic t(14;18) translocation. This translocation fuses the BCL2 gene to the IgH locus on chromosome 14 and leads to the inappropriate expression of BCL2 protein, which functions to prevent apoptosis.
Follicular lymphoma usually presents as frequently generalized painless lymphadenopathy. The bone marrow almost always involved at the time of diagnosis. The median survival is 8 years, but this lymphoma is not easily curable. In about 40% of patients, it progresses to a diffuse large B-cell lymphoma, which is an ominous change.

Diffuse Large B-Cell Lymphoma (DLBCL): as a group, this is the most important type of NHL lymphoma in adults (50% of adult NHL).
Microscopic features :
The nuclei of the neoplastic B cells are large (3-4 times the size of resting lymphocytes).
There are two morphologic variants of DLBCLs
A. Centroblastic: the cells have round, or cleaved nuclear contours & several distinct nucleoli, and moderate amounts of pale cytoplasm.
B. Immunoblastic: the cells have a large round or multilobulated nucleus, one or two centrally placed prominent nucleoli, and abundant cytoplasm.
The cells express pan-B-cell antigens (CD19 and CD20). Many also express surface IgM and/or IgG.
Approximately 30% of tumors have a t(14;18) translocation involving the BCL2 gene. Such tumors may represent "transformed" follicular lymphomas.
Several distinctive clinicopathologic subtypes are included in the general category of diffuse large B-cell lymphoma.
1. Diffuse large B-cell lymphomas complicating AIDS and iatrogenic immunosuppression (e.g., in transplant patients). EBV is implicated in the pathogenesis of this type.
2. Primary effusion lymphomas within the pleura, pericardium, or peritoneum. Human herpesvirus type 8 (HHV-8), the agent of Kaposi sarcoma, is associated with this rare subtype. Patients are usually immunosuppressed.
3. Mediastinal large B-cell lymphoma usually presents in young females and shows a predilection for spread to abdominal viscera and the central nervous system.


Although the median age at presentation is about 60 years, DLBCLs can arise at any age; they constitute 15% of childhood lymphomas. Patients typically present with a rapidly enlarging mass at one or several sites. Extranodal presentations are common, with the GIT and the brain among the more frequent sites. DLBCLs are aggressive tumors that are rapidly fatal if untreated.

Burkitt Lymphoma is endemic in some parts of Africa and sporadic elsewhere. Both the African and nonendemic forms are identical, although there are clinical and virologic differences.
In endemic areas, tumor cells in almost all patients carry EBV genome. In such endemic areas concomitant (endemic) malaria (or other infections) impairs immune competence, allowing sustained B-cell proliferation. Lymphoma cells emerge only when additional mutations, such as the t(8;14) translocation. This involves MYC proto-oncogene on chromosome 8. The latter becomes activated to MYC oncogene as a result of fusion with the IgH gene on chromosomes 14. The net result is the dysregulation and overexpression of the MYC protein. In nonendemic areas, 80% of tumors do not harbor the EBV genome, but all tumors possess the specific t(8 ; 14) translocation.
This suggests that although non-African Burkitt lymphomas are triggered by mechanisms other than EBV, they develop cancer by similar pathways.
Microscopic features.
The tumor cells are uniform and intermediate in size with round nuclei containing 2 to 5 prominent nucleoli. The nuclear size approximates that of benign macrophages within the tumor. There is a moderate amount of basophilic cytoplasm, which on cytological smears often contains small lipid vacuoles.
A high mitotic rate is very characteristic of this tumor, as is cell death. The latter accounts for the presence of numerous tissue macrophages containing ingested nuclear debris. Because these benign macrophages with their pale cytoplasm are scattered within a blue background (of lymphoma cells) a "starry sky" pattern is thus created.
Both the endemic and nonendemic forms affect mainly children and young adults. In both forms, the disease usually arises at extranodal sites.
In African patients, involvement of the maxilla or mandible is the common mode of presentation, whereas abdominal tumors involving the bowel, retroperitoneum, and ovaries are more common in nonendemic areas.
Burkitt lymphoma is a high-grade tumor that is among the fastest growing human neoplasms; however, with very aggressive chemotherapy regimens, the majority of patients can be cured.
Mantle Cell Lymphomas are composed of B cells that resemble cells in the mantle zone of normal lymphoid follicles. They constitute approximately 4% of all NHLs and occur mainly in older males. They involve lymph nodes in a diffuse or vaguely nodular pattern. The tumor cells are usually slightly larger than normal lymphocytes and have an irregular nucleus. Less commonly, the cells are larger. The bone marrow is involved in the majority of cases, and about 20% of patients have peripheral blood involvement.
One unexplained but characteristic tendency is the frequent involvement of the gastrointestinal tract.

Multiple Myeloma and Related Disorders (The plasma cell dyscrasias)

This is covered in the hematopathology lectures.

Hodgkin Lymphoma (HL) encompasses a distinctive group of neoplasms that arise almost invariably in a single lymph node or chain of lymph nodes and spread characteristically in a stepwise fashion to the anatomically contiguous nodes. Despite the fact that HL is a totally separate entity from NHL, molecular studies have shown that it is a tumor of B-cell origin. HL accounts for 30% of all lymphomas
Classification
HL has been reclassified by the rather recently into nodular lymphocyte predominant & classic HLs. Classical Hodgkin's lymphoma are subclassified into 4 pathologic subtypes based upon Reed-Sternberg cell morphology and the composition of the reactive cell infiltrate seen in the lymph node biopsy specimen.
I. Nodular lymphocyte predominant HL in which the neoplastic RS cells are B-cells reacting with CD20 & CD79a. Most of the background small lymphocytes are also B-cells.
II. Classical HL: nearly all RS cells are also derived from B-cells but show different markers from the above, namely CD15 & CD30.
The background lymphocytes are predominantly of T-cells except in the lymphocyte-rich variant, where they are mainly B-cells.
Under this heading are the following subtypes
Nodular sclerosis
Mixed cellularity
lymphocyte rich (rare)
lymphocyte depletion (rare)
Microscopic features
The characteristic microscopic feature of HL is the Reed-Sternberg (RS) cell. This is a large cell (15-45 μm in diameter) with an enlarged bi- or multilobated nucleus, prominent nucleoli, and abundant, usually slightly eosinophilic cytoplasm. Particularly characteristic are cells with two mirror-image nuclei or nuclear lobes, each containing a large acidophilic nucleolus surrounded by a distinctive clear zone; together they impart an owl-eye appearance. The nuclear membrane is thick.
Nodular Sclerosis Hodgkin Lymphoma is the most common form. It is equally frequent in men and women and has a striking tendencdy to involve the lower cervical, supraclavicular, and mediastinal lymph nodes. Most of the patients are adolescents or young adults, and the overall prognosis is excellent. It is characterized microscopically by:
The presence of a particular variant of the RS cell, the lacunar cell. This cell is large and has a single multilobate nucleus with multiple small nucleoli and an abundant, pale-staining cytoplasm. In formalin-fixed tissue, the cytoplasm often retracts, giving rise to the appearance of cells lying in empty spaces, or lacunae.
The presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. The cellular infiltrate may show varying proportions of lymphocytes, eosinophils, histiocytes, and lacunar cells. Classic RS cells are infrequent.
The immunophenotype of the lacunar variants is identical to that of classic RS cells i.e. express CD15 and CD30.
Mixed-Cellularity Hodgkin Lymphoma (MCHL) is the most common form of Hodgkin lymphoma in patients older than the age of 50 years with a male predominance.
Classic RS cells are plentiful within a distinctive mixed cellular infiltrate, which includes small lymphocytes, eosinophils, plasma cells, and benign histiocytes.
Compared with the other subtypes, more patients with mixed cellularity have disseminated disease and systemic manifestations.
Lymphocyte-depleted Hodgkin disease (LDHL), (< 1% of cases): is characterized by the presence of large numbers of RS that are often bizarre morphologically. It is associated with older age and HIV positive status. Patients usually present with advanced-stage disease.
Lymphocyte-rich HL (LRHL), (5%) of cases: in this type of Hodgkin disease, RS cells of the classic or lacunar type are observed, with a background infiltrate of lymphocytes. It requires immunohistochemical diagnosis. Clinically, the presentation and survival patterns are similar to those for MCHL.
Lymphocyte-Predominance Hodgkin Lymphoma (LPHL) is a rare subgroup that often shows formation of poorly defined nodules, which contain a large number of small mature lymphocytes admixed with a variable number of benign histiocytes.
Classic RS cells are extremely difficult to find. Instead there is a scattered of lymphohistiocytic (L&H) variant RS cells that have a delicate multilobed, puffy nucleus, which has been likened in appearance to popcorn ("popcorn cell"). Unlike RS cells,
L&H cells are positive for B-cell antigens, such as CD19 and CD20, and are negative for CD15 and CD30. A diagnosis of NLPHD needs to be supported by immunohistochemical studies because it can appear similar to LRHD or even some non-Hodgkin lymphomas. LPHL presents mostly as isolated cervical or axillary lymphadenopathy and have an excellent prognosis.
The histologic diagnosis of Hodgkin lymphoma rests on the definitive identification of RS cells or their variants in the appropriate background of reactive cells. Immunophenotyping plays an important adjunct role in helping to distinguish Hodgkin lymphoma from reactive conditions and other forms of lymphoma.
In all forms, involvement of the spleen, liver, bone marrow, and other organs may appear in due course. In advanced disease, the spleen and the liver can be enlarged by tumor.


Clinical Staging of Hodgkin (and Non-Hodgkin Lymphoma) (Ann Arbor Classification)
Stage I: involvement of a single lymph node region (I) or involvement of a single extralymphatic organ or tissue (IE)
Stage II: involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited contiguous extralymphatic organs or tissue (IIE)
Stage III: involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIS), limited contiguous extralymphatic organ or site (IIIE), or both (IIIES)
Stage IV: multiple or disseminated foci of involvement of one or more extralymphatic organs or tissues with or without lymphatic involvement
All stages are further divided on the basis of the absence (A) or presence (B) of the following systemic symptoms: significant fever, night sweats, unexplained loss of more than 10% of normal body weight.

Etiology and Pathogenesis of HL

L&H variants of RS cells found in nodular lymphocyte-predominance Hodgkin lymphoma express B-cell markers (e.g. CD20). By contrast, the RS cells in all classic subtypes do not express such markers. However, all show the same immunoglobulin gene rearrangements and that the rearranged immunoglobulin genes have undergone somatic hypermutation; this precludes expression of B cell markers. Thus, it is now generally agreed that Hodgkin lymphoma, whether classic or not, is a neoplasm arising from germinal center B cells. The events that transform these B cells and alter their appearance and gene expression programs are still unknown.
The EBV genome is present in the RS cells in up to 70% of cases of the mixed-cellularity type and a smaller fraction of the nodular sclerosis type. Thus, EBV infection is likely to be a contributing step to the development of Hodgkin lymphoma, particularly the mixed-cellularity type.
It has been found that the RS cells in classical forms of Hodgkin lymphoma, regardless of their EBV status, contain high levels of activated NF-κB, a transcription factor that normally stimulates B-cell proliferation and protects B cells from pro-apoptotic signals. Several EBV proteins that are known to activate NF-κB are expressed in EBV-positive RS cells. Thus, hyperactivation of NF-κB may be a central event in the genesis, growth, and survival of RS cells.
The characteristic non-neoplastic, inflammatory-cell infiltrate seems to result from a number of cytokines secreted by RS cells, including IL-5 (which attracts and activates eosinophils). Conversely, the responding inflammatory cells produce factors (such as CD30 ligand) that can aid the growth and survival of RS cells.

Prognosis of HL

A definitive distinction from NHL can be made only by examination of a lymph node biopsy specimen. With current modalities of therapy, however, the clinical stage is the most important prognostic indicator. The 5-year survival rate of patients with stage I-A or II-A disease is close to 100%. Even with advanced disease (stage IV-A or IV-B), the overall 5-year disease-free survival rate is around 50%. However, therapeutic successes have also brought problems. Long-term survivors of radiotherapy protocols are at much higher risk of developing certain malignancies, including lung cancer, melanoma, and breast cancer.

MISCELLANEOUS LYMPHOID NEOPLASMS

Extranodal Marginal Zone Lymphomas are low-grade mature B-cell tumors that arise mostly in mucosal-associated lymphoid tissue (MALT), such as salivary glands, small and large bowel, and lungs. They tend to occur in the setting of autoimmune disorders (such as Sjögren syndrome and Hashimoto thyroiditis) or chronic infections with such organisms as Helicobacter pylori, suggesting that sustained antigenic stimulation contributes to their development. In the case of H. pylori-associated gastric MALT lymphoma, eradication of the organism with antibiotic therapy often leads to regression of the tumor. When arising at other sites, MALT tumors can often be cured by local excision or radiotherapy.
Mycosis Fungoides (MF) and Sézary Syndrome :
These are composed of neoplastic CD4+ T cells that involve the skin, thus are examples of cutaneous T-cell lymphomas. MF usually presents initially as reddish cutaneous rash (erythrodermic phase) that progresses to plaque phase & then a tumor phase. Microscopically, there is infiltration of the epidermis and upper dermis by neoplastic T cells, with a marked infolding of the nuclear membrane (cerebriform nucleus). Involvement of the epidermis is in the form of localized collections referred to as Pautrier microabscess. With progressive disease, there is lymph & visceral dissemination. Sézary syndrome is a clinical variant characterized by the presence of
1. Generalized exfoliative erythroderma
2. Tumor cells (Sézary cells) in the peripheral blood.
Patients with the initial erythrodermic-phase MF often survive for many years, whereas survival is reduced to 2 years for patients with tumor-phase disease, visceral disease, or Sézary syndrome.
Peripheral T-Cell Lymphomas
This is a heterogeneous group of tumors that together make up about 15% of adult NHLs. In general, they present as disseminated disease, are aggressive, and respond poorly to therapy.


THE SPLEEN
Splenomegaly
The spleen is frequently secondarily involved in a wide variety of systemic diseases. In virtually all instances, the response of the spleen causes its enlargement (splenomegaly). Evaluation of splenomegaly is a common clinical problem that is aided considerably by knowledge of the usual limits of the splenic enlargement that is seen in the context of specific disorders. As an aid to diagnosis, splenomegaly is classified according to the degree of its enlargement:
Massive splenomegaly (weight more than 1000 gm)
Chronic myeloproliferative disorders (chronic myeloid leukemia, myeloid metaplasia with myelofibrosis)
Chronic lymphocytic leukemia
Hairy cell leukemia
Lymphomas
Malaria
Moderate splenomegaly (weight 500-1000 gm)
Chronic congestive splenomegaly (portal hypertension or splenic vein obstruction)
Acute leukemias
Hereditary spherocytosis
Thalassemia major
Autoimmune hemolytic anemia
Mild splenomegaly (weight <500 gm)
Acute splenitis
Acute splenic congestion
Infectious mononucleosis
Miscellaneous acute febrile disorders, including septicemia, SLE, and intra-abdominal infections
An enlarged spleen often removes excessive numbers of one or more of the formed elements of blood, resulting in anemia, leukopenia, or thrombocytopenia. This is referred to as hypersplenism, a state that can be associated with many of the diseases affecting the spleen listed above. In addition, platelets are particularly susceptible to sequestration in the red pulp; as a result, thrombocytopenia is more prevalent and severe in individuals with splenomegaly than are anemia or neutropenia.

THE THYMUS

Thymic Hyperplasia
Hyperplasia of the thymus is often associated with the appearance of lymphoid follicles, or germinal centers, within the medulla. These germinal centers contain reactive B cells, which are normally present in only low numbers in the thymus. Thymic follicular hyperplasia is present in most patients with myasthenia gravis and is sometimes also found in other autoimmune diseases, such as SLE and rheumatoid arthritis.

Thymomas

These are tumors in which epithelial cells constitute the neoplastic element. Scant or abundant precursor T cells (thymocytes) are present in these tumors, but these are non-neoplastic. Thymomas are classified as follows
1. Benign or encapsulated thymoma: cytologically and biologically benign
2. Malignant thymoma
Type I: cytologically benign but biologically aggressive and capable of local invasion and, rarely, distant spread
Type II (thymic carcinoma): cytologically & biologically malignant
Gross features
Thymomas are lobulated, firm, gray-white masses up to 15 to 20 cm in longest dimension.
Most appear encapsulated, but in 20% to 25% there is apparent penetration of the capsule and infiltration of perithymic tissues and structures.
In thymic carcinomas metastases occur e.g. to the lungs.
Microscopic features
Almost all thymomas are made up of a mixture of epithelial cells and a variable infiltrate of non-neoplastic thymocytes (T-lymphocytes). The relative proportions of the epithelial and lymphocytic components are of little significance.
Benign thymomas show spindled or elongated epithelial cells that resemble those normally populate the medulla, hence the designation medullary thymomas. In other tumors the above cells are admixed with plump, rounder, cortical-type epithelial cells; this pattern is referred to as a mixed thymoma. The medullary and mixed patterns account for 60% to 70% of all thymomas.
Malignant thymoma type I is a tumor that is cytologically bland but locally invasive. These tumors occasionally (and unpredictably) metastasize and account for 20% to 25% of all thymomas. They are composed of varying proportions of epithelial cells and reactive thymocytes; the epithelial cells usually resemble cortical ones i.e having abundant cytoplasm and rounded vesicular nuclei. They often form palisades around blood vessels. Sometimes spindled epithelial cells are also present. The critical distinguishing feature is the penetration of the capsule and the invasion of surrounding structures.
Malignant thymoma type II (thymic carcinoma): these constitute 5% of thymomas and, in contrast to the type I malignant thymomas, are malignant cytologically. Most resemble either poorly or well-differentiated squamous cell carcinomas. The next most common malignant pattern is lymphoepithelioma-like carcinoma, which is composed of anaplastic cortical-type epithelial cells mixed with large numbers of benign thymocytes. Tumors of this type are more common in Asian populations and sometimes contain the EBV genome.


All thymomas are rarities, the malignant more so than the benign. They typically occur in middle adult life. In a large series, about 30% were asymptomatic; 30% produced local manifestations such as a mass demonstrable on computed tomography in the anterosuperior mediastinum associated with cough, dyspnea, and superior vena caval syndrome; and the remainder were associated with some systemic disease, principally myasthenia gravis. 20% of patients with myasthenia gravis have a thymoma. Removal of the tumor often leads to improvement in the neuromuscular disorder. Additional associations with thymomas include hypogammaglobulinemia, SLE, & pure red cell aplasia.