| | Splenic histology and histopathology: an updateAbstract The spleen can be a troublesome specimen for the surgical pathologist, not only because experience with the range of “normal” splenic histology is limited by its rarity but also because there is an often a frustrating discordance between the patient’s clinical condition and the perceived findings. Patients with a dramatic clinical presentation that points to splenic pathology (“hypersplenism” or marked splenomegaly) not infrequently have no discernable or have barely perceptible histologic abnormalities of the spleen. Similarly, patients whose spleens contain histologic findings that seem to deviate significantly from the “norm” (histiocytic proliferations, vasoformative lesions, stromal hyperplasia) may have no clinically detectable hematologic complaints. For most pathologists, the frame of reference for normal splenic histomorphology derives largely from experience with autopsy spleens and spleens removed for trauma or immune thrombocytopenia. These are all settings in which pre-existing disease, the immune status of the patient, and therapy influence the findings and - in cases in which fixation has been delayed - even the ability to make the findings. This review presents practical aspects of splenic development and immunoarchitecture and relates this to the pathologist’s approach in evaluating the abnormal spleen and assists in resolving such discordances. Benign conditions that contrast with the subjects of subsequent articles in this issue are emphasized.
MUCH OF WHAT we know about benign and neoplastic disorders of the spleen derives from our knowledge of the normal cellular components of that organ. Primary lymphomas, for instance, arise from or home to the marginal, mantle, or follicular compartments of the white pulp, and classification of these diseases follows criteria founded on B-cell ontogeny. The same can be said of pseudoneoplastic, hamartomatous, and vasoformative lesions, which may have as their ontogenic substrate, the histiocytic, stromal, ‘pericytic,’ lymphatic, vascular, and splenic endothelial (littoral) cells of the normal spleen. Because the spleen is uncommon as a diagnostic specimen in all but large tertiary medical centers (and because it is seldom given more than cursory treatment in textbooks), the general pathologist is often unfamiliar with the full range of splenic pathology. This article presents practical aspects of splenic development and immunoarchitecture and relates this to the pathologist’s approach in evaluating the abnormal spleen. Benign conditions that contrast with the subjects of subsequent articles in this issue are emphasized.
Development, functional structure, and immunoarchitecture  The embryonic spleen appears in the first trimester of gestation as a multiply lobated condensation of highly vascular mesenchyme that is interposed in the arterial circulation in the dorsal mesogastrum.1 While the full scope of the genetic underpinnings of organogenesis is incompletely known, Hox11, WT1, and other genes are essential for the development of the splenic anlage.2, 3 Defects in the expression of these and other homeobox genes lead to asplenia or polysplenia.1, 4 Subsequent expression of capsulin is required for complete organogenesis,5 apparently through control of branching morphogenesis of vessels; in capsulin knockout mice, the spleen anlage develops but then disappears through apoptotic mechanisms.5, 6 In its mature state, the spleen maintains many of the attributes of its vascular and mesenchymal origins.7, 8 Its principle structure is based on an arborizing array of arterioles that bifurcate and narrow until they terminate either 1) into the stroma of the cords, forming the open circulation; or 2) directly into the sinusoids which, being in continuity with the venous system, form the closed circulation of the spleen (Fig 1). The cordal elements include histiocytes, antigen presenting reticulum cells, pericytes, fibroblasts, and other cells necessary to maintain the discontinuous basal lamina that separates the cords from the sinus lumena.9 Lymphatics are inconspicuous, but can be identified in the T-cell rich zones of the periarteriolar lymphoid sheaths if special techniques are applied.10, 11 A Periodic Acid Schiff (PAS) stain is particularly helpful in evaluating the histomorphology of the spleen since the reagents both clear the hemoglobin from red blood cells and accentuate the presence of the discontinuous basal lamina that separates the cords from the sinuses (Fig 2). The arterial vascular tree, lined by conventional CD31+ CD34+ endothelial cells, branches into arterioles that terminate abruptly in caps of cordal macrophages that formed blood elements must cross in order to enter the sinusoids (Fig 1). The sinusoids, essentially the origin of the venous component of the splenic vasculature, are lined by specialized “littoral” cells with combined phagocytic and endothelial qualities and a distinctive CD31+, CD34-negative, CD68+, CD8+ (ααtype) phenotypic profile (Fig 3). 12, 13, 14 Similar to conventional vasculature, pericytic support cells, with an SMA+, desmin ± phenotype are also present (Fig 4). 15, 16, 17) Interdigitating reticulum cells, with their CD45+, s100+ phenotype, are distributed throughout the peri-arteriolar sheaths. Fibroblasts within the red pulp of the perifollicular zone play a role in lymphocyte homing to specific white pulp compartments through a regulated display of cell adhesion molecules not characteristic of fibroblasts elsewhere.18 The development lymphoid compartment of the spleen, the white pulp, begins early in the second trimester as interdigitating reticulum cells mediate the migration and coalescence of lymphocytes along the vascular tree. T lymphocytes, principally CD4+, form a continuous layer along the length of the vessels (“periarteriolar sheaths”), while CD8+ T cells home to and reside in the splenic cords (Fig 5). 8 A specialized subset of γ/δT-cell homes to the red pulp cords as well, though in adults is generally inconspicuous except in altered immune states such as graft versus host disease.19 IgD+ and IgG+ B lymphocytes form localized deposits, the primary follicles. In utero, this B-cell compartment is also rich in CD20+, CD5+ B cells, although this diminishes in quantity after birth and re-emerges in adults in some systemic conditions associated with autoimmunity. Secondary follicles arise postnatally, after first exposure to immunologic stimuli and have a distinctive tripartite structure that includes a germinal center, distinct IgD+ mantle zone, and a peripheral IgD-negative, IgM+, IgG± marginal zone (Fig 6). 20, 21 Prosection issues Clinical intent Trauma, staging, and surgical convenience together account for over half of all splenectomies at large medical centers, with therapeutic splenectomy in patients whose diagnosis is already established accounting for the bulk of the remainder.22 Unexpected pathology is encountered in these specimens and is rare (∼1% of cases), although it can be clinically significant.22. Significant splenomegaly (spleen weight >300 g) or focal lesions are the prosector’s cue that the specimen requires more than a routine evaluation. Approximately 10% of the time the spleen is removed with diagnostic intent because radiologic studies disclose either splenomegaly or discrete splenic masses and evaluation of peripheral blood, bone marrow, and lymph nodes fails to disclose the cause. It is these latter cases that can consume a disproportionate amount of the pathologist’s time: care in prosection and triaging of tissue is the key to rendering a timely diagnosis in difficult cases. Hilar fat is often present on the splenectomy specimen, and it should be carefully sectioned, with representative tissue from hilar lymph nodes distributed for all appropriate studies, including flow cytometry. Compared to lymph nodes, the more abundant stroma of the spleen can interfere with the efficiency of disaggregating viable cells for flow cytometric analysis. Then, too, the patterns of morphologic changes associated with specific reactive conditions are more readily recognized in lymph node specimens, which lack the distorting effects of the stroma, red blood cells, and marginal zone compartments of the spleen. Primary fixation Few factors contribute more to ease of diagnosis in splenectomy specimens than proper fixation. Both the lymphoid constituents and the reticular structure of the splenic red pulp are delicate, and delayed or incomplete fixation has a more profound effect on splenic histology than it does other organs. Ideally, the ratio of formalin to tissue in the jar used for primary fixation should be ∼10:1 so that the bloodiness of the specimen does not dilute the efficacy of the formalin. With adequate formalin fixed material, B5 fixation can be used selectively or omitted in therapeutic or incidental splenectomies, but the superior cytologic detail that it offers makes it quite helpful in diagnostic cases. Ancillary studies Because most cases of unexplained splenomegaly are eventually diagnosed as some form of low-grade lymphoma22 having material available for flow cytometric analysis is invaluable in the work-up of enlarged spleens. Polymerase chain reaction-based studies can be applied to paraffin embedded material, but the quality of DNA is better in fresh tissue and a broader array of molecular tests can be performed, so an effort should be made to snap freeze lesional tissue wherever possible. Fluorescence in situ hybridization probes for most of the disease-defining translocations are commercially available and can be applied either to formalin fixed material or touch preparations made from the fresh spleen. Such touch preparations can also be stained with a Wright-Giemsa stain or used for myeloperoxidase and naphthyl butyryl esterase stains when full characterization of a myeloid disorder is necessary.23 Macroscopic findings and their histopathologic correlates The gross appearance of splenectomy specimens is closely predictive of final diagnostic categories, with splenic masses leading to one set of common diagnoses, and splenomegaly leading to another.22, 24 Macroscopic findings therefore are of great practical value not only in targeting which areas to sample, but also in establishing an initial differential diagnosis from which a rational plan for ancillary studies can be made. Unexplained splenic masses With few exceptions, clinically unexplained noncystic splenic masses are caused by a malignancy, and, in virtually all cases (Table 1), the diagnosis seldom requires sophisticated ancillary studies or esoteric markers. In one study of 1280 sequential splenectomy specimens,22 the single most common diagnosis was large cell lymphoma, with metastatic carcinoma following close behind. Hamartomas, histiocytic neoplasms, and vascular tumors fall within this category too, and, where frozen section or touch preparation findings dictate, setting tissue aside for electron microscopy may be of help in establishing a final diagnosis.  | Neoplastic | |
| Large cell lymphoma | |
| Follicular lymphoma (grades II and III) | |
| Hodgkin lymphoma | |
| Metastatic carcinoma | |
| Metastatic sarcoma | |
| Primary vascular and littoral tumors (benign and malignant) | |
| Reactive | |
| Cysts and pseudocysts | |
| Hamartomas | |
| Peliosis | |
| Infarcts | | | | |
Unexplained splenomegaly Diffuse splenomegaly is commonly caused by lymphoma,22, 24, 25, 26 but benign conditions are frequent enough in this setting (Table 2) that it is essential for the prosector to distribute tissue for the full range of ancillary studies. Although marginal zone lymphoma was the most common type of lymphoma to cause unexplained splenomegaly in one large study,22 other low-grade lymphomas that can closely mimic marginal zone lymphoma accounted for over half of the cases in this category.27, 28 In addition, rare cases of both large cell lymphoma29 and metastatic carcinoma may involve the spleen in a diffuse manner30 and have unexpectedly aggressive clinical course. Leukemias of lymphoid and myeloid types both produce diffuse splenomegaly25, 31, 32 but the diagnosis is seldom unknown at the time of splenectomy. | Neoplastic | |
| Low-grade lymphomas, all types (including grade I follicular lymphoma) | |
| Prolymphocytic leukemia/lymphoma | |
| T lineage lymphomas, all types | |
| Hemophagocytic syndrome | |
| Myeloid malignancy (myelodysplasia, myeloproliferative disorders, mast cell disease) | |
| Amyloid deposition in the setting of a plasma cell dyscrasia | |
| Reactive | |
| Granulomatous splenitis (infectious, sarcoidal) | |
| Extramedullary hematopoiesis | |
| Congestive splenomegaly (sinusoidal erythrocytosis, stromal hyperplasia) | |
| Storage disorders | |
| Infection (infectious mononucleosis, mycobacterial, leishmania, malaria) | |
| Hemoglobinopathies (hereditary spherocytosis, thalassemia) | |
| Immune mediated hemolytic anemia, thrombocytopenia | |
| Felty’s syndrome | |
| Nonspecific lymphoid hyperplasia | | | | |
Normal red pulp and red pulp hyperplasia The contents of the cords and sinuses together constitute the red pulp of the spleen, whose principle function is filtration of serum components of the blood and targeted culling of red blood cells that are poorly deformable either because of intrinsic factors or because of inclusions or parasites. In nonprimate mammals, the red pulp of the spleen serves as a site for ongoing hematopoiesis and storage reservoir of red blood cells, but these are of vestigial significance in adult humans.9 Expansion of the red pulp compartment or red pulp hyperplasia may occur in any hyper-phagocytic condition, when the spleen assumes an extramedullary hematopoietic function, or as a result of diffuse stromal hyperplasia.33, 34 Minor amounts of erythrophagocytosis are invariably present in the spleen, reflecting the normal culling of senescent red blood cells, but it may be pronounced in autoimmune conditions, immune-mediated hemolytic anemia, viral infection, and in allo-immunized transfusion recipients (Fig 7A). 35, 36, 37 Some acute myeloid leukemias and some lymphomas, (particularly peripheral T-cell lymphomas38 and those that elaborate autoreactive antibodies), are malignancies that may also lead to significant splenic erythrophagocytosis (Fig 7B).39 Free macrophages within the sinusoids contain red blood cell fragments and, when the process is pronounced, the activated littoral cells become cuboidal and stand out on the basement membrane in a ‘hobnail’ like fashion. In contrast to autoimmune hemolytic anemia, hemoglobinopathies such as hereditary spherocytosis and elliptocytosis lead to sequestration of the poorly deformable red blood cells in the cords, but relatively little intra-sinusoidal erythrocytosis or hemophagocytosis. There is no histopathologic means of distinguishing secondary and incidental hemophagocytosis from the potentially life-threatening primary or idiopathic hemophagocytic syndromes: the clinical setting and laboratory values such as serum ferritin are a better guide.40 Extramedullary hematopoiesis is commonly encountered in the “normal” spleen, usually in the form of rare megakaryocytes and occasional clusters of intra-sinusoidal pronormoblasts (Fig 8A). 41 However, the presence of appreciable numbers of myeloid precursors should prompt investigation for an underlying myeloproliferative or myelodysplastic disorder.42, 43 These are most conspicuous immediately adjacent to the trabeculae and in the interface between red pulp and peri-arteriolar sheaths, and they can be rendered more conspicuous by Leder (chloracetate esterase) and Giemsa stains (Fig 8B). Typical splenic findings in myelodysplasia include erythroid colonies in the sinusoids, cordal plasmacytosis, and active erythrophagocytosis by the littoral cells, all changes that correlate to some degree with the patient’s ineffective hematopoiesis, neutropenia, and degree of transfusion-related alloimmunization.23 Touch preparations facilitate recognition of dyserythropoietic and dysmyelopoietic precursors, and an enumeration of specific elements (such as blasts and monocytes) can be made (Fig 9A). CD34 and CD117 immunostaining may help identify early myeloid precursors and blasts, but, since there are no recognized guidelines, histological sections are also of limited use in defining patients in transition to accelerated phase, nor in distinguishing between myeloproliferative disorders and myelodysplastic syndromes (Fig 9B). Submission of fresh tissue for cytogenetic analysis is much more helpful in this regard. Chronic obstruction to the vascular outflow of the spleen typically produces mild or moderate amounts of splenomegaly through stromal hyperplasia, although it may lead to benign massive splenomegaly in some cases. The histologic changes of stromal hyperplasia are subtle on H&E stained sections (Fig 10A) , and, if the clinical condition causing the obstruction is not clear (or is not disclosed) the pathologist may find himself/herself in the frustrating situation of having no explanation for a spleen that is up to 1000 g in size. Paraffin section immunohistochemistry will disclose the presence of an increase in the number of red pulp histiocytes (CD68) a global increase in the number of stromal myoid cells (SMA)16, 17 and extra-cellular matrix (reticulin, collagen IV, and laminin stains)44 (Fig 10B). A nodular array of stromal elements is not a typical congestive change, should prompt consideration of benign or borderline mesenchymal neoplasms,12, 45, 46 as well as reactive histiocytic or vasoformative processes such as mycobacterial spindle cell tumors and bacillary angiomatosis (Fig 11). In the benign spleen, the cords vary in thickness but tend to range from 4 to 6 cell widths thick. In benign cordal lymphocytosis, there may be focal expansions such that there are dilatations of the sinus-sinus interspace to 10 to 12 cell width span, but most cords area of normal (4-6 cell widths) dimension. Such changes are easiest to recognize on a PAS or CD8 stain (Fig 12). The lymphocytes are small and cytologically bland, and histiocytes, macrophages, and occasional activated lymphocytes are intermingled. Diffuse red pulp lymphocytosis in the form of uniform expansions of the cords is an abnormal finding that should prompt the pathologist to investigate the clinical circumstances that led to splenectomy. Uniform expansions of the cords without concomitant germinal center hyperplasia in a child may relate to a congenital immunodeficiency state, particularly hyper-IgM syndrome. In adults, uniform expansion of all cordal plates is highly suspicious for lymphoma; findings of cytologic monotony, atypia, and breakdown of the cord-sinus boundaries are helpful additional clues (Fig 13). 47, 48 Because the principle lymphocyte type in the cords of the normal spleen is the CD8+ T cell, increased numbers of CD20+ B cells, CD4+ T cells or CD56 or CD57+ natural killer suggests some form of lymphoma or leukemia.49 Large granular lymphocyte leukemia, in particular, may present in cryptic fashion, with rheumatoid arthritis-like symptoms, selective cytopenias, and splenomegaly, and spleens from such patients may initially be removed for the clinical diagnosis of Felty’s Syndrome.50, 51, 52, 53 Viral infections may also cause a cordal lymphocytosis, and splenectomy may be performed because of spontaneous or trauma-related rupture. In infectious mononucleosis, the cue to the diagnosis is the characteristic mixture of polyclonal lymphoplasmacytic and immunoblastic cells within the cords and peri-arteriolar sheaths; in situ hybridization for Epstein Barr virus encoded ribonucleotides (EBERs) and rising IgM anti-viral capsid antigen titers should be confirmatory (Fig 14). 54, 55, 56 There is a strong correlation between hepatitis C virus infection and cryoglobulinemia,57 and the spleen is almost invariably enlarged as much because of the evolving hepatitis and/or cirrhosis is because of cordal expansions by lymphocytes and plasma cells. The process is often polyclonal in nature, but Dutcher bodies, breakdown of the cord-sinus boundaries (PAS stain, CD68 stain), amyloid deposition, or cordal lymphocytosis with concomitant expansion of the marginal zone of the follicles all favor lymphoma.39, 58 Immunophenotypic studies are essential to secure the diagnosis. Normal white pulp and white pulp hyperplasia A singularly important function of the spleen is immunosurveillance, and the spleen plays a central role in removing opsonized pathogens, encapsulated bacteria, and antibody-coated erythrocytes and platelets from the circulation. The periarteriolar lymphoid sheaths (PALS) and Malpighian corpuscles together constitute the white pulp of the spleen where maturation of the immune response occurs.11 The PALS are the primary location for most of the spleen’s CD4+ T cells, and the Malpighian corpuscles, with their characteristic tripartite follicular-mantle-marginal zone structure, represent periodic expansions of the PALS at branch points along the penicilliary arterioles. In addition, the spleen is home to a substantial number of cordal plasma cells that secrete immunoglobulin as part of the humoral immune response.59 White pulp hyperplasia is usually a diffuse process, but it may occasionally be localized and therefore be macroscopically evident as a 1cm (or larger) white nodule in a background of uniformly punctate Malpighian corpuscles. This focal nodular lymphoid hyperplasia60 retains many of the morphologic features of follicular hyperplasia, but there may be some overlap with the morphology of lymphoma (Fig 15). Demonstrable polarization of bcl2-negative germinal centers, retained IgD+ mantle and marginal zones, polytypia by flow cytometry and polyclonality on molecular studies all support a benign interpretation and assist in excluding other conditions.60, 61 Multicentric Castleman’s disease and other altered immune states may involve the spleen,62, 63 although never in isolation from nodal disease, and it is in the hilar lymph nodes that the pattern of follicular hyperplasia, interfollicular plasmacytosis, and restricted pattern of lambda light chain expression in perifollicular immunoblasts will be recognized. Generalized lymphoid hyperplasia is a more common pattern, and the key feature is a balanced and proportionate expansion of all lymphoid compartments — the follicles, the mantle and marginal zones, and the PALS. A disproportionate expansion of the mantle or marginal zones, particularly in the presence of cordal B-cell lymphocytosis, is highly suspicious for a low-grade B-cell lymphoma (Fig 16). 60 Because most lymphomas composed of small B cells have the capacity to expand the marginal zone compartment, classification should incorporate immunophenotypic as well as cytologic and architectural features.64, 65, 66 If fresh tissue for immunophenotypic analysis was not set aside from a splenectomy specimen that proves to contain a clonal population of cells by gene rearrangement studies, peripheral blood and bone marrow analysis by flow cytometry may yield the necessary information for complete classification. Selective hyperplasia of the PALS without concomitant germinal center formation is exceptional, and instead is more characteristic of peripheral T-cell lymphomas, particularly if it is associated with cordal lymphocytosis. Summary For the pathologist in training and attending alike, the spleen can be deceptively simple. It is rare as a surgical specimen and, when it is encountered, it seldom contains an abnormality. However, occasionally the spleen’s troublingly complex nature is unmasked when findings do not correspond to a well-defined category of disease or the splenic parenchyma obscures diagnostic features. Inevitably, it is these cases in which there is often great clinical pressure, and the temptation may be great to force the findings into an existing category of node-based or soft tissue-based nosology. The key to timely and accurate diagnosis in such situations lays in preparation: obtaining complete clinical information about the patient, taking a systematic approach to prosection, preparing thin sections from well-fixed tissue, and becoming familiar with the stains and studies that define the intactness of splenic immunoarchitecture. References 1.
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a Division of Immunopathology, Department of Pathology, Weill Medical College of Cornell Medical Center, New York, NY, USA  Address reprint requests to Madeleine D. Kraus, MD, Division of Immunopathology — Starr 709, Weill Medical College of Cornell Medical Center, 525 East 68th St, New York, NY 10021, USA
PII: S0740-2570(03)00024-8 doi:10.1016/S0740-2570(03)00024-8 © 2003 Elsevier Inc. All rights reserved. | |
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