EMH—Extramedullary hematopoiesis

Diffuse Nonneoplastic Disease

Extramedullary hematopoiesis (EMH), lymphoid hyperplasia (LH), and amyloidosis can cause diffuse changes and gen­eralized splenomegaly. Extramedullary hematopoiesis and lymphoid hyperplasia are often diagnosed from the same spleen, in both dogs and cats. Although normal to reduced echogenicity is expected, few reports describe the ultrasonographic appearance of the spleen with these conditions (Figures 10-42 and 10-43). Approximately 40% of cats with extramedullary hematopoiesis, lymphoid hyperplasia, or both had splenomegaly with normal echogenicity (Figure 10-44).44 Hypoechoic nodules ranging in size from 0.7 to 3.0 cm were also present in about 25% of these cats (Figure 10-45, see also Figures 10-16 and 10-17). The spleen was hypoechoic or mottled in another 25% of the cats with extramedullary hematopoiesis or lymphoid hyperplasia. Figures 10-46 to 10-49 are examples of diffuse EMH and LH in dogs, showing the wide range of the potential appearances.

View chapterPurchase book

Hematopoietic System

V. E. O. (Ted) Valli, ... R. Darren Wood, in Jubb, Kennedy & Palmer's Pathology of Domestic Animals: Volume 3 (Sixth Edition), 2016

Hematopoietic alterations

Extramedullary hematopoiesis (EMH) results when there is cytokine induction for increased cell production and pluripotent hematopoietic stem cells available. These cells normally circulate in very low numbers and, in preparation for EMH, they return to embryonic sites of colonization, sparing the germinal centers and periarteriolar lymphoid sheaths. Although EMH is commonly found to some degree within the spleen of normal dogs, extensive EMH occurs with chronic anemia, chronic respiratory or cardiovascular disease, various bacterial septicemias, or with certain neoplastic conditions, for instance, hemophagocytic histiocytic sarcoma. Grossly, the spleen appears unremarkable or mildly enlarged. Histologically, EMH is characteristically includes all 3 lineages (Fig. 2-125), but one cell line may predominate, such as the granulocytic system in canine pyometra or the erythroid system in hemolytic anemia. Megakaryocytes are the most obvious hematopoietic precursor and characteristically lie adjacent to the smooth muscle trabeculae when stimulation is mild, but may become diffusely distributed in the sinus areas when stimuli are pronounced and prolonged. Splenic erythropoiesis is coincident with increased splenic red cell destruction in immune hemolytic anemias.

Myeloid metaplasia in spleen and other sites of embryonic hematopoiesis occurs in myelofibrosis (MF), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN), and combinations of MF with MDS or MPN. If the animal has idiopathic myelofibrosis in bone marrow, myeloid metaplasia in spleen is benign, and typically consists of all hematopoietic lineages with synchronous maturation. Grossly, the spleen is uniformly enlarged with turgid capsule and rounded borders. The parenchyma is dry and light pink owing to hematopoietic tissue, rather than dark and cyanotic as in congestion. If the animal has MDS or MPN, there is predominance of one cell lineage, most often granulocytes, but other cell lineages may also be present. The predominant cell lineage typically has dysplastic changes, and fills the splenic sinusoids. Dyspoiesis may affect only one cell lineage, or more commonly all 3, and may consist of multinucleated rubricytes, incipient Howell-Jolly bodies, giant metamyelocytes and band neutrophils, donut-shaped nuclei, and hypolobulated megakaryocyte nuclei. Myeloid metaplasia is often accompanied by lymphoid hyperplasia, hemosiderosis, and splenic fibrosis. With increasing splenic myeloid metaplasia, there is gradual reduction in the lymphoid compartment, and eventual lymphoid atrophy. Small infarcts develop and are likely the result of loss of plasticity, and fibrous impairment of vascular structures.

Rarely, the spleen contains a myelolipoma, which appears grossly as a focal pale nodule on cut surface. Histologically, myelolipomas are composed of well-differentiated adipocytes with large fat vacuoles that are sharply demarcated from the normal splenic parenchyma (Fig. 2-126). Adipocytes are admixed with hematopoietic and largely erythropoietic cells that can be sparse or dominate the neoplastic mass. Myelolipomas are usually incidental findings.

View chapterPurchase book

Non-human primates

Ronnie Chamanza, in Background Lesions in Laboratory Animals, 2012

Hemolymphoreticular system

Extramedullary hematopoiesis (EMH) occurs frequently in the adrenal gland (Fig. 1.53), liver, kidney and other tissues in marmosets. The severity and incidence of this finding is usually associated with the frequency of blood sampling, with marmosets being very sensitive to frequent bleeds (Tucker 1984). This spontaneous finding should be differentiated from inflammation, inflammatory-cell infiltrates or treatment-related EMH. Spontaneous EMH in macaques is extremely rare, but has sporadically been observed in lymph nodes of healthy control cynomolgus macaques (Chamanza et al 2010).

Multinucleate lymphocytic syncytia, resembling the Warthin–Finkeldey bodies associated with measles (Fig. 1.12), have been observed with some frequency in the bronchial-associated lymphoid tissue (BALT) of the larynx and the gut-associated lymphoid tissue (GALT) of the large intestines in normal healthy cynomolgus macaques (Chamanza et al 2010). It is not known whether these represent subclinical measles infection, but no necrosis of lymphocytes is observed within the lymphoid nodules, nor are viral inclusions present within the cells. Natural measles infections which may originate from animal handlers, are known to occur in both marmosets and macaques (Scott 1999).

The presence of prominent lymphoid follicles within the bone marrow is a common background finding in macaques (Fig. 1.13). This lesion, together with lymphoid follicular hyperplasia and prominent germinal centres in other sites, such as the spleen (Fig. 1.14), lymph nodes and salivary glands, have been associated with subclinical type D retroviral infection (Guzman et al 1999, Lowenstine 1993). However, most non-human primates used in preclinical studies are routinely screened for, and are known to be free from, simian retroviruses (type D). Thus hyperplastic lymphoid follicles in the spleen and other tissues are considered to indicate heightened non-specific immunosurveillance in animals which have been reared in a relatively disease-free environment and are known to be free from major pathogens. Periodontal disease, glossitis and tonsillitis are other common minor inflammatory lesions known to be associated with lymphoid follicular hyperplasia and mononuclear cell infiltrations in other organs.

The accumulation of brightly eosinophilic amorphous material (hyalinization) in the centre of lymphoid follicles in non-human primate spleens is a common observation of no known clinical significance. The eosinophilic substance is thought to be proteinaceous in content and composed of antigen–antibody complexes. Russell bodies can occasionally be observed in the vicinity of hyalinized germinal centres, giving more credibility to the theory of immunoglobin composition of the amorphous material.

View chapterPurchase book

Splenomegaly

In Clinical Veterinary Advisor: Birds and Exotic Pets, 2013

Diagnosis 

Differential Diagnosis

•

Extramedullary hematopoiesis due to chronic systemic inflammatory processes (usually gastrointestinal disease)

•

Autoimmune hemolytic anemia

•

Splenic lymphoma

•

Other splenic neoplasms

•

Passive congestion: because no valves are present in the splenic venous system, pressure in the splenic vein reflects the pressure in the portal vein

•

Idiopathic hypersplenism

Initial Database

•

Clinicopathologic changes in splenomegaly are not specific, except for idiopathic hypersplenism, in which a reduction in the number of circulating thrombocytes and occasionally of leukocytes and erythrocytes is seen.

•

Persistent lymphocytosis, hypoalbuminemia, and mild elevations in globulins suggest chronic bowel inflammation but are not specific for this condition.

•

No significant meaning is attached to an ultrasound finding of splenomegaly. However, if multifocal hypoechoic areas are seen in the parenchyma, the suspicion of lymphosarcoma-associated splenomegaly is justified.

Advanced or Confirmatory Testing

•

Fine-needle aspirate of the spleen may be performed.

○

Several slides should be prepared from each specimen.

○

Cytologic preparations may be stained with Diff-Quik and evaluated in-house; definitive diagnosis should be performed by a pathologist.

○

Benign cases of splenomegaly arising from chronic systemic inflammation are heralded by a bloody aspirate containing peripheral blood elements with large numbers of immature red and white blood cells, and occasional megakaryocytes (located primarily within the feathered edge).

○

Most cases of splenic lymphoma will result in a cellular aspirate with a monomorphic population of lymphocytes.

○

Splenic aspirates from older animals with lymphoma may be falsely negative owing to the mature appearance of the neoplastic lymphocytes.

View chapterPurchase book

Cytology and Hematology of Small Mammals

James Walberg DVM, Diplomate ACVP, Andrew S. Loar DVM, Diplomate ACVIM, in Ferrets, Rabbits, and Rodents (Second Edition), 2004

Figure 38-18. Spleen extramedullary hematopoiesis: aspirate from the spleen of a ferret showing mostly myelocytes (Wright's stain, × 100). These cells vary in size even though they are at the same stage of maturation (crowding or thick smears can prevent cells from spreading out, making them difficult to identify). Also present are plasma cells, rubricytes, and occasional macrophages. Most enlarged ferret spleens show EMH. Lymphosarcoma is a differential diagnosis for splenomegaly but should result in a monotypic population of generally immature lymphoid cells. M, Myelocyte; P, plasma cells; R, rubricytes; MA, macrophage.

View chapterPurchase book

Neurologic Manifestations of Hematologic Disorders

J.D. Sussman, G.A.B. Davies-Jones, in Aminoff's Neurology and General Medicine (Fifth Edition), 2014

Thalassemia

Chronic anemias are associated with extramedullary hematopoiesis. There have been a few reports of spinal cord compression, most commonly in the middle to lower thoracic region. Surgical decompression plus radiotherapy is curative. Treatment with corticosteroids, blood transfusions, and local radiotherapy has also been successful. Transfusion to maintain the hemoglobin level above 12.5 g/dl may resolve minor compression of the spinal cord, with near-complete resolution of the extradural hematopoietic mass.14 Visual failure secondary to suprasellar extramedullary hematopoiesis in β-thalassemia has been described.

Severe forms of β-thalassemia, particularly following splenectomy, can be associated with hypercoagulability, with an increased risk of cerebral venous thrombosis.15 There is a reported association with moyamoya syndrome. Axonal sensorimotor neuropathy may also be a feature of β-thalassemia.

View chapterPurchase book

Hematopoietic System

Lila Ramaiah, ... Susan A. Elmore, in Fundamentals of Toxicologic Pathology (Third Edition), 2018

Secondary Hematopoietic Organs

Any physiological demand for blood cells may result in EMH in tissues other than the BM, such as the spleen, liver, and perirenal adipose tissue. Increased EMH may be seen as a reaction to injuries such as hematotoxic insult, anemia or infections elsewhere in the body. The spleen and liver are most often involved since they normally have foci of EMH to increase production when needed. However, other organs, such as the lymph nodes and kidneys, may also be involved via hematogenous spread and tissue infiltration by multipotential stem cells from the BM. In all organs that support EMH, hematopoietic cells are composed of varying numbers of myeloid, erythroid, or megakaryocytic cells, depending on the need and inciting cause. Cell lines sharing a common progenitor may also be affected (RBC and platelets). The erythroid component may predominate secondary to hemorrhage or RBC destruction, and the myeloid component may predominate secondary to inflammatory or immunoproliferative conditions. The diagnosis (erythroid, myeloid, or granulocytic hyperplasia) is based on the most prominent lineage involved. Some degree of EMH is normally present in the livers and spleens of rodents. Marked EMH with a predominant myeloid component (e.g., response to severe inflammation) shares some histological similarities with granulocytic leukemia. Increases in lymphocytes are best identified by immunohistochemistry since the morphologic appearance of lymphocytes is similar to that of HSCs.

In the spleen, EMH is characterized by varying numbers of MKs as well as clusters of myeloid and erythroid precursors throughout the red pulp. In severe cases the entire red pulp may be occupied by erythroid precursors. Extensive splenic EMH occurs secondary to anemia, blood loss, or hypoxia. In the spleen, EMH is more common in mice, young compared to old rodents, and in females compared to males. EMH as a response to injury may be seen as an increase in the number and/or size of foci of hematopoiesis or as a diffuse (nonneoplastic) hyperplasia of the red pulp.

EMH is abundant in the fetal and neonatal liver but small, scattered foci still exist in adults and are typically found within the sinusoids, around central veins, and around portal vessels. In response to injury, foci of EMH may be scattered within the hepatic sinusoids as well as around central veins and portal vessels, and may increase in size and/or number.

View chapterPurchase book

Neurological Manifestations of Hematological Disorders

G.A.B. Davies-Jones, Jon D. Sussman, in Neurology and General Medicine (Fourth Edition), 2008

Thalassemia

Chronic anemias such as thalassemia are associated with extramedullary hematopoiesis, usually in the liver, spleen, or lymph nodes. There have been a few reports of extramedullary hematopoiesis in thalassemia producing spinal cord compression and paraparesis, the hematopoietic tissue presumably arising from embryonal rests in the extradural areolar tissue of mesodermal origin. Most commonly the lesion is situated in the middle to lower thoracic region of the spinal canal, and surgical decompression plus radiotherapy is curative. Treatment with corticosteroids or repeated blood transfusions together with local radiotherapy to the tumor without surgical decompression has also been successful.34 Transfusion alone to maintain the hemoglobin level above 12.5 g/dl has been reported to relieve the signs of spinal cord compression, with near-complete resolution of the extradural hematopoietic mass.35 Visual failure secondary to suprasellar extramedullary hematopoiesis in β-thalassemia has been described.36 In one study, 20 percent of β-thalassemic patients were found to have clinical and electrophysiological findings of a predominantly motor sensorimotor neuropathy.37 Severe forms of β-thalassemia are associated with an increased risk of cerebral thrombosis as well as portal and deep vein thrombosis and pulmonary embolism.38

View chapterPurchase book

Nonneoplastic Mass Lesions of the Central Nervous System

S.B. Omay, ... J.M. Baehring, in Handbook of Neuro-Oncology Neuroimaging (Second Edition), 2016

Other Entities

Extramedullary Hematopoiesis

Mostly related to thalassemia and myelofibrosis, extramedullary hematopoiesis is rare in the cranial vault and the spinal canal and is usually an incidental finding, but on rare occasions it can cause mass effect and present with neurologic dysfunction. CT reveals heterogeneous density in the extra-axial space (Figure 5). MRI demonstrates extra-axial masses that are isointense on T1W and hypointense on T2W images with postcontrast enhancement.83,84



Sign in to download full-size image

Figure 5. Other entities. (A) Extramedullary hematopoiesis. A hyperintense mass lesion compresses the thoracic spinal cord posteriorly (arrowheads; T1W). (B) Amyloidoma. A subependymal heterogeneously enhancing mass lesion is seen adjacent to the body of the left lateral ventricle. Biopsy revealed amorphous material identified as β-amyloid by immunohistochemistry (T1W with gadolinium). (C) Radiation necrosis. A superficial inflammatory mass is seen in the right parietal lesion (arrowheads). There is extensive vasogenic edema in the underlying white matter. The patient had received radiosurgery to a scalp melanoma (T2W). (D) Polymorphic posttransplant lymphoproliferative disorder. A heterogeneously enhancing mass lesion is seen in the left frontal parasagittal region (T1W with gadolinium).

Amyloidoma

Like in amyloid angiopathy and senile plaques, amyloidoma is also formed by the deposition of amyloid protein and presents as single or multiple intracranial masses. Surgical intervention may be required for diagnosis but only rarely for mass effect. Imaging characteristics including enhancement patterns vary.85

Radiation Necrosis

Radiation necrosis (RN), also referred to as pesudoprogression, poses a considerable diagnostic challenge as it is difficult to differentiate from tumor recurrence. Clinically, both pathologies present with signs and symptoms of focal mass effect. Therapy involves corticosteroids, bevacizumab, or surgical intervention. Radiologically, a "soap bubble" appearance on post-gadolinium sequences has been described as characteristic for RN. Perfusion-weighted MRI may reveal increased cerebral blood volume in tumors and decreased cerebral blood volume in RN. [18F]Fluorodeoxyglucose PET, SPECT, and MR spectroscopy provide additional information but none of these studies has sufficient sensitivity or specificity.86

Polymorphic Posttransplant Lymphoproliferative Disorder

Occurring in organ transplant recipients on chronic immunosuppression, these lesions represent unchecked B-cell polyclonal or oligoclonal hyperplasia and may involve the CNS. Clinical symptoms are variable and depend on the location of the lesions. First-line therapy is reduction of immunosuppression. They may present as multiple hemispheric masses with variable MRI features and enhancement patterns, depending on their cellularity. Left untreated, degeneration into lymphoma occurs. This is reflected by MRI findings (restriction of water diffusion, homogeneous or rim enhancement.87

View chapterPurchase book

Integumentary System

Peter Greaves MBChB FRCPath, in Histopathology of Preclinical Toxicity Studies (Fourth Edition), 2012

Extramedullary hematopoiesis

Inflammation at injection sites needs to be distinguished from injection site extramedullary hematopoiesis. Cynomolgus monkeys given recombinant human interleukin 3, a hematopoietic growth factor, developed small firm nodules at the subcutaneous injection sites. These nodules contained immature cells of myeloid, erythroid and megakaryocytic series that extended from the subcutaneous tissues into the deep dermis and surrounding adnexa. Eosinophil precursors were the most common with cells of the megakaryocytic series being also prominent in the lesions. Mild fibrosis, neovascularization, edema, perivascular extravasation of blood cells, and at high doses collagen degeneration alongside degenerating eosinophils, were also described.70

View chapterPurchase book