March 2016

A 63 year old male with easy fatigability

Ali Aldawood, M.D., Olukemi Esan, M.D.

Overview

A 63 year old male presents with worsening abdominal pain. He had a previous history of low-grade myelodysplastic syndrome with macrocytic anemia and thrombocytopenia. A CT-scan of the abdomen shows significant diffuse hepato-splenomegaly. There is no focal splenic or hepatic mass.

Gross and Microscopic Descriptions

Gross

An enlarged 1170 g, 23 x 16 x 7.5 cm spleen was received. The capsular surface was pink-grey and smooth. Sectioning revealed diffusely congested splenic parenchyma with dark red pulp congestion. No focal lesions were identified.

Microscopic

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Figure 1: H&E 200X magnification. Splenic parenchyma with red pulp expansion.
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Figure 2: H&E 400X magnification. Many megakaryocytes (arrow) present.
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Figure3: IHC 400X magnification. CD34 demonstrates virtually no myeloblasts. Vascular endothelial lining cells are highlighted.
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Figure 4: IHC 400X magnification. CD71 highlights clusters of erythroid precursors .
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Figure 5: IHC 400X magnification. Myeloperoxidase highlights some myeloid cells.
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Figure 6: IHC 400X magnification. FVIII stains megakaryocytes (arrows) as well as vascular endothelial lining cells (arrow heads).
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Figure 7: IHC 200X magnification. CD3 stains appropriately located T-lymphocytes.
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Figure 8: IHC 200X magnification. CD20 stains few B-lymphocytes .

Diagnosis

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Answer

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Discussion

The spleen is markedly enlarged, weighing 1170 grams. H&E sections reveal splenic parenchyma with marked red pulp expansion and relatively decreased white pulp (Figure 1). Many megakaryocytes are identified within the red pulp (Figure 2). Immunohistochemical stains showed very rare CD34 positive blasts (Figure 3) thus excluding a myeloid sarcoma. CD71 and myeloperoxidase stain erythroid precursors and granulocytic elements respectively (Figures 4 and 5). Factor VIII highlights the megakaryocytes (Figure 6). CD3 and CD20 stain appropriately located T- and B-cells, respectively, with a predominance of the former (Figures 7 and 8). No atypical lymphoid aggregates are identified. There are no features of splenic involvement by lymphoma. The overall findings are consistent with splenic extramedullary hematopoiesis in the setting of a patient with myelodysplasia.

Extramedullary hematopoiesis is the proliferation of immature blood elements in organs outside the bone marrow [1]. It usually involves two or more of the erythroid, megakaryocytic or granulocytic lineages. Prior to onset of hematopoietic process in bone marrow cavities during fetal life, the hepatosplenic tissues and the yolk sac are the main sites of hematopoiesis. In infants, extramedullary hematopoiesis is considered physiologic but it regresses as the infant grows. In adults, it is considered a pathological state under normal situations [2]. Sites of fetal hematopoiesis are most commonly involved i.e. spleen and liver. However, it has been reported in numerous other sites including lymph nodes, adrenal, kidney, retroperitoneal fat, pancreas, digestive tract, brain, spinal cord, etc [1].

Different mechanisms have been suggested to explain the etiology of extramedullary hematopoiesis. The first is the “filtration theory” whereby immature hematopoietic cells passing into the blood stream are trapped at non-medullary locations and proliferate [2].This theory is strongly considered for spleen involvement with extramedullary hematopoiesis [3]. A second theory is as a compensatory mechanism by the body for any cause of bone marrow failure resulting in compromise or damage to the marrow space limiting medullary hematopoiesis [4]. This leads to stimulation of dormant hematopoietic precursors at sites of fetal hematopoiesis. In this situation, extramedullary hematopoiesis usually occurs in the liver and spleen which are the sites of previous fetal hematopoiesis [1]. The third theory suggests stimulation of local adult stem cells at extramedullary sites by chemokines, cytokines or growth factors with subsequent differentiation into hematopoietic precursors. This is supported by the fact that recent therapeutic introduction of growth factors e.g. granulocyte monocyte colony-stimulating factors (GM-CSF), may be associated with extramedullary hematopoiesis in spleen and liver. In most cases, more than one of these factors are involved in the etiology of extramedullary hematopoiesis.

Histologically, the distribution of extramedullary hematopoiesis varies by the organ involved. Splenic extramedullary hematopoiesis is predominantly characterized by red pulp expansion with white pulp atrophy. Histologically distinct architectural patterns are nodular, diffuse and mixed; with trilineage, granulocytic and erythroid predominant cell lines, respectively [5]. Immunohistochemically, CD61, CD42b, or factor VIII are performed to analyze megakaryocytes [2]; CD71 and E-cadherin are used to highlight erythroid precursors [6]; while myeloperoxidase (MPO) , CD68, or lysozyme identify granulocytic or monocytic precursors [7].

Therapy of extramedullary hematopoiesis depends on the underlying disease. Splenectomy can be carried out in patients with massive splenomegaly that is causing symptoms [1]. The patient in this case most likely developed extramedullary hematopoiesis to compensate for compromised medullary hematopoiesis due to ongoing marrow myelodysplasia. The splenomegaly further complicated his peripheral blood cytopenias due to splenic sequestration. In addition, the splenomegaly was leading to abdominal pain. Splenectomy was performed and the peripheral blood cytopenias improved.

References

  1. Miranda RN, Khoury JD, Medeiros LJ. Extramedullary hematopoiesis in lymph nodes. In: Atlas of lymph node pathology. Springer; 2013:481-484.
  2. O'Malley DP. Benign extramedullary myeloid proliferations. Modern Pathology. 2007;20(4):405-415.
  3. Wolf BC, Neiman RS. Hypothesis: Splenic filtration and the pathogenesis of extramedullary hematopoiesis in agnogenic myeloid metaplasia. Hematol Pathol. 1987;1(1):77-80.
  4. Conor O'keane J, Wolf BC, Neiman RS. The pathogenesis of splenic extramedullary hematopoiesis in metastatic carcinoma. Cancer. 1989;63(8):1539-1543.
  5. Prakash S, Hoffman R, Barouk S, Wang YL, Knowles DM, Orazi A. Splenic extramedullary hematopoietic proliferation in philadelphia chromosome-negative myeloproliferative neoplasms: Heterogeneous morphology and cytological composition. Modern Pathology. 2012;25(6):815-827.
  6. Rollins-Raval MA, Fuhrer K, Marafioti T, Roth CG. ALDH, CA I, and CD2AP: Novel, diagnostically useful immunohistochemical markers to identify erythroid precursors in bone marrow biopsy specimens. Am J Clin Pathol. 2012;137(1):30-38. doi: 10.1309/AJCP0QFQ0FTSZCPW [doi].
  7. Miranda RN, Omurtag K, Castellani WJ, De Las Casas, Luis E. Myelopoiesis in the liver of stillborns with evidence of intrauterine infection. Arch Pathol Lab Med. 2006;130(12):1786.