Paraspinal extramedullary hematopoiesis in hereditary spherocytosis with a concurrent follicular lymphoma: case report and review of the literature

HS is a group of chronic inherited anemias in which the characteristic feature is the presence of spherocytes, defined as small round erythrocytes with a higher concentration of hemoglobin. The cause is a deficiency of proteins associated with the erythroid membrane that play a critical role in the capacity of cell deformability. The proteins related to this disease are alpha-spectrin, beta-spectrin, ankyrin 1, protein 4.2 and band 3. This deficiency results in the instability of the cellular membrane with subsequent formation of membrane vesicles and secondary reduction of the surface-to-volume ratio. The spherocytes are retained in the red pulp of the spleen and part of these cells are destroyed, while the rest survive and return to the peripheral blood with even more spherocytic features. The majority of patients present signs of hemolytic anemia, such as jaundice, pallor and variable splenomegaly. Laboratory tests show mild anemia, presence of spherocytes and reticulocytes, higher mean corpuscular hemoglobin concentration and increase of the osmotic fragility of the erythrocytes. The most frequent complication of this form of chronic hemolytic anemia is the development of bilirubin gallstones. Less frequently the patient could present with skin lesions, myopathy, cardiovascular disease, neuromuscular and SNC diseases [1, 2]. HS has been rarely described in association with neoplasms, including one diffuse large B cell lymphoma [5], two acute lymphoblastic leukemias [6, 7], one splenic B-cell lymphoma [8], one schwannoma [9] and one ganglioneuroma [10]. The case of HS and ganglioneuroma presented initially as a mass in the adrenal gland and a differential diagnosis with EMH was considered.

EMH is defined by the presence of hematopoietic tissue outside the bone marrow. This phenomenon could be normal or pathologic. Pathologic EMH is usually associated with hematologic disorders affecting the bone marrow, peripheral blood and less frequently with vascular diseases or can even appear without any other underlying disorder. Spleen and liver are typical sites for EMH [3, 4]. In the largest case series, Koch et al. found 510 biopsies reporting EMH. In 483 patients, this lesion occurred in liver and spleen. In the rest of the patients, it appeared in other sites, such as paraspinal region, lymph nodes, retroperitoneum, lung, pleura, genitourinary region and skin. The underlying associated diseases were chronic myeloproliferative neoplasms, such as primary myelofibrosis, post polycythaemic myelofibrosis or chronic myeloid leukemia, chronic lymphocytic leukemia, vascular malformations and inherited or chronic hemolytic anemias [3].

Development of extramedullary hematopoiesis in the clinical context of HS has been well documented. Paraspinal, thoracic and mediastinal regions are the most frequent sites of involvement [11‐20]. Independent of the underlying disease, in some patients it may present as a pseudotumoral mass, mimicking a solid tumor, and therefore a differential diagnosis with other neoplasms must be taken into account [21‐23]. A concurrent lymphoproliferative disorder and EMH in the same lesion has been described in only four case reports [24‐27]. In one case [24] there was no history of a previous lymphoid neoplasm, and the development of the EMH probably was in the context of a hemorragic infarct secondary to a intravascular diffuse large B-cell lymphoma in the blood vessels of the uvea. In the other three cases the lymphoproliferative disorder was previously known and the finding of EMH and a concurrent lymphoma was made afterwords. The findings of these reports are summarized in Table 1. This infrequent association between EMH and lymphoma may underestimate the presence of an underlying atypical lymphoid infiltrate, especially when extramedullary hematopoiesis presents as a pseudotumoral lesion in patients with chronic anemia or myeloproliferative disorders.

In the current case, the presence of a follicular lymphoma with a predominantly diffuse pattern demonstrated in the EMH mass, in peripheral blood and in the bone marrow, is quite remarkable. Our patient did not have lymphadenopathies or other evident lesions suspicious of FL by physical examination or imaging studies. This situation is reminiscent of the recently described primary follicular lymphoma of the bone marrow in which the tumor cells were observed in this location without evidence of lymphadenopathies or organomegalies, although three of the four patients also had circulating tumor cells in peripheral blood as was observed in our patient [28]. These four cases had a diffuse, nodular or interstitial pattern of bone marrow infiltration, always with involvement of the paratrabecular area. The restricted expansion of lymphoma cells in the bone marrow in these cases suggests that the tumor cells may have a particular tropism for the hematopoietic niche [28]. The close association between the lymphoma cells and the extramedullary hematopoiesis in our case may suggest a similar phenomenon. Three of the previously described patients were asymptomatic, while the fourth one had history of bone pain without B symptoms. One patient died three months after the diagnosis without treatment response and the rest were alive at least one year after, according to their clinical follow-up. The lack of symptoms related to the lymphoma in our patient is also similar to those patients with primary FL of the bone marrow [28].