Splenectomy--a therapeutic option in splenic marginal zone cell lymphoma

Splenectomy – a Therapeutic Option in Splenic Marginal Zone Cell Lymphoma

ANA-MARIA VLĂDĂREANU1*, MINODORA ONISÂI1, CRISTINA CIUFU1, H. BUMBEA1, DIANA CÎŞLEANU1, IRINA VOICAN1, ANCA NICOLESCU1, SÎNZIANA RADEŞI1, ANAMARIA VINTILESCU1, CRISTINA BĂLUŢĂ1,

CAMELIA DOBREA3, C. ŞAVLOVSCHI2, L. GRECU2, D. ŞERBAN2, G. SERAFIM2 1Department of Hematology, Emergency Universitary Hospital Bucharest, “Carol Davila” University of Medicine and Pharmacy,

Bucharest-UMFCD 2Department of Surgery, Emergency Universitary Hospital Bucharest, UMFCD

3Department of Immunohistochemistry Diagnosis, “Victor Babeş” National Institute, Bucharest, UMFCD, Romania

We present the case of a 65 years old male, admitted in the Hematology Department of the Universitary Emergency Hospital Bucharest, complaining of physical asthenia and weight loss; periodical medical examination has revealed splenomegaly and leucocytosis with lymphocytosis, persistent for the past 3 years. The clinical and paraclinical exam demonstrated splenomegaly (21cm in diameter on computer tomography scan), hepatomegaly and generalized lymphadenopathies. The laboratory tests confirmed leucocytosis with lymphocytosis – a clonal population of B lymphocytes CD20+ CD19+ CD23+/- CD79b+(low), CD43+ FMC7+ CD5+ CD38+ ZAP70 + cyclin D1 –. Lymph node and bone marrow biopsy together with flowcytometry established the diagnosis of Malignant non-Hodgkin Lymphoma – Atypical Splenic Marginal Zone B-cell lymphoma (aberrant expression of CD5) stage IVB, with leukemic picture, complicated with autoimmune hemolytic anemia with highly positive Coombs’ tests. We performed therapeutic splenectomy, which was difficult because of the dimensions of the organ. The short term evolution was complicated by acute complete thrombosis of the splenic vein, but the long term evolution (1 year follow-up) was favorable – remission of anemia, significant improvement of performance status, decrease of leucocytosis and reduction of the tumoral mass.

Key words: splenic marginal zone cell lymphoma, flowcytometry, splenectomy, huge splenectomy.

Splenic marginal zone cell lymphoma (SMZL) is a chronic lymphoproliferative disorder defined by the clonal proliferation of CD19+ CD5-B-lymphocytes from the marginal zone of the lymphoid follicle; it is an indolent lymphoma, with a slow growth rhythm, which affects especially men over 30 years-old. The typical presentation includes splenomegaly, frequent involvement of the bone marrow (95%); the examination of the peripheral blood generally reveals absolute and relative lymphocytosis, the lymphocytes presenting a typical phenotype. The patient may present infection with hepatitis C virus or autoimmune pathology – with therapeutic implications. The evolution is generally slow, but there may be progression to aggressive blastic forms. Although SMZL is chemo- and radio-sensitive, the patients in stage III-IV do not tend to acquire remission and are more likely to relapse; removal of the spleen remains a good therapeutic option. The medium survival period is around 7–9 years.

CASE REPORT

A 65 years old male presented to the Hematology Department of the Universitary Emergency Hospital Bucharest complaining of mild asthenia and weight loss – about 6 kg in the last year. The personal medical history of the patient included a benign prostate adenoma (confirmed of a biopsy) and a lumbar herniated disc. Also, the periodical medical tests revealed a medium leucocytosis – about 25 000 leucocytes/µL and enlarged spleen; both changes were progressive – the patient described leucocytosis in the past 3 years (under 20 000 leucocytes/µL), and the enlarged spleen had been seen on ultrasound examination – 140mm in diameter.

The clinical examination revealed a patient with stable vital signs, in a good clinical condition, without fever, with slight pallor, normal cardiovascular and respiratory examination; small non-painful superficial lymphadenopathies were noticed – cervical, axillary and inguinal – with

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increased consistency, freely movable, about 1cm in diameter; he also presented enlarged liver (lower limit at 5cm below the ribs) and spleen (inferior pole at the umbilicus).

LABORATORY TESTS

The blood tests showed increased WBC – 23000 leucocytes/µl, with 80% polymorphous lymphocytes (Fig. 1), medium regenerative normo-chromic normocytic anemia (Hb 8.2g/dL, Ht 27.0%, reticulocytes 5.6%), normal platelet count (152 000/µL). The Coombs tests were positive – direct Coombs test positive (3+), indirect Coombs test for IgG and IgG&C3 – intense positive (4+), thus establishing the autoimmune hemolysis as a possible cause for anemia and stating that the transfusion has to be fulfilled with special precautions – strictly in the same phenotype. The biochemistry tests were slightly modified: very slightly increased renal tests, normal serum iron, increased LDH (303U/L, compared to 250U/L as the highest normal value of the laboratory), normal coagulation tests, inflammatory syndrome (ESR 70mm/h, fibrinogen 728mg/dL); the electrophoresis of the serum proteins did not show monoclonal peak. The serological tests for HBV, HCV and HIV were negative.

DIAGNOSIS

Based on the clinical and laboratory examination, we raised the suspicion of a chronic lymphoproliferative syndrome (CLS) associated with autoimmune hemolytic anemia. In order to establish the type of CLS, we performed lymph node biopsy (axillary node) and bone marrow biopsy, both sent to “Victor Babeş” Research and Development Institute Bucharest, for morphology and immunohistochemistry, as well as flowcytometry of lymphocytes in peripheral blood at Universitary Emergency Hospital Bucharest – Hematology Department.

The lymph node biopsy showed a tumoral infiltrate with small cells, round or cleaved, with little cytoplasm; the cells were located around the germinal centers; there was a small number of large centroblastic cells (about 2%); very rare mitosis was observed. The tumoral cells were positive for CD20 (B-cell marker, offering the possibility of an effective therapeutic answer to rituximab, monoclonal

antibody for CD20), but it was also positive for CD5 (T-cell marker, also expressed in some small B-cell non-Hodgkin lymphomas, such as mantle cell lymphoma or lymphocytic lymphoma); bcl2 was positive in the tumoral cells; Ki67 proliferation index was low (5%) – conferring a favorable prognosis; cyclin D1 (marker for t (11;14)(q13;q32), which is positive in most of the mantle cell lymphomas), was negative; CD45RO (T cell marker) was negative in the tumoral cells.

The bone marrow biopsy showed an infiltrate with lymphocytes (thus pleading for stage IV lymphoma) – about 20–25% small lymphocytes; the immunohistochemical tests were positive for CD20 and CD5, and negative for cyclin D1 (Fig. 2).

Therefore, the histopathological examination and the immunohistochemical tests on the bone marrow biopsy and the lymph node biopsy were compatible with the diagnosis of a malignant non-Hodgkin Lymphoma with small B-cell CD20+ CD5+ bcl2+. The absence of proliferation centers, and hence of prolymphocytes and paraimmunoblasts, and the absence of CD23 excluded a Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukemia. The presence of the centroblasts in the tumoral infiltrate and the lack of cyclin D1 excluded a Mantle Cell Lymphoma. In this context, we established the diagnosis of malignant non-Hodgkin Lymphoma – Splenic Marginal Zone B-cell lymphoma with aberrant CD5 expression.

The immunophenotyping by flowcytometry demonstrated the presence of clonal atypical B lymphocytes (90% of total lymphocyte count), expressing the following profile: B-cell lineage markers [CD20+ CD19+ CD23+/– (30%) CD79b+ (low)], CD43+ [a marker for activated B cell], FMC7+ [B-lineage marker associated with non-Hodgkin lymphomas], CD5+, CD38+ (in 79% of the atypical B lymphocytes) and ZAP70+ – showing an increased risk of progression; cyclin D1 was negative (Fig. 3).

In order to complete the diagnosis, and because of the massive splenomegaly, we performed CT-scan of the thorax and the abdomen; it revealed important hepatomegaly with homogeneous structure (the lower limit of the right lobe was at 1cm from the iliac crest), important homogeneous splenomegaly (the spleen was 19/12/21cm) and retroperitoneal enlarged lymph nodes, with the diameter around 1–1.5cm.

The clinical examination and the investigations performed established the complete diagnosis – Malignant non-Hodgkin Lymphoma – Atypical

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Splenic Marginal Zone B-cell lymphoma (aberrant expression of CD5) stage IVB, with peripheral involvement (absolute and relative lymphocytosis with atypical clonal lymphocytes) – leukemic picture, complicated with autoimmune hemolytic anemia with highly positive Coombs’ tests.

LITERATURE DATA

Non-Hodgkin marginal zone lymphoma (MZL) is defined by the malignant proliferation of CD19+ CD5-B-lymphocytes from the marginal zone of the lymphatic follicle; there are three major groups defined by clinical and pathological criteria: MALT lymphoma, nodal marginal zone lymphoma and splenic marginal zone lymphoma [1].

The common aspects of the marginal lymphomas are presented below [1]:

Similarities in the histological features of the three subtypes.

The immunophenotype expresses a few common features: • The presence of B lineage markers:

CD20+, CD19+, CD79a+ • The lack of expression of CD5, CD23,

CD10 • The presence of surface immunoglobulins –

frequently IgM, variable IgD • The lack of expression of cyclin D1

(a marker for the protein resulting from the translocation t(11;14)(q13;q32))

Bcl-2 protein is expressed in most cases.

Splenic marginal zone lymphoma was first described in 1984, and it was initially known as B cell monocytoid lymphoma. It is presented as a provisional separate entity in the REAL Classification in 1994 and is later defined as a distinct entity in the WHO Classification in 2001 [2]. SMZL is an indolent lymphoma – with a slow tumoral growth rhythm; the neoplastic cells are small lymphocytes, with an intermediate stage of development between the lymphocytes in chronic lymphocytic leukemia and hairy cell leukemia [1][3][4].

The epidemiological studies establish that SMZL is a rare malignant disorder, representing under 1% of all lymphomas [5][6] and about 20% of the marginal lymphomas [1]; it appears rarely at persons under 30 years old (the medium age at diagnosis is 63 years old [7]) and it affects men

more often than women. It may be associated with hepatitis C viral infection, which leads to important therapeutic implications [1][8][9]. The medium survival period is 7–9 years from diagnosis.

The typical clinical presentation includes [1][2][4][10–15]: important splenomegaly, usually unaccompanied by superficial lymphadenopathies, but frequently with enlarged lymph nodes in the splenic hilum; medullar involvement is common (95% of the cases) and, therefore, the onset is generally in advanced stage (III–IV, with leukemic picture). Most of the patients present with B symptoms. Autoimmune disorders may be associated [1][5][9][16–18]: hemolytic anemia or other immune cytopenias, monoclonal peak, serum cryoglobulins; there were reported rare cases of antibodies against coagulation factors [1]. Autoimmune cytopenias such as anemia or thrombocytopenia may represent commencement elements of SMZL [1].

Considering the hematological features, the constant element is the leucocytosis with relative and absolute lymphocytosis (due to frequent medullar involvement) – leukemic pattern [16]. The malignant lymphocytes may have a characteristic feature – “villous lymphocytes” [16]: small/medium size, round or oval nucleus with nodular chromatin, sometimes a small nucleolus, medium basophilic cytoplasm, with the typical presence of short membrane projections that appear at one pole of the cell [1][4][10][15][16]. There are circumstances when the lymphocytosis is poly-morphous, predominantly with small/medium lymphocytes, but also with larger cells, with round/ovalar incised nucleus, condensed chromatin, moderately abundant, pale cytoplasm [16]; this variant generally has a more aggressive evolution [19].

The diagnosis of SMZL is based on morpho-logical and immunohistochemical examination on bone marrow and lymph node biopsies, associated with immunophenotyping of peripheral lymphocytes. The pattern of the bone marrow involvement is variable – there may be intrasinusoidal, interstitial, nodular, or even paratrabecular infiltrates; the intra-sinusoidal infiltrate is very characteristic for SMZL – it is rarely encountered in other B-cell indolent lymphomas [12][13][20–23]. The histological examination generally shows polymorphous infiltrate, with small/medium lymphocytes, but also with larger cells, with incised nucleus, condensed chromatin, moderately abundant cytoplasm, sometimes with short membrane projections like hairy cells [4][10] [16]. The mitoses are rare.

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The morphological and immunohistochemical examination may be also applied on the spleen after splenectomy, thus serving as a diagnostic tool [1][5][7]. The spleen is generally very large, with multiple visible nodules [13]. The infiltration affects mostly the white pulp of the spleen, both the mantle and the marginal zone (especially the marginal zone); the pattern is different from the hairy cell leukemia which affects generally the red pulp. The infiltration pattern is nodular, affecting mainly the marginal zone and the periarteriolar sheaths [3] and it may extend gradually to the red pulp. The lymph nodes in the splenic hilum are generally affected, in a diffuse pattern [3].

Immunophenotype: the phenotype of the malignant cell in SMZL is comparable to the one in nodal and extranodal marginal zone lymphoma and it includes [3][4][7][13][16][24][25]: monoclonal surface immunoglobulins (sIg+) and cytoplasmic immunoglobulins (cIg+) – the presence of IgD is almost specific; B lineage markers (CD19, CD20, CD22, CD79a); the lack of expression of CD5, CD10, CD23, CD43; CD45 is highly positive [10]. Based on the malignant cell phenotype, the differential diagnosis includes mainly hairy cell leukemia, which has the following phenotype [3][4][11][12][16][24] [25]: CD11c+++, CD25+, CD103+, FMC7+ with high expression of B-cell markers CD19, CD20, CD22, and marginal lymphoma, which is CD11c+/-, CD25-, CD103-, FMC7-.

The cytogenetic examination shows clonal rearrangements for light and heavy chains of the immunoglobulins, and usually somatic mutations of the genes encoding the variable regions of the heavy chains [5][26][27]. The most frequently encountered cytogenetic anomaly in SMZL was the loss of 7q31-32 allele [1][3][28–30], considered by some authors relatively specific for SMZL [1][7][31], and associated by others with an unfavorable prognosis [32].

The difficulties of diagnosis for SMZL may include:

Atypical morphologic features, suggesting SLL/MCL

Atypical phenotype – the presence of CD5 Atypical cytogenetics: t (11; 14) or the presence

of CCND1 Sometimes there can be difficulties of

differential diagnosis with other chronic lymphopro-liferations such as hairy cell leukemia, atypical chronic lymphocytic leukemia, prolymphocytic leukemia, mantle cell lymphoma [13][16][25].

The evolution of SMZL may be towards transformation to a more aggressive histologic subtype (10 to 15% of SMZL may transform in Large B-Cell Lymphoma) [1][33] or towards spontaneous regression.

There are several treatment options for SMZL. The best time for starting the treatment has to be established very carefully; the therapy is generally started at 2–3 years from the diagnosis, and the indications are represented by [1]: symptomatic disease (due to progressive or important cytopenia, or symptomatic splenomegaly) or histologic trans-formation. The absence of treatment does not influence the course of the disease and some patients may have a stable disease for up to ten years [1][20][34]. Although generally SMZL is chemo- and radio-sensitive, the patients in stage III/IV do not tend to obtain remission or tend to relapse.

The treatment strategies may include: • “Watch and wait” – treatment is not applied

when [1][5][13][15]: patients are asymptomatic at diagnosis, patients are elderly, or patients have a low performance status.

• Therapeutic splenectomy • Splenectomy followed by monochemotherapy • Splenectomy followed by rituximab (R)

(monoclonal antibody for CD20 – it has a particular efficiency in SMZL because the malignant cells have a high expression of CD20)

• Splenectomy followed by R-CHOP (Rituximab plus Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)

• Monochemotherapy (with Chlorambucil or Fludarabine)

• Rituximab as monotherapy • R-CHOP • Splenic radiotherapy.

The splenectomy is presented by the current data in the literature as the first line of treatment [1][5][13][15][35][36] and it may be performed in over 70% of the cases. The indications for the surgery are: symptomatic splenomegaly or immune cytopenias [13]; the benefits are multiple [1][5][15] [34]: remission of cytopenia, improvement of performance status, decrease of symptomatology; there are several studies that describe a reduction of the bone marrow infiltrate after splenectomy and this may persist for several years, even if lympho-cytosis progresses [1][13][15]. The retrospective studies show that the patients who had undergone splenectomy had superior global survival compared to the ones who received chemotherapy without

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splenectomy, but we have to consider the fact that the patients who receive chemotherapy without splenectomy are generally in a worse clinical state than the ones who are operated [13][34][36].

Chemotherapy may be applied after splenectomy or as a single treatment option; it represents the only therapeutic option in patients with advanced disease or with a poor clinical status, making the surgery impossible [13]. There are several proposed regimens, both as monochemo-therapy (alkylating agents [1][20][34] – Chlorambucil, Cyclophosphamide – , purine analogues, Rituximab [37], Fludarabine [1][38–40]) and as polychemo-therapy (usually as CHOP, with or without Rituximab – R-CHOP-chemo-immunotherapy). The polychemo-therapy regimens are indicated in cases with a poor prognosis; Rituximab offers a particular advantage in cases refractory to standard chemotherapy regimens or in elderly patients who cannot tolerate chemo-therapy [1][41].

Patients who have coexisting hepatitis C virus infection benefit from adding interferon, with or without ribavirin [1][42].

Splenic radiotherapy may represent a helpful option in patients who cannot tolerate either splenectomy nor chemotherapy; the benefits are correction of cytopenia, reduction of symptoms due to the tumoral spleen or even a decrease of the number of circulating villous lymphocytes [13][43].

The prognosis factors used in SMZL are those described in the International Prognostic Index; the following parameters are considered particularly negative: the level of β2-microglobulin, the degree of leucocytosis/lymphocytosis, the presence of monoclonal component or of other autoimmune events, the serum LDH, the serum albumin, the performance status [1][44].

Some authors consider that chemotherapy as the first line of treatment has a negative influence on the survival period [1][7][15][34].

DISCUSSION

Considering the data presented, the following entities will be considered for the differential diagnosis in the case presented above: • First, other chronic lymphoproliferative disorders

must be excluded, based on the lymph node and bone marrow biopsy and on the immuno-phenotype of the peripheral lymphocytes, which sustain the diagnosis of splenic marginal zone

lymphoma in spite of the presence of CD5 (usually negative in this histologic type) – the discussion was presented at the diagnosis section.

• The differential diagnosis of splenomegaly includes: infectious disease, hereditary hemolytic anemias, congestion, infiltrative disorders, malignant diseases (chronic myeloproliferative diseases, hairy cell leukemia, other lymphopro-liferative diseases) – all these disorders were excluded based on the tests presented above.

• The differential diagnosis of anemia includes other types, such as: iron deficiency anemia or anemia secondary to chronic disease (excluded based on the normal serum iron and the characteristics of the red cells – normochromic normocytic anemia), different types of congenital anemias – minor thalassemia, congenital hemolytic syndromes – which may be associated in this case, and therefore, supplementary tests (hemo-globin electrophoresis, autohemolysis and osmotic resistance tests, etc.) will be performed after the partial correction of the anemia.

The prognosis in this particular case is based on general prognostic factors. The negative prognostic factors are: the gender (male), the age (over 60 years old), the advanced stage of disease (stage IV due to the medullar involvement), the presence of B symptoms, the atypical phenotype with CD5+ (which is associated by the literature data with a more aggressive evolution [25]). The favorable prognostic factors include: the histologic pattern (SMZL is an indolent lymphoma, with a slow mitotic rate), LDH quasi-normal (slightly increased, probably due to the hemolysis), very good performance status.

Treatment: the therapeutic plans applied in this case were as follows: • Hygienic and diet measures, especially avoiding

trauma in the area of the spleen • The treatment for the renal dysfunction:

hydration, allopurinol (for the correction of the slightly increased serum uric acid) – followed by the normalization of the renal parameters

• The treatment for hemolytic anemia – oral Prednisone with gastric protection – with a favorable response: the hemoglobin increased to 10–11g/dL.

• The pathogenic treatment of the lymphoma – according to the present international recommenda-tions, the first line of treatment in SMZL is splenectomy [1][5][13][15][35][36], which is performed also in this case:

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Before the surgery, the patient received the vaccines for Streptococcus pneumoniae and Haemophilus influenzae.

The operation began with a midline incision for complete exposure of the peritoneal cavity; a giant cyanotic spleen (18/16/7.5cm) was discovered, weighing 1475grams (according to the pathology exam performed after surgery) – Fig. 4; it occupied nearly all the left abdomen.

The removal of the spleen was extremely difficult because of parietal and visceral adherences.

The spleen was sent for histopathological examination – the splenectomy also served as a diagnostic tool, because the histologic and the immunohistochemical (Fig. 5a and 5b) examinations confirmed the diagnosis of Splenic Marginal Zone B-cell lymphoma CD20+ with aberrant expression of CD5.

• Protective measures after surgery – broad spectrum antibiotic (Imipenem 2g/day; the patient does not develop any infectious complications), selected red blood cell transfusion (due to the hemolytic component), pain medication, prevention of post-surgery thrombosis (prophylactic loss of low molecular weight heparin).

Evolution: The immediate post-surgery evolution was favorable – hemoglobin was constantly above 10g/dL, the platelet count increased slowly, up to 900 000/µL (Fig. 6) (medication to inhibit platelet aggregation was associated when platelet count exceeded 400 000/µL). The patient did not present fever or any significant symptoms.

At 10 days after the surgery, the patient developed edema in the lower part of the body and started to eliminate transparent fluid at the drain position in the splenic bed (the drain had been suppressed 5 days before); the quantity of the liquid increased progressively, but the abdomen remained painless. The emergency CT scan with iv contrast showed an acute thrombus in the splenic vein which occupied all its diameter; anticoagulant treatment was initiated using low molecular weight heparin – Clexane 0.1mL/10kgc sc every 12hrs, followed by significant and progressive clinical improvement, up to the complete remission of the symptoms. Oral anticoagulant therapy was then

introduced, using Sintrom, under the control of INR. It is important to mention that the patient permanently received Aspenter and that the correct dose of Sintrom was very difficult to establish, because his INR was constantly under 1.5 in spite of a high dose of Sintrom. The oral anticoagulant combined with antiaggregant was continued for 12 months, without any other thrombotic or hemorrhagic complications.

The long term evolution (currently the patient is at 1 year after surgery) is favorable: the anemia is completely corrected – the hemoglobin is constantly over 14g/dL; the degree of leucocytosis is reduced, with a medium of 15 000 leucocytes/µL; there is still a constant absolute and relative lymphocytosis, but both values are lower than the ones before the surgery (respectively 50–60% lymphocytes, corresponding to less than 10 000 lymphocytes/µL); the platelet count stabilized at the higher limit of the normal range, around 400 000/µL, without any thrombotic or hemorrhagic incidents as described before; the inflammatory syndrome is partially corrected (ESR is 20mm/h and fibrinogen is 500mg/dL); the CT reevaluation shows slight hepatomegaly and small retro-peritoneal lympha-denopathies (under 1.2–1.4cm). The patient maintains a very good clinical status, without asthenia, without any B symptoms (he even had a significant weight gain after the surgery).

CONCLUSIONS

The presentation reports the value of a surgical intervention in a hematological malignancy, which, in opposition to solid tumors, rarely benefits from surgical therapy. In the case of SMZL, and particularly in this case, the indication for surgical treatment – splenectomy – is clearly recommended and has major consequences (even if it did not act as a radical treatment): it significantly reduced the tumoral mass, it induced the correction of the hemolytic anemia (splenectomy serves as an efficient treatment for this pathology), it leads to the reduction of the leucocytosis and of lympho-cytosis, it reduced the major risk of accidents by the rupture of the tumoral spleen, and it was followed by a very important improvement in the patient’s performance status.

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We selected the case above for presentation due to some particular features: 1) the good response to splenectomy; 2) the atypical phenotype of the lymphocytes with the presence of CD5, which posed difficulties of hematological diagnosis;

3) the atypical phenotype was not yet associated with an aggressive evolution – on 1 year follow-up; 4) the development of total thrombosis of the splenic vein after surgery which was completely painless.

Prezentăm cazul unui pacient de 65 de ani, care este internat în Clinica de Hematologie, Spitalul Universitar de Urgenţă Bucureşti pentru astenie fizică şi scădere ponderală; testele periodice medicale anterioare relevă splenomegalie şi leucocitoză cu limfocitoză, persistente în ultimii 3 ani. Examenul clinic şi imagistic demonstrează splenomegalia (21cm în diametru la examenul computer-tomograf), hepatomegalie şi limfadenopatii generalizate. Testele de laborator confirmă leucocitoza cu limfocitoza – populaţie de limfocite B atipică, clonală, cu fenotip CD20+ CD19+ CD23+/– CD79b+(low), CD43+ FMC7+ CD5+ CD38+ ZAP70+ cyclin D1 –. Biopsia ganglionară şi cea osteomedulară, completate cu flowcitometria, stabilesc diagnosticul de Limfom Malign non-Hodgkin Marginal Splenic atipic (cu expresie aberantă de CD5), stadiul IVB, cu tablou leucemic, complicat cu anemie hemolitică autoimună cu teste Coombs intens pozitive. Se efectuează splenectomie terapeutică, intervenţie dificilă datorită dimensiunilor organului. Evoluţia pe termen scurt este complicată cu tromboza acută de venă splenică, dar pe termen lung (la 1 an de urmărire), evoluţia este favorabilă – corectarea anemiei, îmbunătăţirea importantă a statusului de performanţă, scăderea leucocitozei şi reducerea masei tumorale.

Corresponding author: Ana-Maria Vlădăreanu, Professor

Department of Hematology, Emergency Universitary Hospital Bucharest, Romania, 169 Splaiul Independenţei, 050098, Bucharest, Romania Phone no: +4021 318 05 22, Fax: +4021 318 05 70 E-mail: [email protected]

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