A complex cause of lymphadenopathies and fever in a patient with a history of thyroid β-cell lymphoma: kikuchi disease and second lymphoma

M. Valet¹, J.L. Solorzano², C. Panizo Santos³

The differential diagnosis of lymphadenopathies associated with fever is wide. In a patient with a history of lymphoma, the first concern is to rule out a relapse, especially if adenopathies and fever are associated with weight loss or night sweats. On the other hand, it is important to keep attention over various other pathological conditions associated with these symptoms. If fever and lymphadenopathy persist despite effective treatment, it is important to follow the diagnosis procedure, performing an open biopsy of an involved lymph node, which is the gold standard for the differential diagnosis of persistent lymphadenopathies. In patients with a history of lymphoma, it can be difficult to distinguish whether a second lymphoma found after years of remission is a relapse or a new disease. Differencing these situations is important since it can affect prognosis and management. This work will focus both on the diagnosis and treatment difficulties in front of a patient presenting a complex cause of fever and lymphadenopathies.

A 66 year-old woman with a history of diffuse large B-cell lymphoma came earlier than planned to the follow-up consult because a 2-month course of cough, fever, fatigue and an abnormal cervical swelling which appeared 5 weeks before presentation at the hospital.

Eleven years before (May 2003), the patient had been diagnosed with a thyroidal diffuse large B-cell lymphoma, stage I-E (International Prognostic Index, IPI 0), treated with four cycles of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone), followed by thyroidectomy and involve field radiotherapy (30 Gy). Complete remission was achieved and maintained for ten years. She had been in her usual health until two months before admission, when she experienced “influenza-like” symptoms: irritative cough, daily fever up to 38°C and fatigue. Five weeks prior to presentation, she noted an abnormal right cervical swelling. She was taking L-thyroxin for her postoperative hypothyroidism and Irbesartan 150mg, due to essential hypertension. The patient referred being allergic to salicylates and latex. Physical examination upon admission revealed cutaneo-mucous pallor and tenderless cervical and axillary lymphadenopathies (3cm maximum diameter), without hepatosplenomegaly. No fever was documented, the ECOG score was 1 and the Karnofsky score was 80. The remainder of the examination was normal.

Blood and urine analysis revealed normocytic normochromic anaemia as the sole abnormality (complete laboratory findings showed in table 1, first admission 20/02/2014). A CT-scan revealed cervical (major: 2 cm), mediastinal, axillary bilateral (major: 2,1 cm), periaortic (major: 1,6 cm), iliac axes (major: 2,8 cm) and inguinal (major: 1,3 cm) adenopathies (figure 1). As a disseminated diffuse large B-cell lymphoma relapse was highly suspected, a biopsy-exeresis of a cervical lymph node was performed. Pathological examination of the specimen showed a large central necrotic strip with nuclear dust and thickening of the capsule with fibrosis (figure 2). This observation was compatible with a Kikuchi disease (histiocytic necrotizing lymphadenitis) which is a rare benign condition of unknown cause characterised by cervical lymphadenopathies and fever, which generally resolves spontaneously within one to four months. Laboratory analysis showed important anaemia and thrombocytopenia; ANA, anti-DNA antibodies, SS-A, SS-B, Sm, RNP/Sm, Scl 70 and Jo-1 dosings were all negatives, ruling out lupus erythematosus. A Mycobacterium Tuberculosis PCR was negative. The patient was reassured and discharged home with symptomatic treatment (Nonsteroidal antiinflammatory drugs).

During the following weeks, she worsened with persistent daily fever until 38,8°C, night sweating, intense fatigue, growing tender adenopathies, abdominal distension with nausea and hyporexia. She was given Prednisolone (1mg/ kg/day), which partially ameliorated her symptoms.

Two and a half months after the initial presentation, she returned to the hospital for revision. She presented a pleuropericardial effusion, diffuse pain, fatigue and lower limbs oedema. Butterfly wings erythema, cheilitis and oral aphthas were also observed. A CT-scan showed progression of the adenopathies and a moderate-size splenomegaly (15,4cm) (Figure 3). A cardiac ultrasound was performed, showing mild pericardial effusion and ascitis.

An axillary lymph-node biopsy was performed showing a mixed celullarity lymphoma compatible image (Figure 4). Two types of cells were observed: 45% of B-lymphocytes, mostly large ones, compatible with diffuse large B-cell lymphoma, the same type as the previous ones the patient had had eleven years earlier and 29% of small cells, CD4+, compatible with angioimmunoblastic T-cell lymphoma. The analysis by a second pathologist confirmed these data but could not demonstrate a T-cell monoclonality. Then, a PETscan was performed, showing upper- and under-diaphragmatic tumoral lymph nodes involvement. Approximately five months subsequent to the initial presentation, the diagnosis of a mixed cellularity lymphoma, Ann-Arbor stage IV-B (IPI 4), associated with Kikuchi disease, was made. One week after the diagnosis, a chemotherapeutic and immunotherapeutic treatment was started.

A 66-years-old woman with a history of thyroid large B-cell lymphoma treated, eleven years before, by chemotherapy, thyroidectomy and radiotherapy was admitted to the haematology department because of a 2 month-course of fever, irritative cough, fatigue and cervical and axillary adenopathies. A lymph node biopsy was performed, concluding a Kikuchi disease. The weeks after, fever and adenopathies worsened and a symptomatic treatment with prednisolone was set up. The symptoms did not resolve with this treatment and a complete diagnosis procedure including serologies, urinalysis, CT-scan, PET-scan, echocardiography and a new lymph node biopsy was performed. It concludes a new, mixed cellularity (T and B cells), stage IV-B lymphoma. The decision was made to treat her with four cycles of R-megaCHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), given every 3 weeks, followed by autologuous hematopoietic cell transplantation.

This case has two major interests. First, it illustrates an atypical case of a rare disease, Kikuchi disease (also called Kikuchi-Fujimoto or Kikuchi histiocytic necrotizing lymphadenitis) and it constitutes an interesting case of a second, biclonal, lymphoma in a patient which was in a long remission period, and its subsequent differential diagnosis and treatment options. These two situations may be linked.

As Kikuchi disease was the first diagnosis made for this patient for her current problem, it would be the first subject treated here. Kikuchi disease is a rare, self-limited disease of unknown etiology1, which typical clinical manifestations are lymphadenomegaly (necessary condition for the diagnosis, 100%, usually cervical and localized), fever (35% of the cases), erythematous rashes (10%), fatigue (7%) and joint pain (7%). Usually, laboratory investigations are unremarkable, except for elevated erythrocyte sedimentation rate, mild neutropenia, anemia and lymphocytosis2. It generally occurs in young women (70% are less than 30 yearold). A CT scan is often performed and may be helpful to suspect this disease and to make the differential diagnosis, which includes systemic lupus erythematosus (which is associated in 13% of the reported cases, at the time of diagnosis), lymphomas (associated in 3% of the cases), infectious mononucleosis, cat-scratch disease and toxoplasmosis. These observations suggest that patients with Kikuchi disease should be explored and followed to rule out SLE and lymphomas3. Lymph node biopsy is necessary to exclude more serious conditions and generally sufficient to confirm the diagnosis. Sometimes, this condition is difficult to differentiate from lymphoma, even with a biopsy. In 2000, Yoshino et al. described the first two cases of Kikuchi disease following large B-cell lymphoma in two women (27 and 30 years-old), in the course of their remission, suggesting that there is an association between these conditions, as there could be for our patient4. As it is a spontaneously resolving disease, there is no specific etiologic treatment for Kikuchi disease. Acetaminophen and NSAIDs can be used to reduce the fever and the pain, if present. Jang et al. reported three cases of patients with severe persisting or recurrent symptoms successfully treated with prednisone5. Two case reports illustrate a dramatically good response to hydroxychloroquine, one for recurrent disease and the other in a 9 year-old girl6, 7. In our case, the initial symptoms were first treated with NSAIDs, based on a mechanism- based reasoning. Given the persistent, nay worsening, fever, the decision to begin prednisone was made, given the successful cases met in the literature. The patient responded partially to this medication: the fever disappeared. And this fever recurred after the first cycle of chemotherapeutic treatment and was again successfully treated with prednisone. Thus, this case constitutes a new illustration of a severe, persisting, atypical (advanced age, generalized adenopathies) Kikuchi disease, responding to large doses of corticosteroids.

The second concern of this case is the lymphoma. Various issues seem to be interesting regarding this lymphoma in this patient. First, it is her second lymphoma; the subsequent question to ask is: is this a relapse of her elevenyear- old diffuse large B-cell lymphoma or a new one, with a different clonal origin (various studies have shown that long term survivors of lymphomas have an increased risk of developing a second malignancy)? The biopsy is necessary to make the diagnosis, but comparison of histological characteristics alone could frequently be insufficient to distinguish new lymphomas from recurrences, as it was in this case. An interesting technique to differentiate between a recurrence and a new mutation in B-lymphomas is the analysis of VDJ rearrangement of B-cell IgH genes8. In our case, this analysis was made on the B-cell component of this second lymphoma and was positive, but was not performed eleven years ago, so the comparison is impossible and the uncertainty persists...Thus, in this case, distinguishing both conditions is important to determine the subsequent treatment. Actually, non-relapsing advanced stage (Ann Arbor III-IV) diffuse large B cell lymphoma are usually treated with high-dose systemic chemotherapy and the recombinant anti CD-20 antibody (Rituximab), although a study showed that early autologuous stem cell transplantation improved progression-free survival among patients with high-risk disease who responded well to induction therapy as well9, while relapsing cases are preferentially treated by transplantation, if the patient is eligible.

Another diagnosis challenge is how to classify histologically this lymphoma. Is it really a biclonal, diffuse large B cell and angioimmunoblastic T, lymphoma or a special entity called T-cell rich/histiocyte-rich large B cell lymphoma, described for the first time in 2002 by Achten et al.10 and recognized by the World Health Organisation as a separate clinicopathological entity since 200811. Table 2 sums the principal arguments toward (+) and against (-) one and the other pathological conditions.

There is no immunohistochemical or genetic proof of T-cell monoclonality in the first analysis of the biopsy, neither than in the second one. On this basis, the diagnosis of T-cell rich B cell lymphoma is more likely, but the certain diagnosis cannot be made. Shimizu et al. reported, in 1989, a case of a T-cell lymphoma following a B-cell lymphoma after years of remission that could be explained by two mechanisms: should it be a treatment-related second lymphoma (in our case, added to a relapse) or a transformed lymphoid stem cell that underwent intraclonal conversion from B- to T-cell lines12.

The question of the management should now be asked. The two conditions have an aggressive behaviour and should be treated rapidly. The CORAL study has shown that the best treatment for relapsing diffuse large B cell lymphoma is chemotherapy (ICE or DHAP), plus Rituximab if the patient had not received it before, followed by autologuous hematopoiteic cell transplantation (auto-HCT), followed or not by Rituximab maintenance therapy13. For the angioimmunoblastic T lymphoma, retrospectives and observational studies have shown that auto-HCT is associated with higher complete remission and survival rates than prednisone therapy alone or combination chemotherapy14, 15. Until the date, no study has been done regarding the treatment of T-cell rich/histiocyte rich large B cell lymphoma, but a mechanism-based reasoning would recommend an empiric treatment based on chemotherapy plus Rituximab, possibly followed by auto-HCT if it is an advanced stage or relapsing disease.

There is no consensus or guideline regarding the treatment to establish in this case, as the precise diagnosis of the type of lymphoma cannot be made. Given the evidence existing for the possible types of lymphoma and the fact that the first lymphoma occurred eleven years ago and wasn’t treated with the maximal dose of anthracyclines, first-line aggressive treatment should be tried. The elevated IPI score, the patient’s age and relatively good health and the concomitant Kikuchi disease are other arguments to consider an autologuous hematopoietic stem cell transplantation following intense chemotherapy (four cycles of R-megaCHOP regimen), as it was decided for our patient.

The interest of this case is to present a diagnostic challenge for a lymphoma in a patient with a history of another lymphoma. First, regarding the clinical presentation and the results of the first biopsy, the diagnosis of Kikuchi disease was made, supported by the fact that this disease was associated with a history of B-cell lymphoma in two cases reported in the literature4. The patient was treated with the recommended first-line, and afterwards, given the persisting symptoms, second-line treatments, as recommended in the literature2, 5. But this rare, benign disease has hidden a second lymphoma; here is the second part of the challenge: classifying precisely a mixed cellularity lymphoma in a patient with a history of lymphoma: is it a relapse or a new lymphoma? What is the precise type of lymphoma encountered here? What is it subsequent pathological mechanism? With the actual knowledge, these questions are hard to answer...Following the strict rules of the WHO classification of tumors of hematopoietic and lymphoid tissues, our case enters into no precise classification9. But the aim of the physician is to treat the patient and, regarding the most recent and reliable data from the literature, the best treatment option seems to have been chosen in our particular case.

Our case emphasizes the importance of outruling a serious and frequent disease which can explain a clinical condition when a patient doesn’t respond to the treatment of a firstly diagnosed benign condition. In the case of adenopathies, biopsies should be repeated if severe symptoms resist treatment. In a patient with a history of lymphoma in remission with a second lymphoma, it’s important to distinguish between a relapse and a new disease only insofar as it could have an effect on prognosis and treatment.

¹ Department of Hematology, Clinica Universidad de Navarra, Pamplona

² Department of Pathology, Clinica Universidad de Navarra, Pamplona

³ Department of Hematology, Clinica Universidad de Navarra, Pamplona

Kikuchi disease and second lymphoma

Maladie de Kikuchi et lymphome secondaire