ABSTRACT

Composite lymphoma refers to the simultaneous presence of two or more morphologically and immunophenotypically distinct lymphomas within the same tissue or organ. While cases of composite lymphoma consisting of classical Hodgkin lymphoma (cHL) and B-cell lymphoma have been reported, the combination of splenic marginal zone B-cell lymphoma (SMZL) and cHL is extremely rare. In this report, we present a case initially treated with insufficient response for SMZL, later experiencing recurrence, followed by a diagnosis of cHL. Additionally, thyroid tissue from the same patient revealed the presence of thyroid papillary and medullary cancers with a poor prognosis. This report presents a case of composite lymphoma involving four different primary malignancies occurring simultaneously.

INTRODUCTION

Composite lymphoma refers to the simultaneous presence of two or more lymphomas with different morphological and immunophenotypic features in the same tissue or organ¹. Although cases of composite lymphoma consisting of classical Hodgkin lymphoma (cHL) and B-cell lymphoma have been reported, the combination of splenic marginal zone B-cell lymphoma (SMZL) and cHL is extremely rare². This report presents a case where a patient initially treated for SMZL with inadequate response was later diagnosed with cHL following a repeat biopsy. Additionally, a biopsy of thyroid tissue from the same patient revealed a rare papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC).

Informed consent was obtained from the patient involved in this case report. They were informed about the medical procedures and the scientific purpose of this study.

CASE REPORT

A 69-year-old male farmer with a known history of diabetes mellitus and cholelithiasis presented with fever, weight loss, night sweats, and left upper quadrant pain. This table summarizes key laboratory results from the patient’s clinical report. Abdominal ultrasound revealed multiple lymphadenopathies in the liver hilum, with the largest node measuring 3.2 cm, and splenomegaly with a spleen size of 17 cm. A bone marrow biopsy was performed, and the immunohistochemical findings (positive for CD20, CD23, CD3, BCL 2) along with the morphological assessment were consistent with SMZL (Figure 1 presents the results of immunohistochemical staining). On the positron emission tomography/computed tomography (PET/CT) scan, the patient had a 47 mm [standardized uptake value (SUV) 6.2] nodular mass in the right lobe of the thyroid gland, a 12 mm (SUV 2.4) mass in the anterior mediastinum, 15 mm (SUV 2.1) bilateral axillary lymphadenopathy, multiple perisplenic lymphadenopathies with the largest being 20 mm, and splenomegaly with a spleen size of 19 cm. After 6 cycles of rituximab treatment, the PET/CT response evaluation showed no significant morphological changes in the hypermetabolic mass lesion in the right lobe of the thyroid gland (Figure 2a), with partial metabolic regression observed. Increased fluorodeoxyglucose (FDG) uptake was noted in the right axillary fossa (Figure 2b), subcutaneous tissue adjacent to the gluteal and paraspinal muscle planes, and bilateral inguinal regions. Complete regression was observed in lymph nodes in the periportal and perisplenic regions, while millimetric lymph nodes showing FDG uptake under mediastinal vascular structures were classified as Deauville score 2. Splenic size was found to be normal. Bone marrow biopsy did not show lymphoma infiltration. Due to a suspicious nodule, the patient underwent total thyroidectomy and an excisional lymph node biopsy from the right axilla. The thyroidectomy material showed MTC in the right lobe, PTC of the follicular variant with capsule invasion in the left lobe, and the right axillary lymph node biopsy revealed mixed cellularity type cHL. The lymph node biopsy showed positive results for CD30, CD15, MUM1, and PAX-5; while CD20, CD45, and EBER were negative (Figure 3 presents the results of immunohistochemical staining). The endocrinology team recommended monitoring with calcitonin and carcinoembryonic antigen every 3 months without treatment. A follow-up neck ultrasound revealed lymphadenopathy in the cervical chain, with the largest node measuring 15x6 mm in the right supraclavicular region, and additional nodes in the right parotid cortex. The patient was diagnosed with stage 3A cHL and began doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine therapy. Genetic testing from the lymph node biopsy using next-generation sequencing (NGS) panel identified possible pathogenic variants: CIITA p.C83fs (loss-of-function) with a variant allele frequency (VAF) of 10% and TCF3 p.R525W with a VAF of 2.9%. After two cycles, the patient achieved a complete response on PET/CT but unfortunately passed away due to pneumonia during the course of treatment.

DISCUSSION

In this report, we present a case of composite lymphoma with four different primary malignancies occurring simultaneously. The coexistence of SMZL and cHL is rare, given that cHL typically presents in lymph nodes². To our knowledge, there are very few reported cases of cHL developing in a patient with SMZL. In one case study, PCR and sequencing analyses revealed that amplified rearranged immunoglobulin genes originated from the same clone³. In another case, where both cHL and mantle cell lymphoma were present, the findings were clonally unrelated⁴. According to a published review, more than 70% of patients with composite lymphoma are ≥55 years old, and the majority are male. The most commonly associated lymphomas are cHL with follicular lymphoma or diffuse large B-cell lymphoma, with over 130 cases reported. The cHL group is frequently of the mixed cellularity type, and compared to other types, it often shows focal/weak CD20 expression, suggesting a distinct pathophysiology. Both groups can share similar IgH/IgK rearrangements and the same pathogenic variants, which supports the hypothesis of a common clonal origin. Thus, composite lymphomas appear to support a common clonal origin and transdifferentiation process during lymphoma pathogenesis⁵. A study of 20 cases with both HL and non-HL (NHL), including three cases diagnosed with SMZL, found that the HL that developed later was usually more aggressive and at a more advanced stage⁶. In most of these cases, malignant clones develop separately from a common precursor cell, often a germinal center B-cell. Thus, this suggests a scenario where malignant precursor cells undergo transformation resulting in the development of two different lymphomas through distinct and repeated transformation events within the germinal center microenvironment. Molecular findings support this view⁷. PTC is the most common endocrine malignancy. The simultaneous occurrence of HL and MTC has been rarely reported. The coexistence of MTC and PTC in the same thyroid gland is classified into two forms. The first form consists of two distinct tumors separated by non-neoplastic thyroid tissue. The other form is a mixed tumor. Our case fits the first form. In thyroid cancers, metastases are usually observed as lymph nodes in the cervical and anterior mediastinal regions, similar to the widespread involvement seen in HL⁸. HL treatment was initiated after total thyroidectomy in our case. In our case, NGS of the lymph node revealed a significant loss-of-function mutation in CIITA p.C83fs with a VAF of 10%. Hematopoietic cancer cells can also present antigens in the context of HLA class II. It has been shown that CIITA methylation can lead to transcriptional down regulation of HLA II genes, allowing these cells to evade antigen presentation. The CIITA gene often breaks and fuses in some lymphomas, playing a key role in how these cancers evade the immune system. In a study of 263 patients with B-cell lymphoma, 15% of those with cHL showed recurring genomic breakages in CIITA⁹. Inactivating CIITA mutations are found in cancers including mediastinal large B-cell lymphoma, cHL, and gastric and colorectal cancers¹⁰. Loss of CIITA function can lead to impaired antigen presentation due to reduced MHC-II expression¹¹. CIITA rearrangements can result in the loss of CIITA function, deletion of tumor suppressors, or overexpression of oncogenic fusion partners⁹.

CONCLUSION

This case provides clinical experience in the management of both HL and NHL when occurring simultaneously, demonstrating appropriate treatment strategies for both. Further research is needed to elucidate the molecular mechanisms that lead to the simultaneous occurrence of multiple malignancies. To the best of our knowledge, this appears to be the first reported case of composite lymphoma coexisting with two distinct primary thyroid carcinomas, resulting in four synchronous primary malignancies.