Anti-TIF1γ antibody positivity without inflammatory myositis leading to expedited diagnosis of synchronous Epstein-Barr virus-positive marginal zone lymphoma and colon cancer: a case report

Introduction

Anti-transcriptional intermediary factor 1 gamma (anti-TIF1γ) autoantibodies have become an increasingly recognized myositis-specific autoantibody associated with idiopathic inflammatory myopathies, particularly dermatomyositis and cancer-associated myositis (CAM) (1). CAM has become an increasingly recognized paraneoplastic syndrome theorized to be the result of immuno-targeting of cancer and muscle tissues with expression of common autoantigens (2-5). This case describes a patient who presented with progressive weakness and weight loss not meeting diagnostic criteria for an inflammatory myositis but was found to have anti-TIF1γ positivity during work-up, prompting an expedited evaluation for malignancy which revealed synchronous aggressive Epstein-Barr virus-positive (EBV+) marginal zone lymphoma (MZL) and colon adenocarcinoma. We present this case in accordance with the CARE reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-24-5/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Informed consent was provided by patient prior to write-up and subsequent submission of this case report and accompanying images for publication. A copy of the written consent is available for review by the editorial office of this journal.

A female in her 60s with a past medical history significant of postural orthostatic tachycardic syndrome (POTS) with autonomic polyneuropathy presented to her primary care provider for worsening fatigue, palpitations, “brain fog”, and gradually deteriorating vision of several years’ duration. More recently, the patient also experienced changes in appetite with early satiety and associated 9 kg weight loss over 6 months. She did not have any dysphagia, dysarthria, erythematous rashes, or asymmetric weakness. She was initially referred to neurology for further evaluation of a suspected worsening neuropathy or possibly demyelinating syndrome.

On exam, she was mildly cachectic; on neurologic exam, she had inducible binocular diplopia that was consistent with a previously known idiopathic cranial nerve IV palsy, subtle bilateral weakness of eyelid closure and lip closure bilaterally, and a generalized decrease in muscle bulk and tone throughout. The patient had generalized weakness with 4/5 strength of most extremities tested proximally and distally. She had no myoclonus, tremor, fasciculations, or pronator drift. Around this time, she presented to the emergency room for her weakness and fatigue. A thorough infections work-up was obtained and was negative, and a computed tomography (CT) scan of the chest, abdomen, and pelvis was performed with no significant findings. Her symptoms continued to progress, and she was referred to rheumatology for further evaluation of her weakness.

Initial lab work-up was completed as noted in Table 1. Given findings on clinical exam not consistent with any clear unifying rheumatologic disease (e.g., Sjogren’s syndrome, dermatomyositis), additional myositis antibody testing revealed elevated anti-TIF1γ antibody titers. Given her progressive symptoms and anti-TIF1γ positivity, an in-depth work-up for malignancy was started, which included a positron emission tomography (PET) scan, performed about 7 weeks following the previously normal CT scan. It demonstrated a 3.0 cm × 1.5 cm hypermetabolic soft tissue mass in the left fossa of Rosenmuller [maximum standardized uptake value (SUVmax) 13.3] which was biopsied (Figure 1), multiple hypermetabolic bilateral cervical lymph nodes, a left supraclavicular lymph node (SUVmax 10.1), and bilateral axillary lymph nodes as well as a 2.1 cm × 1.4 cm focal hypermetabolic lesion in the deep right lower quadrant (SUVmax 11.3) with no CT correlate. There was no significant skeletal muscle hypermetabolism noted on the scan. Overall, PET/CT findings were concerning for an advanced nasopharyngeal carcinoma, and therefore peripheral blood EBV DNA was checked, revealing elevated levels of circulating EBV at 44,600 copies/mL.

Figure 1 Hematoxylin and eosin stain (200×). Nasopharyngeal biopsy shows a fragment of nasopharyngeal mucosa with a benign epithelial lining and a mucosal lymphoid infiltrate with a mixture of predominantly small lymphocytes, with an intermixture of scattered intermediate to large lymphocytes and histiocytes.

Otolaryngology performed an excisional biopsy of the left cervical lymph node (Figures 2-4). The lymph node was effaced by a diffuse to vaguely nodular infiltrate of polymorphous lymphocytes with a predominance of small mature forms. Hodgkin-like cells were not appreciated. A focal area of necrosis was felt to represent the prior fine needle aspiration site. Immunostains showed a heterogeneous mixture of B-cells and more numerous T-cells. B-cells were positive for CD20 and PAX5 without coexpression of CD10, CD5, CD138, kappa, lambda, BCL1, or SOX11. Small, remnant follicular dendritic cell networks were seen on CD23 staining. No residual germinal centers were detected on stains for CD10 and BCL6. In situ hybridization (ISH) for EBV-encoded RNA (EBER) showed scattered, small-appearing positive cells throughout viable appearing areas. T-cells were positive for CD3 with a normal appearing CD4:CD8 ratio and without loss of CD2, CD5, or CD7. CD56-positive, small cells are abundant, but no angiocentricity, no angioinvasion, and no angiodestruction are appreciated. Ki-67 was elevated at 25%.

Figure 2 Hematoxylin and eosin stain (400×). The infiltrate is composed of a polymorphous lymphoid infiltrate including a predominance of small mature forms and scattered intermediate to large forms. Scattered histiocytes are present. Small vessels are prominent.

Figure 3 CD20 immunohistochemical stain (200×). CD20-positive B-cells are predominantly small.

Figure 4 EBER immunohistochemical stain (200×). EBER-positive cells are scattered throughout viable areas. EBER, Epstein-Barr virus-encoded RNA.

Flow cytometry demonstrated a CD5-negative, CD10-negative lambda-restricted B-cell population composing 34% of total events. Background T-cells showed no aberrant antigen expression patterns. No significant background polyclonal B-cell population was detected. Flow on the peripheral blood showed a monoclonal population consistent with that seen in the lymph node.

Molecular testing on the excision showed clonal rearrangements of the immunoglobulin heavy chain and kappa light chain genes and no clonal T-cell receptor gene rearrangements. Fluorescence in situ hybridization (FISH) showed an extra copy of BCL6 in 7% of nuclei. FISH was negative for IGH/BCL2 translocation, MYC/IGH translocation, CCND1/IGH translocation, and rearrangements of MALT1, BCL6 and BCL2. Routine cytogenetic analysis failed due to poor growth.

The primary differential diagnosis included an atypical EBV-positive reactive process and EBV+ MZL. Given lymph node effacement, evidence of B-cell clonality via flow cytometry and molecular methods, FISH evidence for trisomy 3 (a relatively common abnormality in MZL), and EBER positivity in small cells (as opposed to large or atypical cells); a diagnosis of EBV-positive lymphoproliferative disorder with features suggestive of EBV+ MZL with increased reactive T-cells and natural killer (NK)-cells and associated biopsy site changes was rendered (6). In the absence of both T-cell immunophenotypic abnormalities and clonal TCR rearrangements, a T-cell lymphoma was not favored. In the absence of angiocentricity, angioinvasion or angionecrosis, CD56-positive cells were not felt to represent an NK-cell neoplasm.

Following some delays in obtaining the initial biopsies, she had progressive constitutional symptoms with daily fevers and night sweats, and new pancytopenia, so before chemotherapy initiation, a repeat PET was obtained (2 months after initial study). This second study revealed a new finding of splenic enlargement and hypermetabolism and diffuse marrow uptake, presumed secondary to lymphoma and again a persistent hypermetabolic focus in sigmoid colon without a discrete soft tissue mass. A flexible sigmoidoscopy was then performed with initial biopsy results revealing sigmoid colon adenocarcinoma.

At this point, with her poor performance status and pancytopenia from her lymphoma, priority was given to treating the MZL as she would not have been able to tolerate surgery and potentially chemotherapy for colon cancer. She received two cycles of bendamustine and rituximab (BR) with complete disease response based on repeat PET and normal blood counts apart from a slight anemia. EBV DNA had decreased to 455 copies/mL. The patient was then transitioned to rituximab monotherapy and underwent sigmoid colectomy. The primary tumor was completely removed with negative margins, and there were no complications related to surgery. Final pathology revealed pathologic stage IIA colon cancer (pT3N0[0/33]M0) with lymphovascular invasion. In a discussion with the patient, no adjuvant chemotherapy for colon cancer was pursued, and her blood counts started to decrease again prompting a desire to resume treatment for MZL. BR chemotherapy was resumed 6 weeks post-operatively. Repeat PET after two additional cycles of BR continued to show no evidence of lymphoma disease activity, but unfortunately showed new bilobed hypermetabolic focus in the right hepatic lobe. Subsequent biopsy confirmed hepatic metastasis secondary to colon adenocarcinoma.

After a multidisciplinary discussion, the decision was made to start the patient on neoadjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy with the goal to ultimately perform metastasectomy of her liver metastasis. She received two cycles of CAPOX and underwent short-interval imaging that showed disease progression. She was then switched to a regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) with bevacizumab. She received two cycles of this regimen and then declined further treatments due to profound fatigue. Next-generation sequencing of her colon adenocarcinoma showed a KRAS G12D mutation, which is associated with chemotherapy resistance (7). The tumor was found to be microsatellite stable with low tumor mutational burden, wildtype BRAF V600E, no HER2 over-expression, and no RET fusions identified.

After a shared multi-disciplinary discussion, she was referred for surgery; however, she had early progression after FOLFIRI discontinuation with more metastases in the liver, which precluded further surgical plans. Instead, she received radioembolization for temporary disease control. Three months later, she experienced progression with diffuse liver metastatic burden. She poorly tolerated regorafenib and discontinued it after less than a week of therapy. She declined a clinical trial for an oral KRAS G12D specific oral inhibitor and she was thought to be a poor candidate for other chemotherapies. She elected for supportive care alone.

Discussion

This case is the first to document the diagnosis of synchronous primary malignancies after the identification of anti-TIF1γ positivity. Synchronous malignancies are rare in general, but in this patient, both of her cancers were atypical in presentation and subsequent behavior. Her MZL was unusually aggressive, as indicated by expression of EBER-ISH, Ki-67 of 25% and no findings on CT scan to stage IV disease in a 3-month window. The patient’s colon adenocarcinoma also metastasized through BR chemotherapy and had rapid progression despite CAPOX and FOLFIRI with bevacizumab in the setting of a rare mutation associated with treatment resistance.

There are no guidelines in the treatment of synchronous malignancies. The goal in her care was to balance the greatest immediate threat to her life (MZL with progressive weight loss and pancytopenia) with the cancer that threatened her long-term overall survival (OS), colon adenocarcinoma. Following resection of her colon cancer, the decision to forgo adjuvant chemotherapy in the stage IIA setting was difficult. Although there is no OS benefit with the use of adjuvant chemotherapy in stage IIA disease (8), the patient’s concurrent MZL was not controlled with rituximab monotherapy and required further treatment. Her liver metastases after two additional cycles of BR are not unexpected given her immune dysregulation combined with KRAS G12D mutation. There are a limited number of other case reports involving treatment of lymphoma with synchronous solid digestive tract tumors with the vast majority also involving initial therapeutic targeting of the lymphoproliferative malignancy prior to solid tumor resection (9).

Anti-TIF1γ antibody has a well-established association with malignancy (10,11), and was clinically relevant in this patient given it expedited cancer screening in a patient for whom diagnosis may have otherwise been delayed. This patient’s generalized weakness, as well as normal muscle-specific inflammatory markers, were overall consistent with cancer-related cachexia and did not warrant muscle biopsy or more dedicated muscular imaging with magnetic resonance imaging for further evaluation of a primary myositis. The anti-TIF1γ antibody’s correlation with paraneoplastic syndromes to include CAM is clear (12), but its relevance in the diagnosis of cancer without a paraneoplastic myopathy is an area of future research consideration (13,14). There may be a population of patients with antibody positivity but not clinically apparent myositis, as numerous studies have documented TIF1γ overexpression in various tumor cell types (15) and shown that anti-TIF1γ titer levels may even correlate with malignancy activity (14,16). Further investigation into the antibody’s role as a screening tool and further testing in healthy populations could help answer these questions.

The significance of the EBV positivity and the relationship to anti-TIF1γ, and potentially to the synchronous development of MZL and colon adenocarcinoma, is also unknown and represents another potential area of further investigation. EBV is a well-established oncovirus with a strong pathogenic role in many cancers (17). There is a strong association between EBV and lymphomas arising in the setting of immune deficiency or dysregulation, such as post-solid organ or allogeneic transplant, human immunodeficiency virus (HIV) infection, inborn error of immunity, autoimmunity, or immune senescence due to aging, as highlighted in the 5^th edition of the World Health Organization Classification of Haematolymphoid Tumors: Lymphoid Neoplasms (6). In particular, EBV+ MZL is a rare but distinct entity that has been described and is associated with immunodeficiency, almost exclusively post-transplantation (18,19). To our knowledge, this is the first case describing EBV+ MZL in the setting of immune dysregulation associated with TIF1γ.

In this patient, one can speculate that there was likely significant immune dysregulation with the TIF1γ autoantibody which predisposed this patient to EBV-associated MZL as well as a synchronous second primary malignancy. However, more research is needed to better understand any relationship between TIF1γ and lymphomas arising in the setting of immune system dysregulation.

Conclusions

Anti-TIF1γ antibody positivity should prompt work-up for malignancy, to include non-Hodgkin lymphoma. Management of synchronous aggressive B-cell lymphoma and solid tumor malignancies typically involves therapeutic targeting of the lymphoma first as the more immediate life threat, although there are no well-established clinical guidelines to guide this treatment decision. More research is needed to better understand the importance of identifying positive EBER-ISH in indolent lymphomas such as MZL arising in the setting of immune deficiency or dysregulation, as the clinical course might not be indolent. This case report is the first to describe EBV+ MZL in the setting of TIF1γ.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-24-5/rc

Peer Review File: Available at https://aol.amegroups.com/article/view/10.21037/aol-24-5/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-24-5/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Informed consent was provided by patient prior to write-up and subsequent submission of this case report and accompanying images for publication. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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