Bilateral eyelid masses and enophthalmos as the initial manifestation of diffuse large B-cell lymphoma: a case report

Abstract

Background

Ocular adnexal lymphoma is considered an uncommon disease, but it is among the most common malignancies affecting the ocular adnexa. While diffuse large B-cell lymphoma constitutes 10% of ocular adnexal lymphomas, the initial presentation with bilateral eyelid swelling is quite rare and can be diagnostically challenging.

Case presentation

Here, we report a case of a 64-year-old Middle Eastern male patient with no prior history of malignancy who presented with a 5-month history of bilateral upper eyelid swelling, mild enophthalmos, and ptosis. The patient had no systemic symptoms. The masses were surgically resected, and histopathological examination confirmed the diagnosis of diffuse large B-cell lymphoma. Following surgical resection, the patient developed submandibular and parotid gland enlargements. Subsequent contrast-enhanced computed tomography scan revealed an enhancing mass posterior to the descending aorta. The patient received six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone regimen. Despite the aggressive nature of diffuse large B-cell lymphoma, clinical remission has been achieved. Follow-up positron emission tomography revealed no residual disease.

Conclusion

Bilateral eyelid swelling is a rare initial sign of aggressive lymphoma, such as diffuse large B-cell lymphoma, even in the absence of systemic symptoms. Clinicians should consider malignancy in such atypical presentations to ensure early diagnosis and treatment.

Introduction

The ocular adnexa refer to the structural components surrounding the eye, including the orbit, eyelids, lacrimal gland, conjunctiva, and lacrimal sac [1]. Although ocular adnexal lymphoma (OAL) is considered an uncommon disease overall, it is among the most prevalent malignancies affecting this anatomical region, and its incidence has been gradually increasing [2]. OAL accounts for approximately 1% of all lymphomas and nearly 8% of extranodal lymphomas [1]. Non-Hodgkin lymphomas (NHLs) are the most common primary malignancy affecting the orbit in adults [3].

Ocular adnexal lymphoma comprises several histological subtypes of B-cell NHL, primarily including extranodal marginal zone lymphoma (EMZL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and large B-cell lymphoma (LBCL). LBCLs are histologically heterogeneous and are subclassified into many subtypes, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent [2].

Although DLBCL constitutes a smaller proportion of OAL cases, it is considered clinically important due to its aggressive nature, rapid clinical progression, and potential for disseminated disease [4–6]. The average age at presentation ranges from 46 years to 65 years, and there is a slight female predominance [7, 8]. Patients often experience a delayed diagnosis, with symptom onset preceding medical consultation by an average of 12 months [8]. Clinical manifestations usually include palpable masses, proptosis, ptosis, irritation, diplopia, epiphora, eyelid swelling, decreased visual acuity, and “salmon‑patch” mass. Less common manifestations include nasolacrimal duct obstruction, ocular redness, and glaucoma [7–9]. Bilateral involvement of OAL is less frequently observed [7, 8]. Here, we report a rare case of DLBCL presenting with bilateral eyelid swelling and mild enophthalmos, which is highly uncommon manifestation.

Case presentation

Patient history and presentation

A 64-year-old Middle Eastern man with no history of malignancy presented with a 5-month history of bilateral painless upper eyelid swelling and ptosis (Fig. 1 shows the left eyelid; image has been cropped to maintain patient anonymity). About 3 weeks prior to his consultation, the patient also noticed mild enophthalmos. This was a subjective observation made by the patient and not clinically measured during examination. The patient denied any weight loss, anorexia, night sweats, or fever. The patient had no history of any trauma. No changes in visual acuity or diplopia were noted. There were no limitations to eye movement. However, automated static perimetry of both eyes at the onset of symptoms demonstrated a mild visual field defect in the superior lateral quadrant. This functional impairment correlated with the anatomical location of the upper eyelid masses (Fig. 2). His medical history included herpes zoster and Helicobacter pylori infections.

Fig. 1.

Image of patient’s left eyelid 10 weeks after onset of symptoms. Red arrow indicates left upper eyelid swelling. Although only one eyelid is shown to preserve patient anonymity, similar swelling was present in the right upper eyelid

Fig. 2.

Automated static perimetry revealed a mild visual field defect in the superior lateral quadrant of each eye

Diagnostic workup

Laboratory examinations revealed mild anemia with a hemoglobin level of 12.9 g/dL and hematocrit of 38.8%. White blood cell count was within normal limits (7.5 × 10⁹/L), with a lymphocyte count of 20.5%. Notably, thrombocytosis was observed with a platelet count of 511 × 10⁹/L. Renal and liver function test results were normal. Computed tomography (CT) scan of both orbits revealed bilateral hyperdense homogeneous tissue with regular borders at the temporal side of the superior orbit sticking to the eyeball and orbit, with no signs of adjacent tissue infiltration (Fig. 3). Both the optic nerves and eyeballs were normal. CT scan revealed no signs of orbital bone involvement, and there was no calcification in the soft tissues.

Fig. 3.

Preoperative head and neck computed tomography scan, showing bilateral upper eyelid mass located on temporal side of superior orbit (red arrows)

Patient underwent surgical excision approximately 3 weeks after the first medical consultation. Two separate masses, located in the upper eyelids on the temporal side of the superior orbit, were resected (Fig. 4). They were of the same consistency, white in color, and soft, with one measuring 25 × 20 × 8 mm and the other measuring 30 × 30 × 15 mm. Histopathological examination revealed the proliferation of medium- to large-sized anaplastic lymphocytes with large nuclei, small nucleoli, and several mitoses (Fig. 5). The background contained scattered chronic inflammatory infiltrates, particularly lymphocytes. This finding suggested malignant non-Hodgkin lymphoma. Immunohistochemically, all the tumor cells were positive for CD20 but negative for CD5 and CD23 (Fig. 5). Negative CD23 staining excluded mucosa-associated lymphoid tissue (MALT) lymphoma. The background reactive lymphocytes were positive for CD3 and CD5. Ki67 was positive in approximately 50% of the tumor cell nuclei (Fig. 5). Therefore, a final histopathological diagnosis of DLBCL was established on the basis of these findings.

Fig. 4.

Gross image of excised eyelid masses. Two separate white, soft tissue specimens of similar consistency are shown. Both were resected from the temporal aspect of the upper eyelids

Fig. 5.

(A) Hematoxylin and eosin staining ×20. The micrograph shows the anaplastic proliferation of medium-to-large lymphocytes with large nuclei, small nucleoli, and several mitoses. These cells are arranged in sheets with foci of necrosis. The background contains scattered chronic inflammatory infiltrates, especially lymphocytes. The white arrow indicates malignant tumor cells. This micrograph excluded marginal lymphoma of mucosa-associated lymphoid tissue type. (B–F) Immunohistochemistry evaluation. (B) CD20 biomarker was positive in all tumor cells (white arrow) (immunohistochemistry; 40×). (C) CD3 biomarker was negative in all tumor cells and positive in reactive background lymphocytes (immunohistochemistry; 20×). (D) CD5 biomarker was negative in all tumor cells and positive in reactive lymphocytes (IHC; 20×). (E) CD23 biomarker was negative in all tumor cells, which excluded mucosa-associated lymphoid tissue lymphoma (immunohistochemistry; 20×). (F) Ki67 biomarker was positive in approximately 50% of tumor cell nuclei (immunohistochemistry; 40×). The white arrow indicates a cell in the mitotic phase

Bilateral submandibular and parotid gland enlargements developed 5 weeks after surgical excision. Ultrasonography of the submandibular area revealed many cysts and generalized heterogeneity of the parenchyma with blood supply, as confirmed by color Doppler ultrasonography. The largest focus on the right side was 31 mm × 22 mm, and on the left side 17 mm × 40 mm. Parotid gland ultrasonography revealed heterogeneity of the parenchyma, with many hypoechoic and anechoic foci. The largest focus on the right side was 5 mm × 3 mm, and on the left side 6 mm × 4 mm. Ultrasonographic examination of the cervical lymph nodes revealed multiple oval-shaped nodes with preserved fatty hila and well-defined borders, consistent with benign morphology. The largest lymph nodes measured 11 mm and 12 mm on the left and right sides, respectively.

Postoperative contrast-enhanced CT scan (Fig. 6) revealed an enhancing mass behind the lower part of the descending thoracic aorta measuring 25 × 35 × 60 mm with minor left pleural effusion. The CT scan also revealed bilateral renal cysts; the largest cyst measured 90 mm in size in the left kidney. The bilateral renal cysts identified on CT were considered incidental age-related findings, with no radiologic features suggesting infiltration or malignancy. The remaining findings were within normal limits. Owing to the subsequent detection of a deep posterior mediastinal mass and bilateral salivary glands involvement, the disease was staged as stage IV according to the Lugano classification for non-Hodgkin lymphoma. However, the absence of bone marrow evaluation and preoperative positron emission tomography (PET), primarily due to financial constraints, introduces some uncertainty in definitive staging and raises the question of whether eyelid involvement is a primary or part of systemic disease at onset.

Fig. 6.

Postoperative computed tomography of the thorax, abdomen, and pelvis in the sagittal plane. The red arrow indicates the enhancing mass behind the lower part of the descending thoracic aorta measuring 25 × 35 × 60 mm

Management

The therapist selected an immunochemotherapy approach without radiation. Thus, the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen was administered to the patient at intervals of 21 days. The patient tolerated the first five cycles without significant adverse events, but in the sixth cycle, he was given only immunotherapy as his blood count values deteriorated 4 days before the last cycle. Laboratory results at that time showed leukopenia (white blood cell count: 2.6 × 10⁹/L), neutropenia (absolute neutrophil count: 1.17 × 10⁹/L), and moderate anemia (hemoglobin: 8.4 g/dL).

Outcome and follow-up

Following surgical excision of the eyelid masses, bilateral eye proptosis, Lid swelling, and enophthalmos resolved. Laboratory examinations 1 month after the end of immunochemotherapy revealed mild anemia with a hemoglobin level of 10.5 g/dL and hematocrit of 34.1%, normal platelet count of 212 × 10⁹/l, and white blood cell count of 3.97 × 10⁹/l. Urine analysis revealed microscopic hematuria. Ultrasonography of the kidneys revealed several simple cortical cysts, confirming the bilateral renal cysts previously identified on CT. The largest cyst, located in the left kidney, measured 90 mm and appeared radiologically consistent with a benign simple cortical cyst. These findings were consistent across imaging modalities, supporting their interpretation as incidental, age-related findings. A 18-fluorodeoxyglucose PET scan 2.5 months after his last immunotherapy cycle revealed no nodal or visceral metabolic activity. No abnormal fluorodeoxyglucose uptake was observed at the level of the nodal groups in the neck, mediastinum, armpit, peritoneum, pelvis, or groin. A chronological overview from the onset of symptoms to the last follow-up imaging is illustrated in Fig. 7.

Fig. 7.

Comprehensive timeline of this case

Discussion

Ocular adnexal lymphomas (OALs) are rare malignancies, representing approximately 8% of all extranodal lymphomas and 1–2% of non-Hodgkin lymphomas (NHLs) [3, 10]. The ocular adnexa includes five structures: the eyelids, lacrimal sac, conjunctiva, lacrimal gland, and orbit [11]. The relative distributions of OALs include orbital (37%), conjunctival (29%), lacrimal apparatus (20%), and eyelid (14%) [1]. Although diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, it accounts for only 5–15% of OALs [1, 7, 9, 12, 13]. However, DLBCL accounts for only 9% of eyelid lymphomas [14]. The sex predominance in ocular adnexal DLBCL is inconsistent across studies, with two studies reporting a female predominance and one reporting a male predominance, while the median age typically ranges from 68 years to 76 years [4, 5, 8]. Patients with ocular adnexal DLBCL usually present with swelling, irritation or pain, epiphora, and exophthalmos, in decreasing order of frequency [18]. Most cases of eyelid DLBCL present as a unilateral lesion [14]. The most reported clinical signs of ocular adnexal DLBCL include proptosis, mass, globe displacement, chemosis, and limited motility, whereas diplopia and ptosis are less common [4–6]. Notably, our patient presented with bilateral eyelid involvement and enophthalmos, a highly unusual presentation. In the present case, the possible mechanism of enophthalmos is related to direct mechanical compression of the eyeball by the upper eyelid masses. The eyelid masses may have exerted anterior-to-posterior pressure, resulting in mild eyeball displacement. Resolution of enophthalmos following surgical excision further supports a nonstructural, reversible mechanism.

Primary OAL diagnosis requires biopsy-confirmed lymphoma confined to the ocular adnexal region, which may involve unilateral preauricular and submandibular lymph nodes and adjacent structures such as the parotid gland, without any prior lymphoma diagnosis [15]. Typical immunohistochemistry findings of DLBCL, excluding specific variants, are characterized by the diffuse proliferation of CD20-positive, CD3-negative atypical medium or large lymphocytes [16].

The management options for ocular adnexal DLBCL include a variety of therapeutic regimens. Chemotherapy, often in combination with external beam radiation therapy (EBRT) and immunotherapy, is commonly used [8]. The introduction of the cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen significantly improved outcomes for patients with DLBCL, with further enhancements observed when rituximab was added, resulting in a 5-year overall survival rate of 60%. For younger patients aged < 60 years with high-risk profiles, the addition of etoposide to this regimen (R-CHOEP) has shown even better results [1]. A multicenter international study reported that EBRT was the prevalent treatment approach, often followed by rituximab-CHOP or similar chemotherapy regimens [4]. The recommended radiation dose for DLBCL is 3600 cGy [17]. However, R-CHOP was reported as the most frequent treatment utilized in OAL management in a recent retrospective study in East Asia [6]. Radiotherapy-free management in our patient achieved complete remission.

Ocular adnexal DLBCL tends to have a poor prognosis, and outcomes are largely dependent on how soon it is diagnosed and treated [6]. Overall survival is influenced by the Ann Arbor clinical stage and age, whereas factors such as gender, tumor size, molecular type, Ki-67 index, and bone invasion are not significant [18]. However, it was reported that rearrangement of the BCL-6 gene is associated with a positive clinical outcome and may serve as a prognostic factor for this type of lymphoma [19]. According to a retrospective study, eyelid DLBCL has worse 5-year disease-specific survival than orbital or conjunctival DLBCL does, suggesting that anatomical sites may influence prognosis [5].

The survival of patients with DLBCL after chemotherapy is affected by the molecular profiles of the tumors [20]. One limitation in our case is the absence of molecular subtype classification. Given the molecular heterogeneity of DLBCL, tailoring therapies to the unique molecular profiles of patients can increase response rates and potentially improve patient prognosis [21]. This approach can provide alternatives to radiotherapy, potentially sparing patients from complications. Acute complications from radiotherapy typically include mild-to-moderate skin or conjunctival reactions. Long-term complications occur in up to half of patients and are generally minor, such as cataract formation (affecting 30–50% of patients) and mild dry eye (20–40%) [22].

Conclusion

This case highlights a quite rare presentation of diffuse large B-cell lymphoma (DLBCL) initially manifesting with mild enophthalmos and bilateral upper eyelid swelling in the absence of systemic symptoms. The unusual bilateral involvement of the eyelids underscore the importance of considering lymphoma in the differential diagnosis of painless eyelid masses. In our patient, the R-CHOP regimen achieved complete remission. Although gene profiling was not performed in this case, it is advisable to consider it in future similar cases, as it may help guide personalized therapy and improve clinical outcomes. This case contributes to the limited literature on eyelid DLBCL and emphasizes the increased clinical awareness of unusual presentations of DLBCL.

Abbreviations

LBCL

Large B-cell lymphoma

DLBCL

Diffuse large B-cell lymphoma

NHL

Non-Hodgkin lymphoma

OAL

Ocular adnexal lymphoma

R-CHOP

Rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone

Author contributions

TI was involved in the investigation and writing of the original draft. BZ contributed to the conceptualization and writing. MB collected the patient data and contributed to the writing of the original draft. ST performed the surgery and contributed to the writing of the manuscript. RS performed the histological examination and contributed to diagnostic interpretation and manuscript writing. TI, BZ, MB, SM, and RS reviewed and edited the original draft. All the authors read and approved the final manuscript.

Funding

None.

Data availability

The deidentified DICOMs and supporting data used in this study are available from the corresponding author upon reasonable request. All imaging data were deidentified in compliance with HIPAA.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.