A Case of Cavernous Sinus Syndrome Due to Extranodal Diffuse Large B-Cell Lymphoma

The cavernous sinus (CS) is a small but complex intracranial structure including the internal carotid artery, venous and sympathetic plexuses, and cranial nerve. The cavernous sinus syndrome (CSS) is characterized by multiple cranial nerve palsies and autonomic dysfunction presenting with ophthalmoplegia, ptosis, and facial sensory loss. This syndrome results from any disease process that affects CS including tumor, vascular disease, infection, and inflammation1. It is characterized by diplopia, headache, proptosis, ptosis, ophthalmoplegia, Horner syndrome (ipsilateral miosis, ptosis, anhidrosis or enophthalmos due to disruption of sympathetic tone), or trigeminal sensory loss resulting from the functional disturbance of the cranial nerve or sympathetic plexus passing through the CS2.

Primary cutaneous diffuse large B-cell lymphoma (DLBCL) is defined as a B-cell lymphoma of the skin without evidence of extracutaneous disease at presentation and present for 6 months after diagnosis3. Secondary cutaneous DLBCL displays evidence of extracutaneous disease at the time of diagnosis or within the first 6 months of identification. Secondary cutaneous DLBCL usually presents as single or multiple nodules and has worse outcomes than primary cutaneous DLBCL4.

To date, 3 cases of DLBCL presenting as CSS have been reported5, 6, 7. In addition, only four cases of secondary cutaneous DLBCL have been described in the Korean dermatologic literature8, 9, 10, 11. Herein, we report a rare and interesting case of secondary cutaneous DLBCL presenting as CSS.

A 58-year-old male visited the neurologic department with ptosis, ophthalmoplegia, diplopia, and headache confined to right side for 3 months. A non-specific tiny space-occupying lesion was observed in the right CS on brain computed tomography (CT) imaging. Also, non-specific both optic perineuritis was observed on brain magnetic resonance imaging (MRI). He underwent systemic steroid pulse therapy because the Tolosa-Hunt syndrome was suspected; however, there was no improvement on clinical symtoms and subsequent brain MRI evaluation. He was consulted in the dermatology department for a subcutaneous nodule of approximately 2.5×1.5 cm in diameter without surface change on the left upper lip for 3 weeks (Fig. 1). He also complained of size increment without subjective symptoms. We received the patient’s consent form about publishing all photographic materials.

Fig. 1
Ptosis and ophthalmoplegia on the right eye and subcutaneous nodule, approximately 2.5×1.5 cm in diameter on the left upper lip.

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Histopathologic examination of the left upper lip showed dense dermal infiltration of atypical large tumor cells resembling centroblasts and immunoblasts. The tumor cells showed some pleomorphism and increased mitotic activity without prominent lymphoid follicle formation (Fig. 2A, B). On immunohistochemical examination, the tumor cells were positive for CD20 (Fig. 2C), BCL2, BCL6, MYC, and MUM1, and negative for CD3 and CD10. Laboratory examination showed no abnormal findings except for elevated lactate dehydrogenase (387 U/L). Further radiologic evaluations with positron emission tomography-computed tomography (PET-CT), brain MRI, and orbital CT were performed following suspicion of DLBCL based on the histopathologic examination. In PET-CT, asymmetrical fluorodeoxyglucose uptake was observed at right oculomotor muscles. Space-occupying lesions at right CS and several thickenings at the right oculomotor muscles that resulted from lymphoma involvement were shown by brain MRI and orbital CT (Fig. 3).

Fig. 2
(A) Dense dermal infiltration of atypical large tumor cells without prominent lymphoid follicle formation (H&E, ×40). (B) Tumor cells resembling centroblasts and immunoblasts showed some pleomorphism and increased mitotic activity (H&E, ×400). (C) Tumor cells were positive for CD20 and revealed that the tumor was of B cell origin (CD20, ×100).

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Fig. 3
(A) Space-occupying lesion (yellow arrows) at right CS in brain MRI. (B) Several thickenings (blue arrows) at the right oculomotor muscles were shown in orbital CT. CS: cavernous sinus, CT: computed tomography, MRI: magnetic resonance imaging.

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A final diagnosis of extranodal DLBCL involving the right CS, oculomotor muscles, and left upper lip was obtained based on histopathologic and radiologic examinations. The patient received two sessions of chemotherapy, but further treatment was discontinued due to his poor general condition.

CSS can be caused by various etiologies including tumor, vascular disease, infection, or inflammation presenting as multiple cranial nerve palsies and autonomic dysfunction. Bhatkar et al.1 reported that diplopia was the most common clinical presentation followed by unilateral headache, ptosis, facial numbness, and proptosis (90.4%, 70.4%, 68.4%, 56.2%, and 31.5%, respectively). The most commonly paralyzed nerve was the sixth cranial nerve followed by the third and fourth cranial nerves, the trigeminal nerve, and the ophthalmic division (82.1%, 78.1%, 68.4%, 46.5%, and 46.5%, respectively). However, it frequently appears in various combinations of clinical and radiologic findings, and therefore, its diagnosis can be difficult and delayed12. The most common cause of CSS was a tumor, followed by vascular disease, and granulomatous inflammation (63%, 20%, and 13%, respectively). Among tumors, pituitary adenoma and meningioma were the most common cause. MRI is the most sensitive diagnostic tool for tumor diagnosis, but in some cases, it is not enough to reveal the etiology2.

Our patient was initially treated with systemic steroids following suspicion of the Tolosa-Hunt syndrome after brain CT evaluation. The Tolosa-Hunt syndrome is rare and is caused by a non-specific granulomatous inflammation of the CS. It is characterized by painful ophthalmoplegia with paralysis of one or more of the third, fourth, or sixth cranial nerves and usually requires a prolonged immunosuppressive therapy. However, this syndrome must be carefully differentiated from other diseases involving CS that can present with similar clinical characteristics. In most cases, a biopsy is not generally necessary, but it should be considered in patients with rapidly progressive neurologic impairment, at high risk of malignant diseases, or with lack of steroid responsiveness13. In our case, the therapeutic response to systemic steroid was less than that of granulomatous inflammation, and a subcutaneous nodule that gradually enlarged on the left upper lip occurred. Generally, CS is difficult to approach; hence, a biopsy could be a final option after a less invasive diagnostic attempt2. Fortunately, the lip nodule was pathologically compatible with DLBCL, and in this case, this finding gave a clue for revealing the etiology of CSS.

After the biopsy, immunohistochemistry, and further radiologic evaluation, our case was finally diagnosed with extranodal DLBCL involving the right CS, oculomotor muscles, and left upper lip. Tumor is the most common cause of etiology of CSS, but lymphoma is rare, accounting for about 2.3% of them2. DLBCL is the most common type of non-Hodgkin’s lymphoma; however, only three cases of CSS caused by DLBCL have been reported and are summarized in Table 1, 5, 6, 7. In previous cases, the etiology of CSS was directly revealed by a pathologic examination of the tumor itself or affected lymph node.

Table 1
Previous reports of CSS caused by DLBCL

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In the diagnosis of DLBCL, the biopsy of adenopathy or affected extranodal tissue is important14. In this case, the CS was difficult to approach, but the cutaneous lesion was accessible for biopsy and revealed the etiology of CSS. Therefore, we consider this case rare and meaningful, as we show that cutaneous neoplastic conditions found in patients with CSS should be biopsied because a tumor is the most common cause of CSS.