Case Report
Primary Malignant Lymphoma of the Trigeminal Nerve: Case Report and Literature Review Toshihiro Ogiwara1, Tetsuyoshi Horiuchi1, Nodoka Sekiguchi2, Yukinari Kakizawa1, Kazuhiro Hongo1
Key words Malignant lymphoma - Open biopsy - Surgical approach - Trigeminal nerve
- BACKGROUND:
Abbreviations and Acronyms CNS: Central nervous system MPVR: Methotrexate, procarbazine, vincristine, and ranimustine MRI: Magnetic resonance imaging PCR: Polymerase chain reaction
- CASE
-
From the 1Department of Neurosurgery and 2Division of Comprehensive Cancer Center, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan To whom correspondence should be addressed: Tetsuyoshi Horiuchi, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 84, 2:592.e3-592.e7. http://dx.doi.org/10.1016/j.wneu.2015.03.019 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
Primary lymphoma of the central nervous system (CNS) usually arises from the brain parenchyma, particularly the white matter (1, 2, 11). Primary lymphomas of the cranial nerves are extremely rare except for optic nerve lymphoma (14). Only nine cases of lymphoma arising from the trigeminal nerve have been reported to date (1, 3, 4, 6-9, 11, 12). In most of these cases, it was difficult to distinguish from other diseases by neuroimaging and the treatment was apprehensive because its aggravation is rapid. Here, we report a rare clinical presentation of malignant lymphoma arising from the trigeminal nerve in which it took a long time to confirm the diagnosis and two open biopsies were obtained via the lateral suboccipital and subtemporal approaches.
CASE REPORT The patient was a 47-year-old man, suffering from Crohn disease for 2 years, with a 2-
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Primary lymphomas of the cranial nerves are extremely rare except for optic nerve lymphoma, and it is difficult to make a correct diagnosis in the initial stage. Here, we report a case of primary malignant lymphoma of the left trigeminal nerve that presented as trigeminal nerve disorder. DESCRIPTION: A 47-year-old man presented with aggravating left facial pain and hypesthesia within all three divisions of the trigeminal nerve. Magnetic resonance imaging (MRI) revealed a swollen left trigeminal nerve with gadolinium homogenous enhancement. An open biopsy had to be taken from two different locations of the tumor via the lateral suboccipital approach followed by subtemporal approach because adequate specimen volume was not obtained for definitive diagnosis at the first surgery. Histopathological examinations with flow cytometric analysis revealed diffuse large B cell lymphoma. Chemotherapy followed by whole-brain radiation therapy was effective. No recurrence was observed during a 15-month follow-up period.
- CONCLUSIONS:
This is a rare clinical presentation of malignant lymphoma of the trigeminal nerve. It is difficult to establish a correct diagnosis of trigeminal nerve lesions during the initial stages without biopsy. Therefore it is important that a sufficient specimen should be taken for biopsy without hesitation in order to diagnose and treat rapidly. The most suitable operative approach must be selected in trigeminal nerve lesions considering functional preservation, operative difficulty, preference of each surgeon, and quantity of specimen to be removed.
month history of progressive left facial pain and numbness. These symptoms initially developed from V3 territory and spread to all three divisions of the trigeminal nerve. Physical examination revealed left facial hypesthesia, left facial spasmodic prickly pain mimicking trigeminal neuralgia, diminished corneal reflex, disturbance of jaw movement, and wasting of the masseter muscle. Tumor markers including soluble interleukin-2 receptor and other laboratory studies were within the normal limits. The cell count from cerebrospinal fluid (CSF) was 3/mL (mono: 3), and twice the cytology of CSF confirmed no malignant cells. There was no evidence of immune deficiency. Magnetic resonance imaging (MRI) indicated that the left trigeminal nerve at its cisternal portion, as well as at the Meckel cave, was swollen and homogeneously enhanced (Figure 1). Dural tail sign was not present. There was neither invasion
of brainstem nor mass effect. Computed tomography (CT) scan revealed no evidence of bony erosion or hyperostosis. The patient underwent an operation via the lateral suboccipital approach for histopathological confirmation. Intraoperatively, the trigeminal nerve was swollen and a grayish, soft, hemorrhagic granulomatous lesion surrounding the trigeminal nerve was observed (Figure 2A). A biopsy was taken from this lesion without injuring the trigeminal nerve. The patient was woken up immediately after surgery without new neurological deficits. Histopathological examination revealed numerous small cells with large nuclei-like lymphocytes; however, histopathological examination was eventually not able to establish a definitive diagnosis because polymerase chain reaction (PCR) did not confirm monoclonality as the specimen was not sufficiently large to
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.03.019
CASE REPORT TOSHIHIRO OGIWARA ET AL.
PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
subtemporal approach based on the previous operative findings. The lesion infiltrating into the subdural space of the middle fossa was removed. The tumor had the same features as in the previous surgery and was partially removed in the Meckel cave (Figure 2). He tolerated the procedure well. The specimen was studied using H & E staining and was examined by light microscopy. The tumor was highly cellular with mitotic figures and diffusely infiltrative. Immunoperoxidase studies revealed neoplastic cells to be positive for CD20 and MUM1 and negative for CD10 and bcl-6. The Ki-67 staining index was 73%. Flow cytometric analysis of CD20 expression in the resected specimen of the patient confirmed that tumor cells were CD20 positive (Figure 3C). Finally, histopathological examinations revealed diffuse large B cell lymphomas, nongerminal center B type (Figure 3A, B). Whole-brain radiation therapy (45 Gy) after administration of methotrexate, procarbazine, vincristine, and ranimustine (MPVR) therapy appeared to have remarkable effects. Although left facial hypesthesia and pain remained slightly, the patient’s clinical course was uneventful and he did not experience recurrence over a 1-year follow-up period (Figure 4).
Figure 1. AeD: Preoperative magnetic resonance imaging (MRI) showing swelling of the left trigeminal nerve (A) and heterogeneously enhancing tumor with gadolinium extending along the left cavernous sinus and infratemporal fossa extending into the foramen ovale (BeD).
make a diagnosis considering preservation of trigeminal nerve function. An inflammatory disease was suspected and close observation was undertaken. One month after surgery, the patient presented to the outpatient service with diplopia caused by
DISCUSSION/LITERATURE REVIEW
left abducens nerve palsy and aggravation of left facial numbness and pain. MRI revealed enlargement of the lesion with extension to the cavernous sinus and infratemporal fossa through the foramen ovale. He underwent resection of the trigeminal lesion via the
Figure 2. A, B: Intraoperative photograph showing the lateral suboccipital approach. The tumor (arrows) was soft, grayish, and hemorrhagic, and included the left trigeminal nerve (A). Second operative photograph showing the view of subtemporal approach. The tumor (arrows) in the Meckel’s cave had almost same properties as in the first operation (B). V: trigeminal nerve.
WORLD NEUROSURGERY 84 [2]: 592.e3-592.e7, AUGUST 2015
Primary CNS lymphoma accounts for 0.5%e 2.7% of all primary brain tumors. Its frequency is increasing due to the more common observation of immunocompromised patients; however, cranial nerve lymphomas are extremely rare except in the optic nerve (1, 2, 11). Only nine cases of malignant lymphoma arising from the trigeminal nerve have been described in the literature (1, 3, 4, 6-9, 11, 12) (Table 1). The patients were aged from 40 to 77 years old (mean 54.5 years), and 7 of the 10 patients (including our patient) were male. According to previous reports, primary CNS lymphoma patients showed a male-to-female ratio of approximately 3:2 with a mean age of 52 years (15). The initial symptom was facial pain in 8 of 10 patients. Preoperative MRI demonstrated homogeneous enhancement of the lesion after gadolinium administration in all patients. Although each case was unique, these lesions extended from the prepontine cistern to the infratemporal
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CASE REPORT TOSHIHIRO OGIWARA ET AL.
PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
Figure 3. A, B: Histopathological findings demonstrating diffuse large B cell lymphomas. H & E staining. Nuclei with atypia and mitosis were present (A). Many of the tumor cells were positive for CD20 (B). Flow cytometric analysis of CD20 expression in resected specimens. CD45 staining used to gate out hematopoietic cells; these cells are indicated as red dots. Tumor cells (red dots) are CD20-positive (C).
fossa. It was difficult to establish a diagnosis before surgery in all cases. The surgical approach included subtemporal, lateral suboccipital, pterional, and transsphenoidal approaches. Here, we report a case of primary malignant lymphoma of the trigeminal nerve in which diagnosis was
difficult and two surgeries were needed via two different approaches to establish the histopathological diagnosis. It is difficult to establish a correct diagnosis at the initial stage due to several reasons. First, malignant lymphoma of the trigeminal nerve is rare and no attention tends to be paid
Figure 4. A, B: MRI showing that the tumor disappeared and no recurrence was seen.
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for this possibility. In addition, there is no specific clinical evidence. There are several differential diagnoses of the trigeminal nerve and cavernous sinus lesions, including trigeminal neurinoma, meningioma, neurofibroma, and other inflammatory spaceoccupying lesions. The symptoms of malignant lymphoma of the trigeminal nerve include trigeminal neuralgia, facial hypesthesia, and diplopia. These symptoms are caused by trigeminal dysfunction and cavernous sinus syndrome, so the differential diagnosis from other trigeminal lesions is not possible on the basis of these symptoms (3). The preoperative diagnosis was considered neurinoma or neuritis in the present case. Iplikcioglu et al. reported that the most important sign for preoperative diagnosis of trigeminal lymphoma is the short duration of symptoms (6). This should be confirmed and may be a useful diagnostic marker, although it is not definitive. The results of all laboratory investigations were normal in the cases reported in the literature. MRI indicated that the trigeminal nerve at the prepontine cistern and Meckel cave was swollen with homogeneous enhancement involving the cavernous sinus. These radiological findings were similar to other trigeminal nerve lesions, including trigeminal neurinoma. Some cases of chronic granulomatous neuritis, idiopathic trigeminal neuropathy, and herpes trigeminal neuritis, which radiographically mimic trigeminal neurinoma, were reported (2, 5, 12, 14). It is especially difficult to distinguish malignant lymphoma of the trigeminal nerve from trigeminal neurinoma. The definitive diagnosis was not established before surgery in the present case. Malignant lymphoma in the trigeminal region can be classified into two patterns: primary and secondary (13). Malignant lymphoma can occur in the peripheral nerves. This is called neurolymphomatosis and typically does not invade the CNS from the cranial or peripheral nerve roots, which is an example of primary malignant lymphoma. Lymphoma cells infiltrate along anatomical structures in the case of neurolymphomatosis (10). On the other hand, malignant lymphoma can produce perineural infiltration to the trigeminal nerve, which is a metastatic malignant lymphoma invading the trigeminal nerve and is called secondary malignant lymphoma. In our case, the lesion initially occurred at
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.03.019
TOSHIHIRO OGIWARA ET AL.
WORLD NEUROSURGERY 84 [2]: 592.e3-592.e7, AUGUST 2015
Table 1. Summary of Malignant Lymphoma of the Trigeminal Nerve Authors
Age/ Sex
Symptoms
Preoperative Diagnosis
Location
Surgical Approach
Treatment
Clinical Outcome
Nakatomi (9) (1996)
77/M
Facial dysesthesia, diplopia
Lt. prepontine cistern—cavernous sinus Meningioma or Schwannoma
Lateral suboccipital
Radiation þ MTX þ PSL
Death
Abdel (1) (1999)
40/F
Facial pain, hypalgesia
Lt. Meckel cave—cavernous sinus
Schwannoma
Subtemporal
CHOP þ radiation
N.D.
Kinosita (8) (2003) 55/M
Facial pain, diplopia
Lt. Meckel cave—infratemporal fossa
N.D.
Lateral suboccipital
High-dose MTX þ radiation
Death
Facial pain
Lt. Meckel cave—foramen rotundum
N.D.
Subtemporal
Mass reduction
N.D.
50/M
Facial pain, diplopia
Rt. prepontine cistern—cavernous sinus
N.D.
Lateral suboccipital
High-dose MTX þ Ara-C þ radiation
C.R.
Akaza (3) (2009)
60/M
Facial pain
Lt. prepontine cistern—Meckel cave
Schwannoma or Sarcoidosis
(Biopsy from other lesion)
High-dose MTX þ radiation
C.R.
Tanaka (13) (2013) 52/M
Facial pain
Lt. prepontine cistern—Meckel cave
N.D.
Lateral suboccipital
CHASER þ radiation
C.R.
Perera (11) (2014) 55/F
Diplopia
Rt. cavernous sinus—pterygopalatine fossa
Meningioma
Transsphenoidal þ Pterional
N.D.
N.D.
Jack (7) (2014)
57/M
Facial pain
Lt. prepontine cistern—Meckel cave
N.D.
Lateral suboccipital
R-MPV
C.R.
Present case
47/M
Facial pain, diplopia
Lt. prepontine cistern—infratemporal fossa
Schwannoma or Neuritis
Lateral suboccipital, Subtemporal
MPVR þ radiation
C.R.
CASE REPORT
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Bulsara (4) (2005) 52/F Iplikcioglu (6) (2006)
CASE REPORT TOSHIHIRO OGIWARA ET AL.
the cisternal portion of the trigeminal nerve and extended to the cavernous sinus and infratemporal fossa along the trigeminal nerve. Although the progression of the lesion was fast, there was neither invasion of the brainstem nor mass effect. Furthermore, systemic lymphoma was denied by positron emission tomography, whole CT, laboratory, and CSF tests. It was suggested that primary malignant lymphoma of the trigeminal nerve was neurolymphomatosis. According to the standard treatment guidelines, primary CNS lymphoma should be treated with high-dose methotrexate combined with radiation therapy. Despite their use over the past decade, the prognosis for patients with primary CNS lymphoma remains poor with a mean overall survival of 15e45 months, even after extensive chemotherapy and radiation (13). In fact, several patients with malignant lymphoma of the trigeminal nerve did not live long even after radiation and chemotherapy (8, 9). Longterm survival is extremely rare in patients with primary CNS lymphoma. In the present case, whole-brain radiation therapy after administration of MPVR therapy appeared to have a remarkable effect. Therefore early diagnosis is important to obtain a cure. As mentioned earlier, preoperative neuroimaging alone cannot distinguish primary malignant lymphoma of the trigeminal nerve from other diseases in early stage. Therefore biopsy is necessary to confirm the diagnosis. Although open biopsy is essential, it is not easy to approach lesions of the trigeminal nerve or the cavernous sinus. There are two familiar surgical approaches to these lesions (i.e., the lateral suboccipital approach and subtemporal approach), which are determined on the basis of the location and extension of the lesion or surgeon’s preference. In addition, the transsphenoidal approach, pterional approach, and percutaneous approach may also be considered, as in the present case in which the lesion extended to the cavernous sinus (7, 11). In the present case, because preservation of trigeminal function was given priority at the first surgery via the lateral suboccipital approach, an adequate specimen volume could not be obtained and a definite diagnosis was not provided. The subtemporal approach was applied at the second surgery
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PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
in which an adequate specimen volume was obtained. It is important to select the operative approach for trigeminal nerve lesion considering functional preservation, operative difficulty, preference of each surgeon, and quantity of specimen to be taken. Usually, the patient and doctor hesitate in deciding on reoperation and empirical radiotherapy for the lesions in this region is considered because of surgical invasiveness and the risk of morbidity. To exclude extremely rare malignant lymphoma, there is a choice not to operate on for this trigeminal nerve lesion (3). Nevertheless, biopsy was essential in this case and flow cytometric analysis was especially useful for confirmation of malignant lymphoma, because an appropriate radiotherapy regimen could not be ascertained without establishing the histopathological diagnosis. Furthermore, the initial empirical radiotherapy can result in later biopsies being nondiagnostic (11). CONCLUSIONS We reported a rare clinical presentation of malignant lymphoma of the trigeminal nerve. It is difficult to establish a correct diagnosis without biopsy in the initial stage of trigeminal nerve lesions. The possibility of lymphoma should be considered when diagnosing neurinoma or neuritis radiologically, and it is important to diagnose and treat it rapidly. A biopsy via the most suitable approach should be performed. It is important to avoid misdiagnosis or delayed diagnosis of primary malignant lymphoma of the trigeminal nerve. REFERENCES 1. Abdel Aziz KM, van Loveren HR: Primary lymphoma of Meckel’s cave mimicking trigeminal schwannoma: case report. Neurosurgery 44: 859-863, 1999. 2. Ahn JY, Kwon SO, Shin MS, Joo JY, Kim TS: Chronic granulomatous neuritis in idiopathic trigeminal sensory neuropathy. Report of two cases. J Neurosurg 96:585-588, 2002. 3. Akaza M, Tsunemi T, Sanjo N, Wakimoto H, Kobayashi D, Mizusawa H: Malignant lymphoma presented as left trigeminal neuralgia. Clin Neurol 49:432-436, 2009.
5. Domínguez J, Lobato RD, Madero S, BenitoLeón J, Rivas JJ, Gómez PA: Surgical findings in idiopathic trigeminal neuropathy mimicking a trigeminal neurinoma. Acta Neurochir (Wien) 141: 269-272, 1999. 6. Iplikcioglu AC, Dinc C, Bikmaz K, Ozcan D: Primary lymphoma of the trigeminal nerve. Br J Neurosurg 20:103-105, 2006. 7. Jack AS, McDougall CM, Findlay JM: Primary lymphoma isolated to the trigeminal nerve. Can J Neurol Sci 41:103-105, 2014. 8. Kinoshita M, Izumoto S, Oshino S, Nonaka M, Moriuchi S, Maruno M, Yoshimine T: Primary malignant lymphoma of the trigeminal region treated with rapid infusion of high-dose MTX and radiation: case report and review of the literature. Surg Neurol 60:343-348, 2003. 9. Nakatomi H, Sasaki T, Kawamoto S, Fujimaki T, Furuya K, Kirino T: Primary cavernous sinus malignant lymphoma treated by gamma knife radiosurgery: case report and review of the literature. Surg Neurol 46:272-279, 1996. 10. Oya Y: Lymphoma in the peripheral nerves and muscles. Brain Nerve 66:955-967, 2014. 11. Perera C, Fitt G, Kalnins R, Lee S, Gonzalvo A: Lymphoma of the trigeminal nerve—the need for histological diagnosis. Br J Neurosurg 28:278-280, 2014. 12. Savas A, Deda H, Erden E, Kanpolat Y: Differential diagnosis of idiopathic inflammatory trigeminal sensory neuropathy from neuroma with a biopsy: case report. Neurosurgery 45: 1246-1250, 1999. 13. Tanaka T, Kato N, Itoh K, Hasegawa Y: Long-term survival of diffuse large B cell lymphoma of the trigeminal region extending to the Meckel’s cave treated by CHASER therapy: case report. Neurol Med Chir (Tokyo) 54:677-680, 2014. 14. Tien RD, Dillon WP: Herpes trigeminal neuritis and rhombencephalitis on Gd-DTPA-enhanced MR imaging. AJNR Am J Neuroradiol 11:413-414, 1990. 15. Tsutsumi K, Horiuchi T, Uehara T, Aoyama T, Hongo K: Isolated primary malignant lymphoma developing from the optic chiasma. Case report. J Clin Neurosci 20:1783-1786, 2013.
Conflict of interest statement: The authors have no personal financial or institutional interests in any of the drugs, materials, or devices discussed in the article. All authors who are members of The Japan Neurosurgical Society (JNS) have registered online Self-reported COI Disclosure Statement Forms through the website for JNS members. Received 23 January 2015; accepted 11 March 2015 Citation: World Neurosurg. (2015) 84, 2:592.e3-592.e7. http://dx.doi.org/10.1016/j.wneu.2015.03.019 Journal homepage: www.WORLDNEUROSURGERY.org
4. Bulsara KR, Kadri PA, Husain M, Al-Mefty O: Malignant lymphoma of the trigeminal region. Case illustration. J Neurooncol 73:279-280, 2005.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
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Primary Malignant Lymphoma of the Trigeminal Nerve: Case Report and Literature Review Toshihiro Ogiwara1, Tetsuyoshi Horiuchi1, Nodoka Sekiguchi2, Yukinari Kakizawa1, Kazuhiro Hongo1
Key words Malignant lymphoma - Open biopsy - Surgical approach - Trigeminal nerve
- BACKGROUND:
Abbreviations and Acronyms CNS: Central nervous system MPVR: Methotrexate, procarbazine, vincristine, and ranimustine MRI: Magnetic resonance imaging PCR: Polymerase chain reaction
- CASE
-
From the 1Department of Neurosurgery and 2Division of Comprehensive Cancer Center, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan To whom correspondence should be addressed: Tetsuyoshi Horiuchi, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 84, 2:592.e3-592.e7. http://dx.doi.org/10.1016/j.wneu.2015.03.019 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
Primary lymphoma of the central nervous system (CNS) usually arises from the brain parenchyma, particularly the white matter (1, 2, 11). Primary lymphomas of the cranial nerves are extremely rare except for optic nerve lymphoma (14). Only nine cases of lymphoma arising from the trigeminal nerve have been reported to date (1, 3, 4, 6-9, 11, 12). In most of these cases, it was difficult to distinguish from other diseases by neuroimaging and the treatment was apprehensive because its aggravation is rapid. Here, we report a rare clinical presentation of malignant lymphoma arising from the trigeminal nerve in which it took a long time to confirm the diagnosis and two open biopsies were obtained via the lateral suboccipital and subtemporal approaches.
CASE REPORT The patient was a 47-year-old man, suffering from Crohn disease for 2 years, with a 2-
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Primary lymphomas of the cranial nerves are extremely rare except for optic nerve lymphoma, and it is difficult to make a correct diagnosis in the initial stage. Here, we report a case of primary malignant lymphoma of the left trigeminal nerve that presented as trigeminal nerve disorder. DESCRIPTION: A 47-year-old man presented with aggravating left facial pain and hypesthesia within all three divisions of the trigeminal nerve. Magnetic resonance imaging (MRI) revealed a swollen left trigeminal nerve with gadolinium homogenous enhancement. An open biopsy had to be taken from two different locations of the tumor via the lateral suboccipital approach followed by subtemporal approach because adequate specimen volume was not obtained for definitive diagnosis at the first surgery. Histopathological examinations with flow cytometric analysis revealed diffuse large B cell lymphoma. Chemotherapy followed by whole-brain radiation therapy was effective. No recurrence was observed during a 15-month follow-up period.
- CONCLUSIONS:
This is a rare clinical presentation of malignant lymphoma of the trigeminal nerve. It is difficult to establish a correct diagnosis of trigeminal nerve lesions during the initial stages without biopsy. Therefore it is important that a sufficient specimen should be taken for biopsy without hesitation in order to diagnose and treat rapidly. The most suitable operative approach must be selected in trigeminal nerve lesions considering functional preservation, operative difficulty, preference of each surgeon, and quantity of specimen to be removed.
month history of progressive left facial pain and numbness. These symptoms initially developed from V3 territory and spread to all three divisions of the trigeminal nerve. Physical examination revealed left facial hypesthesia, left facial spasmodic prickly pain mimicking trigeminal neuralgia, diminished corneal reflex, disturbance of jaw movement, and wasting of the masseter muscle. Tumor markers including soluble interleukin-2 receptor and other laboratory studies were within the normal limits. The cell count from cerebrospinal fluid (CSF) was 3/mL (mono: 3), and twice the cytology of CSF confirmed no malignant cells. There was no evidence of immune deficiency. Magnetic resonance imaging (MRI) indicated that the left trigeminal nerve at its cisternal portion, as well as at the Meckel cave, was swollen and homogeneously enhanced (Figure 1). Dural tail sign was not present. There was neither invasion
of brainstem nor mass effect. Computed tomography (CT) scan revealed no evidence of bony erosion or hyperostosis. The patient underwent an operation via the lateral suboccipital approach for histopathological confirmation. Intraoperatively, the trigeminal nerve was swollen and a grayish, soft, hemorrhagic granulomatous lesion surrounding the trigeminal nerve was observed (Figure 2A). A biopsy was taken from this lesion without injuring the trigeminal nerve. The patient was woken up immediately after surgery without new neurological deficits. Histopathological examination revealed numerous small cells with large nuclei-like lymphocytes; however, histopathological examination was eventually not able to establish a definitive diagnosis because polymerase chain reaction (PCR) did not confirm monoclonality as the specimen was not sufficiently large to
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.03.019
CASE REPORT TOSHIHIRO OGIWARA ET AL.
PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
subtemporal approach based on the previous operative findings. The lesion infiltrating into the subdural space of the middle fossa was removed. The tumor had the same features as in the previous surgery and was partially removed in the Meckel cave (Figure 2). He tolerated the procedure well. The specimen was studied using H & E staining and was examined by light microscopy. The tumor was highly cellular with mitotic figures and diffusely infiltrative. Immunoperoxidase studies revealed neoplastic cells to be positive for CD20 and MUM1 and negative for CD10 and bcl-6. The Ki-67 staining index was 73%. Flow cytometric analysis of CD20 expression in the resected specimen of the patient confirmed that tumor cells were CD20 positive (Figure 3C). Finally, histopathological examinations revealed diffuse large B cell lymphomas, nongerminal center B type (Figure 3A, B). Whole-brain radiation therapy (45 Gy) after administration of methotrexate, procarbazine, vincristine, and ranimustine (MPVR) therapy appeared to have remarkable effects. Although left facial hypesthesia and pain remained slightly, the patient’s clinical course was uneventful and he did not experience recurrence over a 1-year follow-up period (Figure 4).
Figure 1. AeD: Preoperative magnetic resonance imaging (MRI) showing swelling of the left trigeminal nerve (A) and heterogeneously enhancing tumor with gadolinium extending along the left cavernous sinus and infratemporal fossa extending into the foramen ovale (BeD).
make a diagnosis considering preservation of trigeminal nerve function. An inflammatory disease was suspected and close observation was undertaken. One month after surgery, the patient presented to the outpatient service with diplopia caused by
DISCUSSION/LITERATURE REVIEW
left abducens nerve palsy and aggravation of left facial numbness and pain. MRI revealed enlargement of the lesion with extension to the cavernous sinus and infratemporal fossa through the foramen ovale. He underwent resection of the trigeminal lesion via the
Figure 2. A, B: Intraoperative photograph showing the lateral suboccipital approach. The tumor (arrows) was soft, grayish, and hemorrhagic, and included the left trigeminal nerve (A). Second operative photograph showing the view of subtemporal approach. The tumor (arrows) in the Meckel’s cave had almost same properties as in the first operation (B). V: trigeminal nerve.
WORLD NEUROSURGERY 84 [2]: 592.e3-592.e7, AUGUST 2015
Primary CNS lymphoma accounts for 0.5%e 2.7% of all primary brain tumors. Its frequency is increasing due to the more common observation of immunocompromised patients; however, cranial nerve lymphomas are extremely rare except in the optic nerve (1, 2, 11). Only nine cases of malignant lymphoma arising from the trigeminal nerve have been described in the literature (1, 3, 4, 6-9, 11, 12) (Table 1). The patients were aged from 40 to 77 years old (mean 54.5 years), and 7 of the 10 patients (including our patient) were male. According to previous reports, primary CNS lymphoma patients showed a male-to-female ratio of approximately 3:2 with a mean age of 52 years (15). The initial symptom was facial pain in 8 of 10 patients. Preoperative MRI demonstrated homogeneous enhancement of the lesion after gadolinium administration in all patients. Although each case was unique, these lesions extended from the prepontine cistern to the infratemporal
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CASE REPORT TOSHIHIRO OGIWARA ET AL.
PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
Figure 3. A, B: Histopathological findings demonstrating diffuse large B cell lymphomas. H & E staining. Nuclei with atypia and mitosis were present (A). Many of the tumor cells were positive for CD20 (B). Flow cytometric analysis of CD20 expression in resected specimens. CD45 staining used to gate out hematopoietic cells; these cells are indicated as red dots. Tumor cells (red dots) are CD20-positive (C).
fossa. It was difficult to establish a diagnosis before surgery in all cases. The surgical approach included subtemporal, lateral suboccipital, pterional, and transsphenoidal approaches. Here, we report a case of primary malignant lymphoma of the trigeminal nerve in which diagnosis was
difficult and two surgeries were needed via two different approaches to establish the histopathological diagnosis. It is difficult to establish a correct diagnosis at the initial stage due to several reasons. First, malignant lymphoma of the trigeminal nerve is rare and no attention tends to be paid
Figure 4. A, B: MRI showing that the tumor disappeared and no recurrence was seen.
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for this possibility. In addition, there is no specific clinical evidence. There are several differential diagnoses of the trigeminal nerve and cavernous sinus lesions, including trigeminal neurinoma, meningioma, neurofibroma, and other inflammatory spaceoccupying lesions. The symptoms of malignant lymphoma of the trigeminal nerve include trigeminal neuralgia, facial hypesthesia, and diplopia. These symptoms are caused by trigeminal dysfunction and cavernous sinus syndrome, so the differential diagnosis from other trigeminal lesions is not possible on the basis of these symptoms (3). The preoperative diagnosis was considered neurinoma or neuritis in the present case. Iplikcioglu et al. reported that the most important sign for preoperative diagnosis of trigeminal lymphoma is the short duration of symptoms (6). This should be confirmed and may be a useful diagnostic marker, although it is not definitive. The results of all laboratory investigations were normal in the cases reported in the literature. MRI indicated that the trigeminal nerve at the prepontine cistern and Meckel cave was swollen with homogeneous enhancement involving the cavernous sinus. These radiological findings were similar to other trigeminal nerve lesions, including trigeminal neurinoma. Some cases of chronic granulomatous neuritis, idiopathic trigeminal neuropathy, and herpes trigeminal neuritis, which radiographically mimic trigeminal neurinoma, were reported (2, 5, 12, 14). It is especially difficult to distinguish malignant lymphoma of the trigeminal nerve from trigeminal neurinoma. The definitive diagnosis was not established before surgery in the present case. Malignant lymphoma in the trigeminal region can be classified into two patterns: primary and secondary (13). Malignant lymphoma can occur in the peripheral nerves. This is called neurolymphomatosis and typically does not invade the CNS from the cranial or peripheral nerve roots, which is an example of primary malignant lymphoma. Lymphoma cells infiltrate along anatomical structures in the case of neurolymphomatosis (10). On the other hand, malignant lymphoma can produce perineural infiltration to the trigeminal nerve, which is a metastatic malignant lymphoma invading the trigeminal nerve and is called secondary malignant lymphoma. In our case, the lesion initially occurred at
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.03.019
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Table 1. Summary of Malignant Lymphoma of the Trigeminal Nerve Authors
Age/ Sex
Symptoms
Preoperative Diagnosis
Location
Surgical Approach
Treatment
Clinical Outcome
Nakatomi (9) (1996)
77/M
Facial dysesthesia, diplopia
Lt. prepontine cistern—cavernous sinus Meningioma or Schwannoma
Lateral suboccipital
Radiation þ MTX þ PSL
Death
Abdel (1) (1999)
40/F
Facial pain, hypalgesia
Lt. Meckel cave—cavernous sinus
Schwannoma
Subtemporal
CHOP þ radiation
N.D.
Kinosita (8) (2003) 55/M
Facial pain, diplopia
Lt. Meckel cave—infratemporal fossa
N.D.
Lateral suboccipital
High-dose MTX þ radiation
Death
Facial pain
Lt. Meckel cave—foramen rotundum
N.D.
Subtemporal
Mass reduction
N.D.
50/M
Facial pain, diplopia
Rt. prepontine cistern—cavernous sinus
N.D.
Lateral suboccipital
High-dose MTX þ Ara-C þ radiation
C.R.
Akaza (3) (2009)
60/M
Facial pain
Lt. prepontine cistern—Meckel cave
Schwannoma or Sarcoidosis
(Biopsy from other lesion)
High-dose MTX þ radiation
C.R.
Tanaka (13) (2013) 52/M
Facial pain
Lt. prepontine cistern—Meckel cave
N.D.
Lateral suboccipital
CHASER þ radiation
C.R.
Perera (11) (2014) 55/F
Diplopia
Rt. cavernous sinus—pterygopalatine fossa
Meningioma
Transsphenoidal þ Pterional
N.D.
N.D.
Jack (7) (2014)
57/M
Facial pain
Lt. prepontine cistern—Meckel cave
N.D.
Lateral suboccipital
R-MPV
C.R.
Present case
47/M
Facial pain, diplopia
Lt. prepontine cistern—infratemporal fossa
Schwannoma or Neuritis
Lateral suboccipital, Subtemporal
MPVR þ radiation
C.R.
CASE REPORT
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PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
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Bulsara (4) (2005) 52/F Iplikcioglu (6) (2006)
CASE REPORT TOSHIHIRO OGIWARA ET AL.
the cisternal portion of the trigeminal nerve and extended to the cavernous sinus and infratemporal fossa along the trigeminal nerve. Although the progression of the lesion was fast, there was neither invasion of the brainstem nor mass effect. Furthermore, systemic lymphoma was denied by positron emission tomography, whole CT, laboratory, and CSF tests. It was suggested that primary malignant lymphoma of the trigeminal nerve was neurolymphomatosis. According to the standard treatment guidelines, primary CNS lymphoma should be treated with high-dose methotrexate combined with radiation therapy. Despite their use over the past decade, the prognosis for patients with primary CNS lymphoma remains poor with a mean overall survival of 15e45 months, even after extensive chemotherapy and radiation (13). In fact, several patients with malignant lymphoma of the trigeminal nerve did not live long even after radiation and chemotherapy (8, 9). Longterm survival is extremely rare in patients with primary CNS lymphoma. In the present case, whole-brain radiation therapy after administration of MPVR therapy appeared to have a remarkable effect. Therefore early diagnosis is important to obtain a cure. As mentioned earlier, preoperative neuroimaging alone cannot distinguish primary malignant lymphoma of the trigeminal nerve from other diseases in early stage. Therefore biopsy is necessary to confirm the diagnosis. Although open biopsy is essential, it is not easy to approach lesions of the trigeminal nerve or the cavernous sinus. There are two familiar surgical approaches to these lesions (i.e., the lateral suboccipital approach and subtemporal approach), which are determined on the basis of the location and extension of the lesion or surgeon’s preference. In addition, the transsphenoidal approach, pterional approach, and percutaneous approach may also be considered, as in the present case in which the lesion extended to the cavernous sinus (7, 11). In the present case, because preservation of trigeminal function was given priority at the first surgery via the lateral suboccipital approach, an adequate specimen volume could not be obtained and a definite diagnosis was not provided. The subtemporal approach was applied at the second surgery
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PRIMARY MALIGNANT LYMPHOMA OF THE TRIGEMINAL NERVE
in which an adequate specimen volume was obtained. It is important to select the operative approach for trigeminal nerve lesion considering functional preservation, operative difficulty, preference of each surgeon, and quantity of specimen to be taken. Usually, the patient and doctor hesitate in deciding on reoperation and empirical radiotherapy for the lesions in this region is considered because of surgical invasiveness and the risk of morbidity. To exclude extremely rare malignant lymphoma, there is a choice not to operate on for this trigeminal nerve lesion (3). Nevertheless, biopsy was essential in this case and flow cytometric analysis was especially useful for confirmation of malignant lymphoma, because an appropriate radiotherapy regimen could not be ascertained without establishing the histopathological diagnosis. Furthermore, the initial empirical radiotherapy can result in later biopsies being nondiagnostic (11). CONCLUSIONS We reported a rare clinical presentation of malignant lymphoma of the trigeminal nerve. It is difficult to establish a correct diagnosis without biopsy in the initial stage of trigeminal nerve lesions. The possibility of lymphoma should be considered when diagnosing neurinoma or neuritis radiologically, and it is important to diagnose and treat it rapidly. A biopsy via the most suitable approach should be performed. It is important to avoid misdiagnosis or delayed diagnosis of primary malignant lymphoma of the trigeminal nerve. REFERENCES 1. Abdel Aziz KM, van Loveren HR: Primary lymphoma of Meckel’s cave mimicking trigeminal schwannoma: case report. Neurosurgery 44: 859-863, 1999. 2. Ahn JY, Kwon SO, Shin MS, Joo JY, Kim TS: Chronic granulomatous neuritis in idiopathic trigeminal sensory neuropathy. Report of two cases. J Neurosurg 96:585-588, 2002. 3. Akaza M, Tsunemi T, Sanjo N, Wakimoto H, Kobayashi D, Mizusawa H: Malignant lymphoma presented as left trigeminal neuralgia. Clin Neurol 49:432-436, 2009.
5. Domínguez J, Lobato RD, Madero S, BenitoLeón J, Rivas JJ, Gómez PA: Surgical findings in idiopathic trigeminal neuropathy mimicking a trigeminal neurinoma. Acta Neurochir (Wien) 141: 269-272, 1999. 6. Iplikcioglu AC, Dinc C, Bikmaz K, Ozcan D: Primary lymphoma of the trigeminal nerve. Br J Neurosurg 20:103-105, 2006. 7. Jack AS, McDougall CM, Findlay JM: Primary lymphoma isolated to the trigeminal nerve. Can J Neurol Sci 41:103-105, 2014. 8. Kinoshita M, Izumoto S, Oshino S, Nonaka M, Moriuchi S, Maruno M, Yoshimine T: Primary malignant lymphoma of the trigeminal region treated with rapid infusion of high-dose MTX and radiation: case report and review of the literature. Surg Neurol 60:343-348, 2003. 9. Nakatomi H, Sasaki T, Kawamoto S, Fujimaki T, Furuya K, Kirino T: Primary cavernous sinus malignant lymphoma treated by gamma knife radiosurgery: case report and review of the literature. Surg Neurol 46:272-279, 1996. 10. Oya Y: Lymphoma in the peripheral nerves and muscles. Brain Nerve 66:955-967, 2014. 11. Perera C, Fitt G, Kalnins R, Lee S, Gonzalvo A: Lymphoma of the trigeminal nerve—the need for histological diagnosis. Br J Neurosurg 28:278-280, 2014. 12. Savas A, Deda H, Erden E, Kanpolat Y: Differential diagnosis of idiopathic inflammatory trigeminal sensory neuropathy from neuroma with a biopsy: case report. Neurosurgery 45: 1246-1250, 1999. 13. Tanaka T, Kato N, Itoh K, Hasegawa Y: Long-term survival of diffuse large B cell lymphoma of the trigeminal region extending to the Meckel’s cave treated by CHASER therapy: case report. Neurol Med Chir (Tokyo) 54:677-680, 2014. 14. Tien RD, Dillon WP: Herpes trigeminal neuritis and rhombencephalitis on Gd-DTPA-enhanced MR imaging. AJNR Am J Neuroradiol 11:413-414, 1990. 15. Tsutsumi K, Horiuchi T, Uehara T, Aoyama T, Hongo K: Isolated primary malignant lymphoma developing from the optic chiasma. Case report. J Clin Neurosci 20:1783-1786, 2013.
Conflict of interest statement: The authors have no personal financial or institutional interests in any of the drugs, materials, or devices discussed in the article. All authors who are members of The Japan Neurosurgical Society (JNS) have registered online Self-reported COI Disclosure Statement Forms through the website for JNS members. Received 23 January 2015; accepted 11 March 2015 Citation: World Neurosurg. (2015) 84, 2:592.e3-592.e7. http://dx.doi.org/10.1016/j.wneu.2015.03.019 Journal homepage: www.WORLDNEUROSURGERY.org
4. Bulsara KR, Kadri PA, Husain M, Al-Mefty O: Malignant lymphoma of the trigeminal region. Case illustration. J Neurooncol 73:279-280, 2005.
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