Primary central nervous system Hodgkin’s lymphoma – A case report and review of literature

INTRODUCTION

Hodgkin’s lymphoma (HL) commonly affects the lymph nodes. Central nervous system (CNS) lymphoma can present either as secondary CNS involvement by systemic lymphoma which is more common or rarely as primary CNS lymphoma which is restricted to the brain, leptomeninges, spinal cord, or eyes.^[1-4] CNS involvement in HL is shown to occur in <0.2–0.5% of HL patients when compared to 5–30% CNS involvement in NHL patients.^[5,6] Primary CNS lymphoma of CNS is NHL and is usually secondary to an immunocompromised state and HL has secondary CNS involvement usually in the leptomeninges. Primary CNS involvement is extremely rare and only about 26 cases have been reported so far. Due to its rarity, the exact pathogenesis, its relation to the immune status of the patient, the exact role of Epstein-Barr Virus, its activation of regulator T (T_reg) cells, and the role of programmed cell death ligand (PD-L) 1 in the genesis of primary CNS HL are yet to be investigated fully.

CASE REPORT

A 76-year-old male presented to the Department of Neurosurgery with behavioral change, speech disturbance, with weakness of the right upper and lower limbs for two weeks. The patient was conscious, disoriented, and confused and responded slowly to commands. He had right hemiparesis with Grade 3 power. He had no lymphadenopathy or hepatosplenomegaly. He was not immunocompromised magnetic resonance imaging Brain showed evidence of an irregular heterogeneous contrast-enhancing lesion in the left frontal lobe with surrounding edema and massive midline shift. The features were suggestive of high-grade glioma [Figure 1]. The patient underwent craniotomy and complete excision of the left frontal lobe mass lesion. Intraoperatively, the tumor was well defined with firm margins, moderate vascularity with a good plane of cleavage from the surrounding brain and could be excised en masse. The squash smears showed predominantly histiocytes with emperipolesis. The background showed numerous lymphocytes, histiocytes, occasional neutrophils, and atypical large cells. Scattered glial and neuronal cells are also shown [Figure 2]. Differential diagnosis of Rosai– Dorfman disease, histiocytic neoplasms, lymphoma, and melanoma were considered. Histopathological examination (hematoxylin and eosin-stained sections) showed brain tissue with an infiltrating tumor composed of scattered large cells showing large vesicular nuclei, prominent eosinophilic nucleoli resembling mononuclear Hodgkin’s cells, Reed Sternberg (RS) cells, and popcorn cells [Figure 3]. Atypical mitosis was noted with 7–10 mitotic figures per 10 high-powered fields. Other cells include lymphocytes and histiocytes with active phagocytosis. Large areas of necrosis and broad bands of fibrosis were seen. Immunohistochemical staining CD 45 was positive in all the hematopoietic cells and negative in the large tumor cells. The large cells expressed CD 15, CD30, nuclear positivity of PAX-5, and membranous positivity of CD79a. Ki-67 was 70%. GFAP, PAN CK, and HMB 45 were negative in the tumor cells [Figure 4]. Whole-body positron emission tomography (PET) computed tomography did not reveal any extra-cranial Hodgkin’s disease. Hence, this is a case of primary CNS HL in the left frontal lobe. Postoperatively, the patient made an uneventful recovery. Speech, power, right upper and lower limbs, and behavioral disturbance improved during the postoperative period. The patient was referred for further oncological treatment. The patient had improved completely at the review at two months.

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Figure 1:

MRI Brain (T1 contrast) showing irregular contrast enhancing mass lesion in the left frontal lobe with mass effect.

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Figure 2:

Squash smears predominantly showing histiocytes with emperipolesis, H&E, 40X. H&E: Hematoxylin and eosin.

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Figure 3:

Histopathological images of Hodgkin’s lymphoma with Reed-Sternberg cells, H&E, 40X. H&E: Hematoxylin and eosin.

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Figure 4:

(a) CD45 - Positive in all the hematopoietic elements, (b) CD15 - Cytoplasmic and membranous positivity of large cells, (c) CD30-Cytoplasmic and membranous positivity of large cells, (d) CD79a- Membranous positivity of large cells, (e) PAX-5- Weak nuclear positivity of large cells, (f) Ki-67: 70%, (g) HMB – 45: Negative in the tumor cells, (h) GFAP: Negative in the tumor cells, (i) Pan CK: Negative in the tumor cells, (j) EBV: Negative in the tumor cells.

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DISCUSSION

Classical HL is primarily affecting the lymph nodes and CNS involvement is rare with HL, accounting for 0.2–0.5% of all cases.^[5] The incidence of HL in CNS remains exceedingly rare in the literature with only 26 cases reported so far. The first 22 cases have been summarized by Cecyn et al. and five more cases (including the present case) have been added since then [Table 1].^[7-11] There have been 18 males and nine females, showing a male preponderance. In 17 cases, the lesion was in the supratentorial compartment and the rest in the posterior cranial fossa. In four patients, the lesion was dura-based mimicking a meningioma. Twenty-two patients had normal immunological status and only five had some form of immune deficiency. The most common histological type has been reported as “Classical HL – not otherwise specified” (11 cases), followed by nodular sclerosis type (seven cases) and mixed cellularity (seven cases). The Epstein-Barr virus (EBV) status has been investigated only in 13 patients, and 10 patients have been reported positive for EBV. There has been no consensus on adjuvant therapy after surgery, with varying radiotherapy and/or chemotherapy regimens. The longest reported disease-free survival has been 10 years.

The primary CNS-HL is exceedingly rare and it is of interest to note that primary CNS-HL has not been included in the primary CNS (hematolymphoid tumors) lymphomas in the latest WHO Classification of tumors of the CNS (5^th Edition). Immune compromised state, if present, may contribute to the development of primary CNS HL, though in the available literature, the majority of the patients had no evidence of immune deficiency. There has been male sex preponderance in the literature. The role of EBV has been of interest of late. The presence of EBV in the RS cells seems to correlate with the increased T_reg cells and may contribute to the development of this tumor.^[9] However, further research is needed in this regard. This may lead to better modalities of treatment, like targeting the Treg cells. About 82% of patients with classical HL have PD-L on the surface of tumor cells and EBV infection seems to increase the expression of PD-L on the RS cells.^[9] It is of interest to note that anti-programmed cell death protein antibodies (anti-PD 1) have been used in the treatment of refractory HL. In the future anti-PD 1 antibody, like sintilimab, may form the first-line drug treatment in HL due to its relative safety compared to the potentially toxic first-line drugs used at present.

The present patient was a 76-year-old non-immunocompromised man presented with features of a rapidly growing malignant neoplasm in the left frontal lobe with imaging features suggestive of a high-grade parenchymal tumor possibly glioma. The histopathology and immunohistochemistry clinched the diagnosis of HL. We could not do the EBV DNA testing and PD-L staining which could have been very useful. The whole body PET did not reveal any focus elsewhere in the body. Hence, this is a rare case of primary CNS-HL.

CONCLUSION

Primary CNS-HL should be kept in the differential diagnosis of intracranial malignant tumours, especially in old men, with immunocompromised state. EBV-DNA testing and PD-L staining should be performed in all cases of suspected HL to establish the diagnosis and this will also help in planning adjuvant chemotherapy.