Amah of Oncology 7: 1071-1075, 1996. © 1996 Kluwer Academic Publishers. Printed in the Netherlands.

Clinical case Meningeal localization in a patient with Hodgkin's disease. Description of a case and review of the literature A. P. Anselmo,1 A. Proia,1 C. Cartoni,1 C. D. Baroni,2 R. Maurizi Enrici,3 R. Delfini4 & G. Awisati l 1

Hematology, Department of Human Biopathology, 2Department of Experimental Medicine, Neurological Sciences, University 'La Sapienza', Rome, Italy

Summary

We report the case of a 21-year-old man in whom intracranial localization was discovered during initial staging at the onset of Hodgkin's disease (HD). The patient was treated by surgical excision, irradiation and chemotherapy and 50

Case report

In May 1990, a 21-year-old Caucasian male was admitted to the Division of Haematology at 'La Sapienza' University in Rome because of a right infraclavicular lymphadenopathy. After biopsy, HD of mixed cellularity was diagnosed. No systemic symptoms were present and traditional staging showed localization of the disease to the mediastinum, retroperitoneal lymph nodes and spleen. A bone marrow biopsy was negative. His blood count and chemistry were normal, an ESR was 52 and serum antibodies for HTV and HBV were negative. Bone scintiscan, routinely carried out, showed an increase of radionucleotide compound in the left fronto-parietal area of the skull (Figure 1). Computerized tomography (CT) of the brain, performed just after the bone scintiscan, defined a large circumscribed mass in the convexity of the fronto-parietal region with compression of the lateral ventrical (Figure 2). This extracerebral mass, showing high 'enhancement' after gadolinium (thecal hyperostosis), was further confirmed by magnetic resonance imaging (MRI) of the brain (Figure 3). Despite the presence of the intracranial mass, the patient had no neurologic symptoms and the result of a clinical neurological examination was negative. Following demonstration of the intracranial mass, in June 1990 the patient underwent surgical staging, with biopsy of an intracranial tumor mass which measured 12 x 4 cm (Figure 4), which was pressing upon the left and right pre-rolandic site without bone infiltration. The entire tumor was radically removed with complete

3

Institute of Radiology, 4 Department of

months after completion of therapy is in remission with no evidence of HD. A brief review of the literature regarding 48 patients with intracranial Hodgkin's disease is presented. Key words: chemotherapy, Hodgkin's disease, meningeal lymphoma, radiotherapy

plastic reconstruction of the dura mater, and metal clips were positioned to facilitate radiotherapeutic treatment. Fragments of the biopsed tissue were formalin-fixed and paraffin-embedded; sections were stained with hematoxylin and eosin as well as with Giemsa, revealing the presence of numerous classic Reed-Sternberg and Hodgkin's cells intermingled with other cells including small lymphocytes, histiocytic cells, polymorph neutrophils, eosinophils and plasma cells; therefore, a diagnosis of HD mixed cellularity was made. Immunohistochemical staining was performed on formalinfixed paraffin-embedded sections. The monoclonal antibodies (MoAb) used were: BerH2 (CD30), L26 (CD20), UCHL1 (CD45RO), LeuMl(CD15). Antigen expression was determined by a three-step avidinbiotin immunoperoxidase method. Reed-Sternberg and Hodgkin's cells were CD30- and CD15-positive, while the majority of small lymphocytes were T-lymphocyte-positive for CD45RO MoAb. B-lymphocytes positive for CD20 MoAb were observed either scattered as single cells or grouped in small clusters. Immediately after the diagnosis of HD and completion of the staging procedures the first of eight courses of a MOPP-ABVD-like regimen, called OPP-ABVD [1], was given, followed by extended field (mantle plus inverted Y) irradiation of 20 Gy, and spleen and brain irradiation of 36 Gy and 14.4 Gy. The patient achieved complete remission eight months after the start of the therapeutic program and 50 months after completion of this treatment he is in remission with no evidence of HD.

1072 ing) included: 'HODGKfN'S DISEASE', 'BRAIN', 'SPINAL CORD', 'INTRACRANIAL INVOLVEMENT, 'CENTRAL NERVOUS SYSTEM INVOLVEMENT. General issues

From the data in the literature it is clear that neurological manifestations in HD are rare, with an overall reported incidence of 0.2%-0.6% [2, 3-7]. They are mainly due to direct tumor involvement, but occasionally remote tumor effects in the form of paraneoplastic syndromes such as progressive multifocal leucoencephalopaty [8], subacute cerebellar degeneration [9], granulomatous angiitis [10, 11] and encephalitis [12] are observed. However, as far as the presence of direct tumor involvement of the nervous system in HD is concerned, intracranial HD (ICHD) is very rare. In particular, this tumor was not observed in the series of 8,000 intracranial neoplasms reported by Jellinger et al. [13], but ocPOST curred in 14 of the 7,000 patients (0.2%) with central nervous system (CNS) tumours reported by Zimmerman [14]. Among 1250 patients with HD observed at our Division from 1970 to 1990, only this patient had ICHD disease, for an overall incidence rate of 0.08%. The occurrence of ICHD has been reported predominantly in patients with relapsing disease [2,12,1520], and rarely as an extension of the disease resistant to treatment [21, 22], while primary involvement of CNS occurs more often in HD secondary to congenital or acquired immunodeficiency states such as AIDS [23-26]. ICHD presenting as a primary, extranodal lesion, in the absence of other localizations, is exceedingly rare [27-31]. A 1988 review of the literature [30] dealing with primary isolated ICHD at onset of HD revealed the presence of only 12 cases reported in medical journals since 1946. Taking into account these data we performed a literature search dealing with neurological manifestations and localization of Hodgkin's disease, independently of the presence or absence of other sites ofHD. ANT The records or case reports of 48 patients with Figure 1. Increase of radionucleotide compound In the left fronto- ICHD (22 females and 26 males, ranging from 11 to 69 parietal area of the skull at bone scintiscan. years of age) were identified. Basic characteristics of these patients are presented in Table 1. The majority of them suffered from advanced HD: 40 were in relapse, 2 Review of the literature had progressive disease and only 6 had received no previous treatment (Table 1). The histologic subtypes Data source were mainly nodular sclerosis and mixed cellularity To review the incidence and management of neurologi- (Table 1). Intracranial (IC) sites of disease showed that cal complications of the direct involvement of the CNS dural involvement (n = 23) was more common than with HD, we performed an English language literature parenchyma] lesions (n — 12). In the remaining 13 search, using the MEDLARS online databases of the cases, 12 did not specify the site of IC involvement, National Library of Medicine of Bethesda, for all while one had a simultaneous involvement of 'dura papers reported on MEDLINE and AIDS-LINE files mater' and cerebral parenchyma. Concurrent sites of as of June 1995. Search terms (Medical Subject Head- disease at the time of IC presentation showed a pre-

irm

Figure 2. CT of the brain: the localization of HD in the convexity of the fronto-parietal region in two different sections.

Figure 4. Tumor mass ( 1 2 x 4 cm). Figure 3. Magnetic Resonance Imaging (MRI) of the brain.

dominance of lymph node involvement (Table 1). As a consequence, the mechanism of spread to IC sites from systemic HD is probably vascular and not due to a contiguous spread from involved lymph nodes or bones [2]. Moreover, in all reported cases the presence of ICHD was combined with neurological symptoms such as cranial nerve palsy, motor deficits, seizures, headache or other signs of increased intracranial pressure.

the longest duration of survival in the series of Dujovny et al. was obtained when surgical removal was combined with radiation therapy. In cases where there are multiple intracranial masses or the mass is inaccessible for resection, a CT-guided stereotactic brain biopsy can provide a tissue diagnosis that would allow the institution of appropriate radiotherapy and/or chemotherapy [311Radiotherapy

Treatment modalities

Several therapeutic approaches have been proposed. Surgical

Historically, surgery was the first procedure used for the treatment of neurological complications of ICHD. Dujovny et al. [12] recognized the value of surgical intervention; their review showed that the average postoperative survival time was measured in years as opposed to months for all other treatments. However,

It is well known that HD, as well as other malignant lymphomas, is radiosensitive and some investigators recommend irradiation as the choice of treatment for CNS involvement in HD [2, 22, 31]. Whole brain irradiation of 20 to 30 Gy supplemented by a local boost field to bring the dose to known sites of intracranial involvement from 40 to 50 Gy has been recommended for patients presenting with intracranial metastasis [2]. However, extensive involvement of the spinal cord and a prior history of irradiation of the affected site often rule out this treatment modality.

1074 Table 1. Summary of ICHD reported in the literature 1995. Reference

No. pts

Sex

Age

Phase of disease

Sites

Histology

Neurologic symptoms

Other sites of disease

Therapy

Survival following IC presentation

SURG + XT (60 Y) SURG + XT (44 Gy) + ITMTX CHT + XT (32 Gy) + ITMTX SURG + XT (40 Gy) + CHT SURG + XT (45 Gy) XT (45 Gy) CHT + XT (52 Gy) SURG + XT (40 Gy) + ITMTX CHT + XT (45 Gy) 12/12 XT (40 Gy) 9/12 CHT 20 CHT (CCNU) 3 CHT (CCNU) + XT

73 months 46 months

SURG + XT + ITMTX XT(18Gy) + CHT SURG

9 months 6 months

11 14

1 1

M F

22 32

Relapse Relapse

Cerebral Cerebral

MC NS

Present Present

Nodal Absent

15

1

M

30

Relapse

Dura!

HD

Present

Absent

17

2

M

29-19

Relapse

Dural

1 HD, 1 NS Present

Absent

19 21 27 29

1 1 1 1

M M M M

51 20 60 62

Onset Progr Onset Onset

Cerebral Cerebral Cerebral Dural

MC HD HD NS

Present Present Present Present

Absent Absent Absent Absent

30 31

1 12

Present Present

Absent 10/12 modal

38

23

Present

39 40

1 2

6 nodal 14 extranodal 3 absent Absent 1 absent 1 extranodal

F 53 5 M 11-69 7F 10 F 13-53 13 M F F

37 52-64

HD 8 NS, 2 MC 2HD 21 Relapse 18 dur 2 LP, 11 NS 2 Onset 4 cer 7 MC, 1 LD 1 dur-cer 2 H D Dura] HD Progr Relapse Cerebral HD Onset Relapse

Cerebral Dur/cer

Present Present

10 months 48 months 12 months 6 months 12 months 14 months 6 months Median 10 months Median 11 months

Abbreviations: ICHD - intracranial Hodgkin's disease; dur - dural; cer - cerebral; HD - Hodgkin's disease; NS - nodular sclerosis; MC - mixed cellularity; LP - lymphocyte predominant; LD - lymphocyte depletion; SURG - surgical; XT - radiotherapy; CHT - chemotherapy; ITMTX - intratecal methotrexate.

Chemotherapy Because of the inherent limitations of irradiation and surgery, alternative approaches to the treatment of CNS involvement in HD, particularly chemotherapy, have been investigated. However, there have been only a few reports of treatment with cytotoxic drugs alone [32-35] or such standard cytotoxic regimens as COPP [36], ABVD and ProMACE-cytaBOM [37]. Gersanovich et al. [38] reported that CCNU- and NMU-based chemotherapy is an effective and well tolerated treatment in 23 patients with HD involving the CNS. Corticosteroids should be added, particularly if elevated intracranial pressure is documented or suspected, and tapered gradually [2]. Intrathecal therapy is best reserved for those cases in which cytologic or myelographic documentation of meningeal disease is present [2,14,15,29,39].

Discussion of the case A peculiarity of our case was that the ICHD was localized to the 'dura mater1 without macroscopical evidence of bone erosion. The bone scintiscan showed a local increase of radionucleotide compound due to the reactive hyperostosis secondary to the tumor mass compression of the bone. Moreover, although the brain cortex was infiltrated, our patient presented no evidence of neurological signs or symptoms, as was the

case in all reported patients in the literature. Our patient was treated with a therapeutic program combining surgery, radiotherapy and chemotherapy, and after 50 months of follow-up after completion of the treatment he is alive and in remission. Review of the treatments available for CNS involvement with HD suggests that this therapeutic program is the treatment of choice when ICHD is associated with other nonCNS sites of disease; while for localized ICHD, surgery followed by whole brain irradiation is the treatment of choice. In conclusion, this case and the brief review of the literature clearly indicate that a prompt and complete diagnostic work-up combined with a multidisciplinary therapeutic approach can greatly improve the prognosis of ICHD. As emphasized by Sapozink and Kaplan [2], these patients should be treated with curative intent, using all of the available therapeutic options for HD: surgical, radiotherapeutic and chemotherapeutic. References 1. Anselmo AP, Cartoni C, Cafolla A et al. Alternating MOPPABVD vs. OPP-ABVD chemotherapy in advanced stage Hodgkin's disease. Fifth International Congress of Malignant Lymphoma, Lugano 1993, P74: 89 (Abstr). 2. Sapozink MD, Kaplan HS. Intracranial Hodgkin's disease: A report of 12 cases and review of the literature. Cancer 1983; 52:1301-7. 3. Blake PR, Carr DH, Goolden AWG. Intracranial Hodgkin's disease. BrJRadiol 1986; 59:414-6.

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