464
Surg Neurol 1992;37:464-71
The following article calls attention to the coincidence of intracerebral lymphoma with a variety of extracranial neoplasms, mostly malignant, which it is important to recognize if it is assumed that all tumors in a patient occurring at one time are of the same type: in this case, lymphoma. This article makes the above quite clear and it should be of interest to neurosurgeons. It is worthy of note that there are many additional examples of coincidental occurrences of intracranial and extracranial tumors. Meningiomas, for example, give rise to such occurrences, perhaps more frequently in women than in men, with metastasis of an extracranial carcinoma (often of the breast in women) into the meningioma. Then there is the less common association of a glioma adjacent to a meningioma, designated in the older neurooncologic literature as a "collision tumor." Examples of similar occurrences of metastasis of carcinomas into intracranial tissues are found within pituitary
adenomas from pulmonary neoplasms, as well as from other primary sites. And even one type ofglioma can be found adjacent to another as, for example, an ependymoma that lies side by side with an astrocytoma. A somewhat more remote coincidence is the presence of astrocytic ceils (an astrocytoma?) within an oligodendroglioma. And finally there is the example of the presence in one cerebral location of two primary but different brain tumors by the "conversion" of neuroblastomas into mature ganglion cell neoplasms, sometimes following radiation or chemotherapy. Radiation has also been held responsible for the development of a sarcoma in the pituitary gland following treatment of a pituitary adenoma.
H. M. Z I M M E R M A N , M.D.
Bronx, N e w York
Primary Intracerebral Malignant Lymphoma Associated with Different Histological Types of Carcinoma: Report of Two Cases Toshiki Yamasaki, M.D., D.Med.Sci., Haruhiko Kikuchi, M.D., D.Med.Sci., Yoshihumi Oda, M.D., D.Med.Sci., Kouzo Moritake, M.D., D.Med.Sci., Hiroshi Miura, M.D., D.Med.Sci., and Toshihide Shimada, M.D., D.Med,Sci. Department of Neurosurgery and Department of Laboratory Medicine, Shimane Medical University, Izumo, Department of Neurosurgery, Faculty of Medicine, Kyoto University, and Laboratory of Anatomic Pathology, Kyoto University Hospital, Kyoto, Japan
Yamasaki T, Kikuchi H, Oda Y, Moritake K, Miura H, Shimada T. Primary intracerebral malignant lymphoma associated with different histological types of carcinoma: report of two cases. Surg Neurol 1992;37:464-71.
KEY WORDS: Malignant lymphoma; Multiple primary neoplasm; Brain neoplasm; Therapy; Prognosis; Pathology
Two rare cases with histologically proven multiple primary neoplasms are described: an association of intracere-
Primary malignant lymphoma of the central nervous system (CNS) has a characteristic and diagnostic appearance on computed tomography (CT) [ 11,12,17 ], and it occurs with increased frequency in patients who are immunologically suppressed, such as organ transplant recipients and those with acquired immune deficiency syndrome (AIDS) [7,16,21]. T o date there have been a very small number of isolated case reports on the coexistence of primary CNS lymphoma and different histological types of neoplasms. To the best of our knowledge, there have been only 10 case reports with 22 patients previously recorded in the literature [ 1,2,4,5,9,10,13-15,19]. The associated tumors outside the CNS were histologically
bral malignant lymphoma with hepatocellular carcinoma in one case and with squamous cell carcinoma of the uterine cervix in the other. Therapeutic problems pertinent to the coexistence of primary intracerebral malignant lymphoma and neoplasms of a different histological type are discussed.
Address reprint requests to: Toshiki Yamasaki, M.D., D.Med.Sci., Department of Neurosurgery, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan. Received August l, 1991; accepted December 12, 1991.
6© 1992 by Elsevier Science Publishing Co., Inc.
0090-3019/92/$5.00
CNS Lymphoma Associated with Non-CNS Malignancy
malignant in 15 cases (renal cell carcinoma, colonic adenocarcinoma with hepatic metastasis, gastric and rectal adenocarcinoma, breast cancer, bronchial cancer, thyroid cancer, Hodgkin's disease, and systemic non-Hodgkin's lymphoma) and benign in 7 cases (colonic polyposis, gastric leiomyoma, uterine myofibroma, thyroid and prostate adenoma, astrocytoma grade 2, and meningioma). We present here two cases of multiple primary neoplasms: association of intracerebral malignant lymphoma with hepatocellular carcinoma and with squamous cell carcinoma of the uterine cervix. The overall outcome was unfavorable in all 24 cases, including ours, with this disease entity. The clinical significance of diagnosis, therapeutic management, and prognosis is discussed.
Case R e p o r t s Case 1 A 67-year-old, right-handed man was admitted with a 1month history of progressive disorientation on January 25, 1989. He had received neither organ transplantation nor immunosuppressive therapy. He had no history of homosexual activity or intravenous drug abuse. Examinatio,~. General physical and neurological examinations on admission revealed left parietal signs with a Karnofsky performance scale (PS) score of 50. Initial computed tomography (CT) and magnetic resonance imaging (MRI) of the head disclosed two mass lesions at both the right frontal and the left temporo-occipital regions (Figure 1). The laboratory data, including serum protein electrophoresis and serum IgA and IgM levels, were within normal limits except for slightly elevated levels of serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). There were no significant antibody titers for human immunodeficiency virus type I ~HIV-I), human T-cell leukemia virus type I (HTLV-I), or Epstein-Barr virus (EBV), including capsid, early (EA), and nuclear (EBNA) antigens, and thus the special serologies demonstrated no evidence of such viral infections. Tumor marker study of the serum and cerebrospinal fluid (CSF) did not show any significant abnormality such as an elevation of alphafetoprotein. Examination of the CSF did not reveal histological evidence of abnormal cells. A cerebral angiogram revealed neither abnormal vessels nor tumor stains. Systemic investigations such as abdominal CT and ultrosonography, and ('-Ga-citrate scintigrams, detected mass lesions in the liver, but not in any other sites of the body. Operation. In an attempt to obtain the histological diagnosis and to determine therapeutic guidelines, the
Surg Neurol 1992;37:464-71
465
patient underwent a biopsy of the right frontal lesion through a right frontotemporal craniotomy on February 9, 1989. The two main reasons why the biopsy of the CNS tumors preceded the treatment of hepatic lesions were that his current clinical signs and symptoms were caused by the intracerebral lesions and that liver dysfunction, judged by the serum examination, was only mild.
Pathological examination. The pathological diagnosis from the surgical specimens was non-Hodgkin's lymphoma; they were subclassified as a diffuse, mixed, smalland large-cell type by the International Working Formulation (Figure 2). An immunological marker study by the avidin-biotin complex method was done on paraffinembedded sections of tissues by using monoclonal antibodies against B cells (L-26, MB1) and T cells (MT1, UCHL1) [3,20,22]. It was verified that tumor cells were positively stained by L-26 and MB 1 antibodies, but negatively by MT1 and UCHL1 antibodies, indicating that this neoplasm was of B-cell origin.
Postoperatire course. The postoperative recovery was uneventful, representing the same PS score of 50 as preoperatively. After histological confirmation, radiotherapy was done with a total dose of 50 Gy to whole brain (38 Gy) and the local lesions (12 Gy) in 6 weeks, and subsequently systemic chemotherapy was given in one course. Our regimen consisted of a VEAP protocol, including vincristine (1.0 mg/m 2 on day 1, intravenous), cyclophosphamide (350 mg/m e on day 1, IV), doxorubicin (30 mg/m 2 on day 1, IV), and prednisolone (30 mg on days 1-3, 80 mg on days 4 and 5, per os). A followup cranial CT scan 2 months after biopsy showed a marked decrease in the size of the tumors. In contrast, a follow-up abdominal CT and ultrasonography revealed little change in the size of the hepatic tumors. The patient suffered from pneumonia, and additional treatments could not be carried out. On April 25, 1989, he died of pneumonia and subsequent renal failure.
Postmortem examination. Autopsy revealed a lymphoma cell infiltration in the brain (Figure 2) but not in any other organs. At the site of intracerebral lesions, tumor necrosis was identified that probably was due to the effects of irradiation, while there were sometimes lymphoma cell invasions at the peripheral parts of the tumor particularly along the perivascular space (Figure 2). The hepatic lesions were of hepatocellular carcinoma (Edmonson grade 2; Figure 2). Therefore, the postmortem investigation proved the coexistence of primary CNS lymphoma and hepatocellular carcinoma.
466
Surg Neurol 1992;37:464-71
Yamasaki et al
Figure 1. Preoperative plain (upper left) and enhanced (upper right) cranial C T scans in case I, showing slightly hyperdense lesions with homogeneous contrast enhancement at both right frontal and left temporo-occipital regions. T2weighted (lower left) (TR = 2,000 ms. TE = 80 ms) and proton-density (lower right) (TR = 2.000 ms, TE = 20 ms) M R I with 1.5 tesla apparatus revealing hyperintense lesions with perifocal edema.
Case 2 A 60-year-old, right-handed woman was referred to our institution with a 2-month history of progressive headache and sporadic generalized convulsion on February 17, 1989. She had a history of radical hysterectomy because of squamous cell carcinoma of the uterine cervix 4 years previously. After surgical treatment she had undergone radiotherapy of 45 G y to the local uterine lesion. Subsequent chemotherapy was not done at that time. Sequential t u m o r marker studies of the serum before and after the previous operation for uterine cancer had not revealed a significant abnormality. A followup abdominal CT scan had indicated no local recurrence of the neoplasm. O t h e r systemic examinations such as 67Ga citrate scintigrams had not detected any lesions. Thus, she had obtained a complete remission of 4-years duration. She had received neither organ transplantation
nor immunosuppressive therapy. She had no past history of homosexual or intravenous drug abuse. E x a m i n a t i o n . General physical and neurological examinations on admission showed papilledema and left parietal signs with a PS score o f 70. Initial C T and M R I of the head at this admission displayed a left parietooccipital mass lesion (Figure 3). A cerebral angiogram disclosed a relative hypovascularity. T h e laboratory data, including tumor marker studies, were within normal limits. A special serological examination showed no evidence of H I V - 1 , H T L V - I , or EBV viral infections. Operation. In an effort to confirm the histological diagnosis of the intracerebral lesion as well as to debulk the tumor, the patient underwent a total resection of the left parieto-occipital t u m o r on March 1, 1989.
CNS Lymphoma Associated with Non-CNS Malignancy
Figure 2. Photomicrographs of case 1 specimens, A biopsy specimen (upper left) showing a mixture of small and large neoplastic cells with large vesicular nuclei, many containing a prominent, centrally located oval nucleolus. Postmortem specimens (lower left and right) revealing a perivascular proliferation and infiltration of lymphoma cells, and (upper right) showing a hepatocellular carcinoma (Edmonson grade 2J with either granular or smooth appearance (hematoxylin and eosin: upper left and lower right. × 400: upper right. × 200; lower left, × 100).
Pathological examination. The pathological diagnosis was of non-Hodgkin's lymphoma, and the lesion was subclassified as a diffuse, mixed, small- and large-cell type. An immunological marker study proved a B-cell origin of the intracerebral lymphoma. Therefore the histological examinations verified the development of primary CNS lymphoma associated with a different histological type of squamous cell carcinoma of the uterine cervix (Figure 4). Postoperative course. The patient made an uneventful postoperative recovery. Radiotherapy was carried out with a total dose of 50 Gy to the whole brain (38 Gy) and the local lesion (12 Gy) in 6 weeks. Subsequently systemic chemotherapy was given with four cycles of the VEAP protocol. Thereafter the patient was discharged
Surg Neurol 1992;37:464-71
467
with a PS score of at least 90. A follow-up cranial CT scan 9 months after surgery showed no tumor recurrence. One month later, however, she suddenly developed respiratory disturbance concurrently with tetraparesis and was emergently admitted to the hospital from which she had been referred to us. Then she suffered from pneumonia and expired on January 24, 1990. An autopsy was not performed.
Discussion Multiple primary neoplasms of the brain coexistent with different histological types of tumors are encountered with relatively low frequency [6,8,23]. Although the etiology remains unclear, genetic predisposing factors, tumorigenic stimuli, radiation-induced carcinogenesis, and purely coincidental embryonal relationships may explain the phenomenon of rumor multiplicity [25]. With special reference to primary CNS lymphoma, the coexistence with different histological types of neoplasms is rare, although isolated case reports have recently been a c c u m u l a t e d with advances in diagnostic technology. As far as we could determine in the literature, there have been only 10 publications with 22 patients (Table 1) [ 1,2,4,5,9,10,13-15,19]; the different histological types
468
Surg Neurol 1992;37:464-71
Figure 3. Preoperative plain (upper left) and enhanced (upper middle and right) cranial C T films u,ith axial or coronal view in case 2, showing a hyperdense lesion with homogeneous contrast enhancement at the /eft parieto-occl~ital region. T2-weighted (lower left) (TR = 2,000 ms, TE = 80 ms), proton-density (lower middle) (TR = 2,000 ms. TE = 20 ms), and TI-u.'eighted (lower right) gTR = 400 ms, T E - 20 msJ M R I u4th 0.5 tes/a apparatus disclosing a mixed-intensity lesion with perifocal edema.
of tumors can be classified into two groups, malignant tumors in 15 cases and benign in 7 cases. Our current cases with hepatocellular carcinoma or squamous cell carcinoma of the uterine cervix have not been documented previously. According to the literature [18,24] multiple primary neoplasms are defined by the following criteria: (1) The neoplasm must be clearly malignant as determined by histological evaluation; (2) each neoplasm must be geographically separate and distinct; and (3) the possibility that the second tumor represents a metastasis should be excluded. If the previously reported 22 cases and ours are evaluated by this definition, benign tumors should be excluded and thus 17 patients correspond to these criteria of multiple primary neoplasms. Furthermore, the question of synchronous or metachronous occurrence
Yamasaki et al
depends upon the interval of t u m o r evolution among the multiple histologically different types of neoplasms: W h e n the interval is 1 year or less, the relationship is referred to as a synchronous t u m o r occurrence [18]. W h e n the interval is m o r e than 1 year, metachronous occurrence is implied. O f the 17 collected malignant cases, five were synchronous and nine were metachronous tumors; two of the remaining three underwent incidental detection of systemic tumors, and as to the remaining one details were not described (Table 1). If a case involves multiple t u m o r growths and their relation to the CNS, it is of a great clinical significance to differentiate them from metastatic brain neoplasms for the purposes of therapeutic decision making. In the two present cases a preoperative differential diagnosis was difficult because metastatic brain t u m o r was indistinguishable from the ultimate findings. In case 1 intracerebral l y m p h o m a was detected with synchronous occurrence of hepatocellular carcinoma and the patient survived only 5 months after the initial clinical presentation. In case 2 a metachronously rising intracerebral l y m p h o m a was resected 4 years after treatments (surgery and radiotherapy without chemotherapy) of squamous cell carcinoma of the uterine cervix, and the patient
Table
1.
LiteratureReports of Multiple Primary Neop/asms in A~sociation with Malignant Lymphoma of the Central Nervous System Patient
Authors
CNS lymphoma
Year
Age
Sex
Burstein et al
106~
49
F
Reticulum cell sarcoma (h Te-Pa)
Jelliuger and Radaszkiewicz
I976
68
M
Hara et al
1979
46 71 76 6O 15
F F M M F
Immunocytic type (multiple) (Kiel classification) lmmunoeytic type (bil thalamus) Immunocytic type (lt Fr) lmmunoblastic type (h Fr) Immunoblastic type (multiple) Reticulum cell sarcoma (rt Pa-Oc)
Katayama et al
1981
71
M
Immunoblastic type (rt Te)
Giromini et al
1981
11
M
Burkitt type (It Te-Pal
Nakagawa et al
1987
63
M
Dorreen et al
i988
73
Histologic subtype (location)
58 5q
Large-cell type (lt Fr) (LSG classificationl M Centrocytic/centroblastic (vermis} (Kiel classification) F Lymphoplasmacytoid (C.CI M Centrocytic/centroblastic Ibil Oc)
1990
62
F
Angeid-Backman 1990 and Quint
12
F
DeAngelis
1991
67
1992
69 51 77 63 69 77 67
it
60
F
Kuroiwa et al
Yamasaki et al
F
M
Diffuse, large
Surg Neurol 1992;37:464-71
The following article calls attention to the coincidence of intracerebral lymphoma with a variety of extracranial neoplasms, mostly malignant, which it is important to recognize if it is assumed that all tumors in a patient occurring at one time are of the same type: in this case, lymphoma. This article makes the above quite clear and it should be of interest to neurosurgeons. It is worthy of note that there are many additional examples of coincidental occurrences of intracranial and extracranial tumors. Meningiomas, for example, give rise to such occurrences, perhaps more frequently in women than in men, with metastasis of an extracranial carcinoma (often of the breast in women) into the meningioma. Then there is the less common association of a glioma adjacent to a meningioma, designated in the older neurooncologic literature as a "collision tumor." Examples of similar occurrences of metastasis of carcinomas into intracranial tissues are found within pituitary
adenomas from pulmonary neoplasms, as well as from other primary sites. And even one type ofglioma can be found adjacent to another as, for example, an ependymoma that lies side by side with an astrocytoma. A somewhat more remote coincidence is the presence of astrocytic ceils (an astrocytoma?) within an oligodendroglioma. And finally there is the example of the presence in one cerebral location of two primary but different brain tumors by the "conversion" of neuroblastomas into mature ganglion cell neoplasms, sometimes following radiation or chemotherapy. Radiation has also been held responsible for the development of a sarcoma in the pituitary gland following treatment of a pituitary adenoma.
H. M. Z I M M E R M A N , M.D.
Bronx, N e w York
Primary Intracerebral Malignant Lymphoma Associated with Different Histological Types of Carcinoma: Report of Two Cases Toshiki Yamasaki, M.D., D.Med.Sci., Haruhiko Kikuchi, M.D., D.Med.Sci., Yoshihumi Oda, M.D., D.Med.Sci., Kouzo Moritake, M.D., D.Med.Sci., Hiroshi Miura, M.D., D.Med.Sci., and Toshihide Shimada, M.D., D.Med,Sci. Department of Neurosurgery and Department of Laboratory Medicine, Shimane Medical University, Izumo, Department of Neurosurgery, Faculty of Medicine, Kyoto University, and Laboratory of Anatomic Pathology, Kyoto University Hospital, Kyoto, Japan
Yamasaki T, Kikuchi H, Oda Y, Moritake K, Miura H, Shimada T. Primary intracerebral malignant lymphoma associated with different histological types of carcinoma: report of two cases. Surg Neurol 1992;37:464-71.
KEY WORDS: Malignant lymphoma; Multiple primary neoplasm; Brain neoplasm; Therapy; Prognosis; Pathology
Two rare cases with histologically proven multiple primary neoplasms are described: an association of intracere-
Primary malignant lymphoma of the central nervous system (CNS) has a characteristic and diagnostic appearance on computed tomography (CT) [ 11,12,17 ], and it occurs with increased frequency in patients who are immunologically suppressed, such as organ transplant recipients and those with acquired immune deficiency syndrome (AIDS) [7,16,21]. T o date there have been a very small number of isolated case reports on the coexistence of primary CNS lymphoma and different histological types of neoplasms. To the best of our knowledge, there have been only 10 case reports with 22 patients previously recorded in the literature [ 1,2,4,5,9,10,13-15,19]. The associated tumors outside the CNS were histologically
bral malignant lymphoma with hepatocellular carcinoma in one case and with squamous cell carcinoma of the uterine cervix in the other. Therapeutic problems pertinent to the coexistence of primary intracerebral malignant lymphoma and neoplasms of a different histological type are discussed.
Address reprint requests to: Toshiki Yamasaki, M.D., D.Med.Sci., Department of Neurosurgery, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan. Received August l, 1991; accepted December 12, 1991.
6© 1992 by Elsevier Science Publishing Co., Inc.
0090-3019/92/$5.00
CNS Lymphoma Associated with Non-CNS Malignancy
malignant in 15 cases (renal cell carcinoma, colonic adenocarcinoma with hepatic metastasis, gastric and rectal adenocarcinoma, breast cancer, bronchial cancer, thyroid cancer, Hodgkin's disease, and systemic non-Hodgkin's lymphoma) and benign in 7 cases (colonic polyposis, gastric leiomyoma, uterine myofibroma, thyroid and prostate adenoma, astrocytoma grade 2, and meningioma). We present here two cases of multiple primary neoplasms: association of intracerebral malignant lymphoma with hepatocellular carcinoma and with squamous cell carcinoma of the uterine cervix. The overall outcome was unfavorable in all 24 cases, including ours, with this disease entity. The clinical significance of diagnosis, therapeutic management, and prognosis is discussed.
Case R e p o r t s Case 1 A 67-year-old, right-handed man was admitted with a 1month history of progressive disorientation on January 25, 1989. He had received neither organ transplantation nor immunosuppressive therapy. He had no history of homosexual activity or intravenous drug abuse. Examinatio,~. General physical and neurological examinations on admission revealed left parietal signs with a Karnofsky performance scale (PS) score of 50. Initial computed tomography (CT) and magnetic resonance imaging (MRI) of the head disclosed two mass lesions at both the right frontal and the left temporo-occipital regions (Figure 1). The laboratory data, including serum protein electrophoresis and serum IgA and IgM levels, were within normal limits except for slightly elevated levels of serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). There were no significant antibody titers for human immunodeficiency virus type I ~HIV-I), human T-cell leukemia virus type I (HTLV-I), or Epstein-Barr virus (EBV), including capsid, early (EA), and nuclear (EBNA) antigens, and thus the special serologies demonstrated no evidence of such viral infections. Tumor marker study of the serum and cerebrospinal fluid (CSF) did not show any significant abnormality such as an elevation of alphafetoprotein. Examination of the CSF did not reveal histological evidence of abnormal cells. A cerebral angiogram revealed neither abnormal vessels nor tumor stains. Systemic investigations such as abdominal CT and ultrosonography, and ('-Ga-citrate scintigrams, detected mass lesions in the liver, but not in any other sites of the body. Operation. In an attempt to obtain the histological diagnosis and to determine therapeutic guidelines, the
Surg Neurol 1992;37:464-71
465
patient underwent a biopsy of the right frontal lesion through a right frontotemporal craniotomy on February 9, 1989. The two main reasons why the biopsy of the CNS tumors preceded the treatment of hepatic lesions were that his current clinical signs and symptoms were caused by the intracerebral lesions and that liver dysfunction, judged by the serum examination, was only mild.
Pathological examination. The pathological diagnosis from the surgical specimens was non-Hodgkin's lymphoma; they were subclassified as a diffuse, mixed, smalland large-cell type by the International Working Formulation (Figure 2). An immunological marker study by the avidin-biotin complex method was done on paraffinembedded sections of tissues by using monoclonal antibodies against B cells (L-26, MB1) and T cells (MT1, UCHL1) [3,20,22]. It was verified that tumor cells were positively stained by L-26 and MB 1 antibodies, but negatively by MT1 and UCHL1 antibodies, indicating that this neoplasm was of B-cell origin.
Postoperatire course. The postoperative recovery was uneventful, representing the same PS score of 50 as preoperatively. After histological confirmation, radiotherapy was done with a total dose of 50 Gy to whole brain (38 Gy) and the local lesions (12 Gy) in 6 weeks, and subsequently systemic chemotherapy was given in one course. Our regimen consisted of a VEAP protocol, including vincristine (1.0 mg/m 2 on day 1, intravenous), cyclophosphamide (350 mg/m e on day 1, IV), doxorubicin (30 mg/m 2 on day 1, IV), and prednisolone (30 mg on days 1-3, 80 mg on days 4 and 5, per os). A followup cranial CT scan 2 months after biopsy showed a marked decrease in the size of the tumors. In contrast, a follow-up abdominal CT and ultrasonography revealed little change in the size of the hepatic tumors. The patient suffered from pneumonia, and additional treatments could not be carried out. On April 25, 1989, he died of pneumonia and subsequent renal failure.
Postmortem examination. Autopsy revealed a lymphoma cell infiltration in the brain (Figure 2) but not in any other organs. At the site of intracerebral lesions, tumor necrosis was identified that probably was due to the effects of irradiation, while there were sometimes lymphoma cell invasions at the peripheral parts of the tumor particularly along the perivascular space (Figure 2). The hepatic lesions were of hepatocellular carcinoma (Edmonson grade 2; Figure 2). Therefore, the postmortem investigation proved the coexistence of primary CNS lymphoma and hepatocellular carcinoma.
466
Surg Neurol 1992;37:464-71
Yamasaki et al
Figure 1. Preoperative plain (upper left) and enhanced (upper right) cranial C T scans in case I, showing slightly hyperdense lesions with homogeneous contrast enhancement at both right frontal and left temporo-occipital regions. T2weighted (lower left) (TR = 2,000 ms. TE = 80 ms) and proton-density (lower right) (TR = 2.000 ms, TE = 20 ms) M R I with 1.5 tesla apparatus revealing hyperintense lesions with perifocal edema.
Case 2 A 60-year-old, right-handed woman was referred to our institution with a 2-month history of progressive headache and sporadic generalized convulsion on February 17, 1989. She had a history of radical hysterectomy because of squamous cell carcinoma of the uterine cervix 4 years previously. After surgical treatment she had undergone radiotherapy of 45 G y to the local uterine lesion. Subsequent chemotherapy was not done at that time. Sequential t u m o r marker studies of the serum before and after the previous operation for uterine cancer had not revealed a significant abnormality. A followup abdominal CT scan had indicated no local recurrence of the neoplasm. O t h e r systemic examinations such as 67Ga citrate scintigrams had not detected any lesions. Thus, she had obtained a complete remission of 4-years duration. She had received neither organ transplantation
nor immunosuppressive therapy. She had no past history of homosexual or intravenous drug abuse. E x a m i n a t i o n . General physical and neurological examinations on admission showed papilledema and left parietal signs with a PS score o f 70. Initial C T and M R I of the head at this admission displayed a left parietooccipital mass lesion (Figure 3). A cerebral angiogram disclosed a relative hypovascularity. T h e laboratory data, including tumor marker studies, were within normal limits. A special serological examination showed no evidence of H I V - 1 , H T L V - I , or EBV viral infections. Operation. In an effort to confirm the histological diagnosis of the intracerebral lesion as well as to debulk the tumor, the patient underwent a total resection of the left parieto-occipital t u m o r on March 1, 1989.
CNS Lymphoma Associated with Non-CNS Malignancy
Figure 2. Photomicrographs of case 1 specimens, A biopsy specimen (upper left) showing a mixture of small and large neoplastic cells with large vesicular nuclei, many containing a prominent, centrally located oval nucleolus. Postmortem specimens (lower left and right) revealing a perivascular proliferation and infiltration of lymphoma cells, and (upper right) showing a hepatocellular carcinoma (Edmonson grade 2J with either granular or smooth appearance (hematoxylin and eosin: upper left and lower right. × 400: upper right. × 200; lower left, × 100).
Pathological examination. The pathological diagnosis was of non-Hodgkin's lymphoma, and the lesion was subclassified as a diffuse, mixed, small- and large-cell type. An immunological marker study proved a B-cell origin of the intracerebral lymphoma. Therefore the histological examinations verified the development of primary CNS lymphoma associated with a different histological type of squamous cell carcinoma of the uterine cervix (Figure 4). Postoperative course. The patient made an uneventful postoperative recovery. Radiotherapy was carried out with a total dose of 50 Gy to the whole brain (38 Gy) and the local lesion (12 Gy) in 6 weeks. Subsequently systemic chemotherapy was given with four cycles of the VEAP protocol. Thereafter the patient was discharged
Surg Neurol 1992;37:464-71
467
with a PS score of at least 90. A follow-up cranial CT scan 9 months after surgery showed no tumor recurrence. One month later, however, she suddenly developed respiratory disturbance concurrently with tetraparesis and was emergently admitted to the hospital from which she had been referred to us. Then she suffered from pneumonia and expired on January 24, 1990. An autopsy was not performed.
Discussion Multiple primary neoplasms of the brain coexistent with different histological types of tumors are encountered with relatively low frequency [6,8,23]. Although the etiology remains unclear, genetic predisposing factors, tumorigenic stimuli, radiation-induced carcinogenesis, and purely coincidental embryonal relationships may explain the phenomenon of rumor multiplicity [25]. With special reference to primary CNS lymphoma, the coexistence with different histological types of neoplasms is rare, although isolated case reports have recently been a c c u m u l a t e d with advances in diagnostic technology. As far as we could determine in the literature, there have been only 10 publications with 22 patients (Table 1) [ 1,2,4,5,9,10,13-15,19]; the different histological types
468
Surg Neurol 1992;37:464-71
Figure 3. Preoperative plain (upper left) and enhanced (upper middle and right) cranial C T films u,ith axial or coronal view in case 2, showing a hyperdense lesion with homogeneous contrast enhancement at the /eft parieto-occl~ital region. T2-weighted (lower left) (TR = 2,000 ms, TE = 80 ms), proton-density (lower middle) (TR = 2,000 ms. TE = 20 ms), and TI-u.'eighted (lower right) gTR = 400 ms, T E - 20 msJ M R I u4th 0.5 tes/a apparatus disclosing a mixed-intensity lesion with perifocal edema.
of tumors can be classified into two groups, malignant tumors in 15 cases and benign in 7 cases. Our current cases with hepatocellular carcinoma or squamous cell carcinoma of the uterine cervix have not been documented previously. According to the literature [18,24] multiple primary neoplasms are defined by the following criteria: (1) The neoplasm must be clearly malignant as determined by histological evaluation; (2) each neoplasm must be geographically separate and distinct; and (3) the possibility that the second tumor represents a metastasis should be excluded. If the previously reported 22 cases and ours are evaluated by this definition, benign tumors should be excluded and thus 17 patients correspond to these criteria of multiple primary neoplasms. Furthermore, the question of synchronous or metachronous occurrence
Yamasaki et al
depends upon the interval of t u m o r evolution among the multiple histologically different types of neoplasms: W h e n the interval is 1 year or less, the relationship is referred to as a synchronous t u m o r occurrence [18]. W h e n the interval is m o r e than 1 year, metachronous occurrence is implied. O f the 17 collected malignant cases, five were synchronous and nine were metachronous tumors; two of the remaining three underwent incidental detection of systemic tumors, and as to the remaining one details were not described (Table 1). If a case involves multiple t u m o r growths and their relation to the CNS, it is of a great clinical significance to differentiate them from metastatic brain neoplasms for the purposes of therapeutic decision making. In the two present cases a preoperative differential diagnosis was difficult because metastatic brain t u m o r was indistinguishable from the ultimate findings. In case 1 intracerebral l y m p h o m a was detected with synchronous occurrence of hepatocellular carcinoma and the patient survived only 5 months after the initial clinical presentation. In case 2 a metachronously rising intracerebral l y m p h o m a was resected 4 years after treatments (surgery and radiotherapy without chemotherapy) of squamous cell carcinoma of the uterine cervix, and the patient
Table
1.
LiteratureReports of Multiple Primary Neop/asms in A~sociation with Malignant Lymphoma of the Central Nervous System Patient
Authors
CNS lymphoma
Year
Age
Sex
Burstein et al
106~
49
F
Reticulum cell sarcoma (h Te-Pa)
Jelliuger and Radaszkiewicz
I976
68
M
Hara et al
1979
46 71 76 6O 15
F F M M F
Immunocytic type (multiple) (Kiel classification) lmmunoeytic type (bil thalamus) Immunocytic type (lt Fr) lmmunoblastic type (h Fr) Immunoblastic type (multiple) Reticulum cell sarcoma (rt Pa-Oc)
Katayama et al
1981
71
M
Immunoblastic type (rt Te)
Giromini et al
1981
11
M
Burkitt type (It Te-Pal
Nakagawa et al
1987
63
M
Dorreen et al
i988
73
Histologic subtype (location)
58 5q
Large-cell type (lt Fr) (LSG classificationl M Centrocytic/centroblastic (vermis} (Kiel classification) F Lymphoplasmacytoid (C.CI M Centrocytic/centroblastic Ibil Oc)
1990
62
F
Angeid-Backman 1990 and Quint
12
F
DeAngelis
1991
67
1992
69 51 77 63 69 77 67
it
60
F
Kuroiwa et al
Yamasaki et al
F
M
Diffuse, large
