AIDS: An Overview of the Pathology

Path. Res. Pract. 182, 585-608 (1987)

Diagnostic Seminar

Encephalomye1opathies Associated with Extracerebral Malignant Tumors::J. Peiffer Institute of Brain Research, Eberhard-Karls-University of TDbingen

SUMMARY

It was the aim of this study to examine the probability of pathogenetical relations between extracerebral malignant tumors and lesions of eNS. The term paraneoplastic should be questioned. Among a running series of 2.000 brain autopsies, 456 patients (22.8%) showed such tumors, 362 of these combined with lesions in brain or spinal cord. Out of these cases, 100 had metastases, meningoses blastomatosae or leukotic hemorrhages, 218 other, non-tumoral lesions, and 44 both tumoral and non-tumoral lesions. The last-mentioned 262 cases were the target of the examination. We distinguished 6 groups: a) various welldefinable impacts, diseases or genetical defects (n = 18), b) unspecific terminal resp. agonal changes (n = 49), c) vascular or circulatory disorders incl. embolisations (20 non-leukotic hemorrhages, 148 anemic infarctions or selective neuronal necroses), thromboses, angiitis or calcifications, d) infections and other inflammatory alterations (n = 37), e) metabolic and toxic lesions (9 Wernicke's disease, 12 central pontine myelinolyses), f) anomalies difficult to classify (51 cases with subacute cerebellar atrophy, diffuse leukoencephalopathy, focal spongious axonopathic lesions, myelomalacia and other). After analysing the various lesions and discussing the probable pathogenesis we grouped according to the following scheme: I) tumor-unrelated (casual coincidence) (43.2%), II) therapy-dependent (3.7%), III) agony-related (10.7%), IV) homoiogenic disorders (e.g. larynx carcinoma and Wernicke's disease) (2.0%), V) nosocomial disorders (12.9%), VI) tumor-dependent (local neighbourhood effects, primary or secondary remote effects). As the central group there remain the primary remote effects (17.3 %), separable into specific functional anomalies by tumorous organ destruction, remote effects of tumor cell-born (ectopic) release of hormones or hormone-like substances (n = 2), tumor antigen-dependent immune reactions (n = 20), and pathogenetically still uncleared mechanisms (n = 51). One should apply the term paraneoplastic only for the three last-mentioned conditions.

Introduction The experience that there can be pathogenetic connections between a malignant tumor and disorders in the nervous system or in sceletal muscles is an old one: in * Dedicated to Prof. Dr. A. Bohle on the occassion of his 65th birthday. © 1987 by Gustav Fischer Verlag, Stuttgart

1890, Auche was the first to discuss possible toxicmetabolic influences, followed by Oppenheim (1899) who observed bulbar symptoms in a case with lymghosarcoma, and by Nonne (1900) and other authors ,55. DennyBrown created the term "paraneoplastic syndrome" for these tumor-associated symptoms. Some of the most important more recent investigations are presented in Table 1. This table, which elucidates the various attempts at classifying these remote effects of tumors, shows that 0344-0338/87/0182-0585$3.50/0

586 .

J.

Peiffer

Table 1. Classification of paraneoplastic lesions by some authors Thomas et al. 1972 Metabolic encephalopathies Ectopic hormone proquction Central pontine myelinolysis Wernickes encephalopathy Diffuse polyencephalomyelitis Encephalomyelitis, limbic, bulbar (polio-)myelitis ganglioradiculitis cerebellar Multiple sclerosis PML and other infections with known etiology Cerebellar degeneration Spinal-cerebellar-brainstem deg. Myoclonic encephalopathy Motor neuron diseases Leukoencephalopathies (necrotizing) Myelopathy (acute, chron.) Vascular and hemostatic disorders

Armstrong 1977

+ + + +

+

+

+

+ + +

+ + +

+

there are no complete congruences. Most of the authors agree about the connection between tumor disease and some metabolic disorders as e.g. Wernicke's disease, and most of them have acknowledged that inflammatory reactions, spinal cerebelrar degenerations and necrotizing myelopathy may be tumor-related. Henson and Urich (1982) limited these associations to the four groups of encephalomyelitis, cerebellar cortical degeneration, peripheral neuropathy and myopathies. Our study will be restricted to the CNS. The aim of our study was an unbiased collection of all types of CNS lesions in patients ,with malignant extracerebral tumors and an analysis of the probabilities of their pathogenetic dependence on the tumor disease.

/

2.000 CNS (1978-1984)

1.544 (77,2%) (control collective' for non-tumoral

~

Metastases,Meningoses blastom.,leucotic bleedings without other CNS lesions

100 (21,9%

...---------,

Metastases Meningoses blastom. or leucotic bleedings and additionally non-tumoral CNS-Iesions 44 (6,9% of 456) 1

or. ------.v,.-----J 456) 1....

Tumoral lesions 144 (31,6% of 456)

Henson a. Urich 1982

+

+ + + + + + + + + +

+

+ + + + +

+ + +

+

Hildebrand 1978

+ +

+ + +

+ + +

The need of classifying the different lesions according to their pathogenesis nevertheless led us to arrange them in a spectrum reaching from improbable to very probable pathogenetical relationships. Material and Methods Our study is based upon a running series of 2000 brain autopsies taken from 1978 to 1984. Among this collective we found 456 patients (22.8%) with extracerebral primary malignant tumors. Tabelle 2 gives a review of the distribution of these cases. In 362 (79.4%) lesions in brain or spinal cord could be observed. They were caused in 100 cases (21.9%, related to 456 tumor cases) only by metastases, meningosis blastomatosa or leucotic hemorrhages. Another large group of 218 cases (47.8%) was free from such tumor cell seeding, but manifested other non-tumoral lesions. A third, smaller group of 44 cases (9.6%) represented a mixture of both tumoral affections and non-tumoral lesions. The two last-mentioned groups (262 = 57.4% of 456 tumor cases) will be the target of our study. As control collective served the remaining 1.544 cases without malignant tumors.

Non-tumora I CNS-Iesions

218 (47,8% of 456)

Non-tumoral lesions 262 (57,4% of 456)

+ + + + + + + +

Palma 1985

Table 2

Cancer Remote Effects . 587 The brains examined were cut in the usual manner into coronal slices. From each brain we examined at least blocks of medulla oblongata, pons, cerebellum, caudal and rostral basal ganglia, temporal cortex with ammon's horn as well as frontocentral cortex with deep central white matter. The paraffine-embedded blocks were cut into 8 I.l slices and stained with HemalaunEosine, and after Kliiver-Barrera and van Gieson. In many cases additional regions were examined. Sometimes, additional staining methods were applied (PAP- or AAPAP-methods with antiGFAP, -Cl, -Leu 2a, -3a, -7, -OKMl, -OKT4 resp. -8).

Results

1) CNS lesions by tumor cells It will be helpful to give a short review first of our cases with metastases, meningoses or leucotic hemorrhages: Carcinoma cell seeding could be observed in 68 cases (14.9% of 456 with primary extracerebral carcinomas). Including lymphomas and leukemias 144 (31.6%) had blastomatous alterations of CNS. Table 3 shows the distribution of either brain metastases or meningosis blastomatosa or its combination and the whole percentage of tumoral CNS involvement related to the different primary tumors. Among our carcinoma cases lung and breast tumors were most frequent. In both acute myeloic leucemia and non-Hodgkin-lymphoma the meninges were most frequently involved, followed by breast and lung carcinomas. The alterations of brain tissue in leukemias was limited to tumor bleedings.

a) The age distribution, given in percents, shows - as expected - an age summit in the 6th decade of life. Only in esophagus and ovarial carcinoma were patients afflicted at an earlier age. The same applies to acute lymphatic leucemia or melanoma. In Table 4, the age group with the highest frequency of autopsy cases is printed in italics. b) Concerning sex distribution (Table 5) the extent to which carcinoma of larynx and pharynx, mouth and tongue as well as carcinoma of the liver predominate in males is remarkable. This may be caused by the combination of nicotine abuse and chronic alcoholism as the main pathogenetic factors. I have mentioned this metastatic involvement of the CNS with tumor cells although these lesions are not directly related to the problem of remote effects. But the environment of metastases may provide a mirror of the immunological reaction between tumor and host tissue which may meaningful for the remote effects (see below). 2) Non-tumoral lesions in CNS

Our first attempt at classifying these lesions as unbiased as possible yielded the following groups: a) various well-definable impacts, diseases or genetical defects b) unspecific terminal resp. agonal changes, c) vascular resp. circulatory disorders includ. embolisations, d) infections and other inflammatory alterations,

Table 3. Frequency of metastatic CNS alteration by tumor cells in various extracerebral malignant tumors n=

Only brain metastases

Only meningoses blastomat.

Only metastases and meningoses

Total tumoral alteration of CNS

%

n

Lung care. Mouth, larynx, pharynx care. Esophagus care. Stomach care. Breast care. Liver care. Gallbladder care. Pancreas care. Intestin. traer. care. Kidney, bladder care. Male reprod. organ. care. Female reprod. organ. care. Endocrine organ. care. Hodgkin lymphoma Non-Hodgkin lymphoma Plasmocytoma

AML

CML

ALL

CLL Melanoma mal. Sarcoma

63 23

25 1

32 34 19 12 11

4 8 2

25

5

8

22 13

14 3 9 44 23 41 28

8

9 8 7

456 " tumor bleedings

2

1

2

1

1

3 12* 7* 2* 1*

6 2 1 4

1

1 1 1 7 1 4 3

3

1

13

2

3

2 1

2

83

28

33

3

1

33 3 1 5 14 1 1 2

52.3 13.0 12.5 15.5 41.2 5.3 8.3 18.2

5 2

10.0 15.0

1 1 11 7 29 12 5 5 5 1

33.3 11.1 25.0 30.4 70.7 42.8 62.5 55.5 62.5 14.3

144

31.6

588 .

J.

Peiffer

Table 4. Age distribution of the 456 cases with malignant extracerebral tumors. The decades with the highest percentual dead rate are printed in italics

10-19 20-29 30-39 40-49 50-59 60-69 70-79 80 years

n=

63 23 8 32 34 19 12 11 22 25 13 14 3 9 44 23 41 28 8 9 8 7 456

Lung care. Mouth, larynx, pharynx care. Esophagus care. Stomach care. Breast care. Liver care. Gallbladder care. Pancreas care. Intestin. traer care. Kidney, bladder care. Male reprod. organ care. Female reprod. organ care. Endocrine organ care. Hodgkin Lymphoma Non-Hodgkin lymphoma Plasmocytoma AML CML ALL CLL Melanoma mal. Sarcoma

7.6 11.1 2.4 3.5 37.5

n

cJ

~

63 23 8 32 34 19 12 11 22 25 13 14 3 9 44 23 41 28 8 9 8 7

49 22 7 17

14 1 1 15 34 1 11 2 10 8

18 1 9 12 17 13 6 21 13 20 17 5 5 3 5

7.1 2.3 4.3 14.6 7.1 12.5 12.5

Table 5. Sex distribution.of 456 cases with extracerebral malignant tumors

Lung care. Mouth, larynx, pharynx care. Esophagus care. Stomach care. Breast care. Liver care. Gallbladder care. Pancreas care. Intestin. tract care. Kidney, bladder care. Male reprod. care. Female reprod. care. Endocrine organ care. Hodgkin lymphoma Non-Hodgkin lymphoma Plasmocytoma AML CML ALL CLL Melanom.a mal. Sarcoma

5.2

11.1 39.1 37.5 12.5 20.6 21.0

20.6 17.4 12.5 3.1 17.6 21.0 8.3

8.0 7.6 14.2

18.2 4.0 7.6 7.1

9.1 20.0 15.4 21.4

4.3 25.0 3.1

14 3 3 23 10 21 11 3 4 5 2

e) metabolic and toxic lesions, f) anomalies nosologically difficult to classify, especially - in the gray matter - in the white matter or - multifocal.

11.1 4.5 9.7

25.0

33.3 15.9 4.3 19.5 21.5

42.8

20.4 17.4 24.3 7.1 12.5 11.1 28.6

34.9 17.4 12.5 40.6 32.3 47.6 25.0 45.4 36.4 36.0 23.0 14.2 66.7 44.4 29.5 17.4 22.0 32.1 12.5 44.4 25.0 14.3

27.0 21.7 12.5 28.1 23.5 5.2 50.0 45.4 22.7 28.0 23.0 14.2 33.3 20.4 30.4 7.3 28.6 25.0 33.3 25.0 14.3

6.3 12.5 5.9 16.7 9.2 13.6 4.0 15.4 21.4 6.8 26.1

11.1 12.5

Ad a) Various well-definable impacts, diseases or genetical defects: Among this group we counted 8 traumatic lesions 2 senile changes (presenile and senile M. Alzheimer) 6 malformations 2 multiple sclerosis. Although publications by Neuburger and Rosch (1953) as well as Ulrich (1982) point to higher percentages of senile changes among tumor patients, we are not convinced of the existence of pathogenetic relations. In our material senile changes in the tumor group are not more frequent than in controls. Of course, neither malformations nor traumatic lesions have any relationship. We mention two cases of multiple sclerosis, because Croft et al. (1967) as well as Zimmermann and Netsky (1950) mention some cases of MS in their reports..But, we agree with Allen et al. (1978) that this is only a casual coincidence. Ad b) Unspecific terminal resp. agonal changes. In 29 cases the cerebellar cortex showed acute granular cell necroses without any intravital cellular reaction on the light microscopical level. In 15 cases the brain tissue displayed recent ischemic or edematous changes. In 5 further cases intravital brain death could be diagnosed. Ad c) Vascular or circulatory disorders inc/. embolisation. This group consists of (Tab. 6) 20 cases with non-Ieukotic hemorrhages 148 cases with selective neuronal necroses or anemic infarctions 22 cases with thromboses.

Cancer Remote Effects· 589 Table 6. Distribution of cerebrovascular lesions in different malignant tumors n=

Lung carc. Mouth, larynx, pharynx carc. Esophagus carc. Stomach carc. Breast carc. Liver carc. Gallbladder carc. Pancreas carc. Intestin. tract. carc. Kidney, bladder carc. Male reprod. organ. carc. Female reprod. organ. carc. Endocrine organ carc. Hodking lymphoma Non-Hodgkin lymphoma Plasmocytoma AML CML

ALL

CLL Melanoma mal. Sarcoma

63 23 8 32 34 19 12 11 22 25 13 14 3 9 44 23 41 28 8 9 8 7

Hemmorrhages non-tumoral tumoral 1 1 1 1 4 1 1 2 1 1 3 3

23 10 3 2

456

38

20

Selective neuronal necroses 5 3 1 3 5 7 1 2 2 1 2 1 1 2 5 1 3 4 1

49

Anemic infarcts 9 6 1 7 7 3 8 8 5 9 6 3 1 1 8 4 1 2 2 2 1 94

Thromboses Embolisation

3 2 1 1

1 1

1* 1* 1* 1

1*

1* 1 6 2 1 1

1 1*

2 22

8

* 6 cases with non-bacterial J;;ndocarditis

Without taking into account 38 cases with leukotic tumor hemorrhages, most hemorrhages could be explained by hypertensive angiopathy or other basic diseases including hemorrhagic diatheses due to liver disorders. Among the vascular abnormalities atherosclerosis (severe in 26, moderate in 49 cases) or' hypertensive angiopathy (13 cases) are the most frequent causes of infarcts. In 49 further cases the alterations were restricted to non-terminal selective neuronal necrosis with intravital cellular reactions. The comparison between our tumor collective and the control group (Tab. 7) reveals no differences in the fre-

Table 7. Comparison of the frequency of cerebrovascular CNSlesions among malignoma patients and control cases MalignomaPatients n = 456 Hemorrhages (non-tumoral) 20 Infarction, Necroses 141 Infections, inflammat. processes (non-tumoral) 35 Vessel wall calcifications 18 Angiitis 4 _ 22 Thromboses * p:5 0.005

4.4% 30.9% 7.7% 3.9%* 0.6%* 4.8%*

ControlCollective n = 1544 139 633

6.8% 30.8%

97 18 2 16

6.8% 0.9% 0.1% 0.8%

quency of infarcts or non-tumoral hemorrhages. Their distribution within the tumor group is almost equal. Nevertheless, differences are statistically significant in the frequency of thromboses, angiitis and calcification of vessel walls. We observed 22 cases with thromboses (4.8%). Thromboses are observable in arteries as well as in venes and furthermore in different stages of the development of thrombotic processes (Fig. 1a). 4 cases concern only recent (hyaline) thromboses based on hypercoagulopathy, resp. shock in the terminal stage of tumor disease. Therefore, we hesitate to include these lesions into the remote effect of cancer. Thrombophlebitis, first described by Trousseau (1865), was also interpreted as a paraneoplastic syndrome by Pineo et al. (1974), as well as Henson and Urich (1982). In our material thrombophlebitic lesions were very rare (2 out of 22 thrombotic processes). Figure 1b shows an example of acute cortical necrosis due to thrombophlebitis with migration of polymorphonuclear leucocytes through the vessel wall to the leptomeninges. The higher rate of thrombosis can be considered in the context of investigations by Tohgo et al. (1984) who found an enhanced activity of platelet aggregation in metastasing tumors. As a further possible cause of circulatory eNS-disorders in small cell lung cancer Markiewicz et al. (1986) in a recent report have demonstrated the proliferation of mesothelial cells in cerebral vessels. Thrombotic processes are furthermore aided by increased viscosity of serum in plasmocytoma and Waldenstr6m's disease. They are, however, also frequent in other myelo-

590 .

J.

Peiffer b)

Fig. 1. a) Recent thrombosis in cortical venes (van Gieson 1: 100); b) Thrombophlebitis of a leptomeningeal vessel (HE 1: 40).

proliferative diseases as well as in polycythemia vera 61. As far as thromboses are concerned, we agree with Armstrong (1977), who mentioned among his cases with vascular disorders a very high incidence of non-bacterial thrombotic endocarditis, migratory thrombophlebitis, atypical angiitis and vascular disorders with hyperviscosity. As a possible cause of infarction, embolisation by nonbacterial endocarditis had sometimes been mentioned. Endocarditis in our files was registered in 10 cases (2.2 %), but combined with cerebral infarcts only in 6 of these cases (Tab. 6). This value closely corresponds to the frequency of 1% described by Hildebrand (1978), resp. 4.2% by Ziegler (1968). Ziegler found non-bacterial endocarditis preferentially in cachectic patients with adenocarcinoma. Corresponding to the frequency of the different tumors in our material half of the cases with endocarditis belong to Non-Hodgkin lymphoma (1), AML (6), CML (2), ALL (1) and CLL (1), whereas among carcinoma only larynx resp. pharynx carcinoma (3) showed a relative higher frequency. Non-bacterial endocarditis has been interpreted as a paraneoplastic syndrome llO ,113. If a non-bacterial endocarditis is the probable origin of cerebral embolisation we here would have to deal with a tertiary effect of a malignant tumor. Aita (1972) emphasized that in 85% of thrombotic endocarditis a carcinoma is the basic disease. Even if these high values could not be generalized, we would have to reckon with thrombosis, thrombophlebitis or other forms of vasculitis as possible causes of cerebral infarctions. In any case the combination of malignoma and cerebral infarction should be a reason to discuss the possibility of a non-bacterial thrombotic endocarditis or an angiitis as described by Rewcastle and Tom (1962) in Hodgkin's dis-

ease. The occasional combined occurrence of non-bacterial endocarditis and giant cell angiitis 142 suggests an endothelial lesion as the common pathogenetical factor. Among our 3 cases with angiitis, one case showed a giant cell arteritis (Fig. 2a) as the one described for malignomas by Koeppen et al. (1981) or Ojeda et al. (1984). Nevertheless, we have to distinguish this kind of giant cell arteriitis from another one seen in a second case caused by tuberculous meningitis in a case with laryngeal carcinoma and a suppressed immune state. Those pictures should not be confused with epithelial tumor cell settlements on endothelia, such as in a case with chorioepithelioma. In giant cell arteritis, however, the question arises, wether we have to deal with a nosocomial viral infection

Table 8. Calcified vessel (mostly in basal ganglia) in various malignant tumors

Lung care. Mouth, larynx, pharynx care. Stomach care. Breast care. Liver care. Gallbladder care. Pancreas care. Intestin. tract care. Male reprod. organ care. N<;m-Hodgkin-lymphoma Plasmocytoma

AML

n

Calc.

63. 23 32 34 19

3 1 2 1 1 1 1 1 2 1 3 1

12 11

22 13 44 23 41

18 = 3.9%

Cancer Remote Effects . 591 a)

Fig. 2. a) Giant cell arteritis (HE 1: 400); b) Single carcinoma cells within dorsal nerve roots (van Gieson 1 :400).

by the varicellen-zoster group21,68, or by cytomegaly72. This giant cell arteritis can be restricted to the CNS 65 . Among the 18 cases with calcification of vessel wall (Tab. 8) 12 concern the common mineralisation of arteries and the microvasculature of pallidum, two cases additionally concern the dentate nucleus and the lamina circum-

voluta medullaris of Ammon's horn. In 4 further cases segments of meningeal arteries were mineralized. Price and Birdwell (1978) described those mineralisations as occurring preferentially in children with ALL (in 28 of 163 brains), and interpreted them as a consequence of irradiation. In our material however, we did not find such an

Table 9. Frequency of various infections and inflammatory reactions in cases with malignant tumors Infections with known agents Viral Fungal Bacterial

n

Lung care. Mouth, larynx, pharynx care. Stomach care. Breast care. Liver care. Pancreas care. Intestin. tract care. Kidney, bladder care. Female reprod. organ care. Endocrine organ care. Hodkin lymphoma Non-Hodgkin lymphoma Plasmocytoma

AML

CML

ALL

CLL Sarcoma Melanoma

63

23 32

34 19 11 22 25 14 3 9 44

23

2 1

1

2 1 1

~1

~1

1 ~3

28

1

1

7

3

1 1 1 7 (4 immune supprimed)

1 2 1

1

3

1

41

8 9

Inflammatory reactions of unknown etiology Encephalomyelitis only infiltrates with glial nodes

1

~2

1

~3

1

7 8

7

(4 probably metastatic-septic)

12

592 .

J. Peiffer

accumulation in leukemias. We could not observe any subcortical calcification as demonstrated by McIntosh et al. 1977 in Methotrexate-treated leucotic children, too. We were also unable to observe a special relation to bone metastases except for three cases of plasmocytoma. d) Infections and other inflammatory alterations. We have to distinguish between infections with known agents and inflammatory reactions of unknown etiology (irresa)

pective of the above-mentioned vasculitis) (Tab. 9). Preferentially involved are lymphomas and leukemias, especially AML. Remarkably high is the frequency of bacterial meningitis and fungal encephalomyelitis, each represented by seven cases. In 5 further cases metastatic-septic encephalitis was probable. The most impressive picture among infections with known etiology is offered by progressive multifocal leucoencephalopathy demonstrable in one case each of Hodgkin's and Non-Hodgkin's lym-

b)

Fig. 3. a) PML-like demyelinating pontine focus (HE 1 : 40); b) Plasmocytic infiltrates and activated astrocytic nuclei (HE 1 : 1000).

Fig. 4. a) Swollen axons in pontine focus (van Gieson 1: 400); b) GFAPpositive proliferative astrocytes in pontine focus (anti-GFAP-PAP 1: 400).

Cancer Remote Effects . 593 phoma. The more frequent occurrence of PML in leukemias and lymphomas has been pointed out by Sibley and Weissberger (1961), jellinger and Seitelberger (1965), Boudin et al. (1974), Rubinstein et al. (1975), as well as Gagne et al. (1977). In one of our cases was PML combined with toxoplasma-encephalitis lOl • But not all cases with a multifocal demyelination and inflammatory signs belong to PML: Beneath metastatic-septic foci with accompanying demyelination (Fig. 13) by perifocal edema we found a PMLlike case in candida sepsis (Fig.3a, b, 4b). Microscopically, of course, there were no diagnostic problems, but in CT the pattern can be very similar and therefore misleading. We observed fungal encephalomyelitis in seven cases, in one of which (cryptococcosis) the diagnosis could even be given by CSF cytology. In 4 of these cases immunsuppressive therapy gave an explanation for mycotic infection. We were able to diagnose nearly half of our cases with inflammatory reactions as metastatic-septic encephalitis (1 surely, further 4 probably) or as nosocomial infections of known etiology (Tab. 9, 10). The frequency of CNS infections, however, is not as high as in the tumor cases of Chernik (1973) (33% in lymphoma, 20% in leukemia). But both tumors also revealed a greater number of viral resp. mycotic infections of CNS in our material. Their morphological pattern, however, can be very similar to cases with inflammatory reactions ofunknown etiology. Twelve of the latter 19 cases showed only scattered perivascular lymphocytic infiltrates and glial reactions. The morphological pattern of the inflammatory reactions of unknown etiology has been emphazized by the London group' 24,57-60, furthermore by authors from other countries' 39,81,122, but of course these combinations of lymphocytic infiltrations and glial reactions are unspecific and observable in non-tumoral cases too 26 , 36, 74, 98, 99, 129, 137. The separation of bulbar, limbic and cerebellar encephalitis 58 ,60 reflects some topographic preferences the specification of which, however, is low. It can be even difficult to distinguish cerebellar encephalitis from subacute cerebellar degeneration, as demonstrated by the first case of Greenfield in 1934. Among our 19 cases with this syndrome the infiltrates had been restricted in one case to spinal cord, whereas in 11 cases the infiltrates have been accentuated in brain stem. We cannot exclude that in some

of these cases the infiltrates are due to embolisation of non-bacterial endocarditis that is discussed as a possible paraneoplastic cardiac alterations (see above). But only in one of these cases was endocarditis proved. Hence we have to take into account other pathogenetic factors, too. Inflammatory reactions can also be caused resp. influenced by immune reactions to - tumor antigens and/or - own tissue (by sharing epitopes) or insufficient resp. altered immune competence - by the tumoral process itself and/or - by therapeutic immune suppression Many of the infectious disorders mentioned above are due to altered immune competence. In the inflammatory reactions of unknown etiology, however, the first-mentioned conditions may rather be responsible for the infiltrates. Among the trials to understand the pathogenesis of tumor-induced remote effects it was obvious to look for the immunological reactions next to the primary tumor. Inflammatory infiltrates were examined by Bloom et al. 1970, Brooks et al. 1974, Wood et al. 1979 and von Hanwehr et al. 1984. But the results of these studies have been quite incoherent. Interesting, nevertheless, were observations that serum antibodies of patients with oat cell bronchial carcinoma will sometimes show antigen reactions to retinal neurons 52 , to one fraction of neuronal ribosomes 143 , to neuronal nuclear antigen46 as well as to other neuronal antigens 9 • Antigen-reactions of Purkinje's cells after treatment with serum of carcinoma patients seemed to be more important49 , 63, 130. The relevance of those findings, however, is ambiguous since Greenlee and Sun 1985 were able to demonstrate anticerebellar serum antibodies in patients without any tumor. But Meyer (1984) showed that the anti-T-cell-antibodies UCHT 1 cross-react with Purkinje cells, too. Here ways to a better understanding of remote effects could be opened. In our cases the carcinomatous lymphocytic infiltrates contain many Leu 7and Leu 11-positive cells (Fig. 5), interpreted as NK-cells (Tab. 11). This combination separates carcinomas and craneopharyngeomas from gliomas. According to Arai et al. (1983) the large granular lymphocytes like the Leu 7positive cells 126 have the potency to suppress .the B-cell differentiation. Tanaka et al. (1985) could demonstrate Inflammatory reactions of unknown etiology (n=19)

Nosocomial infections of known etiology (n=18) e.g. PML (2) Fungi (7) .............. Herpes zostervaricella (1) Bacterial Meningi tis (7) Metastatic-septic __ encephalitis (1) --

Table 10

" Carcinomatous Encephalomyelitis" Perivascular lymphocytic cuffs

--

Embol i sati on by non-bacterial endocarditis1 (4)

Lymphocytic infiltrates n=12

594 .

J.

Peiffer

Fig. 5. Anti-Leu-7-positive infiltrate cells around a carcinomatous metastasis (1 :400).

Table 11. Kinds of inflammatory lymphocytes around cerebral metastases and brain derived tumors. (After my coworker A. Stevens, 1. Kloter and W. Roggendorf and their short report given in Verh. Dtsch. Ges. Pathol., 70. Tagung. G. Fischer Verlag, Stuttgart-New York 1986, p. 424) Density of Dominant infiltration 1 T-cell population 2

Percentage of specimens with cells Leu

Frequency of NK cells 3 monocytes 4

18

++(+)

T supp.lcytotox.

22%

(+)

10

+

T supp.lcytotox.

10%

20

+++

T supp.lcytotox. = T helper/inducer T helper/inducer - not done-

90%

++

+

86% 45%

+++ +

+

T supp.lcytotox. = T helper/inducer

33%

(+)

(+)

Histopathological diagnosis

n

Gliomas (IV acc. to WHO classification) (I-II acc. to WHO classification) II Carcinoma metastases Craniopharyngeomas III Meningeomas (endotheliomatous) other tumors

7 11

+++ ++

15

++

(Chordomas 3 Teratomas 3 Chondroma 1 vasco Tumors 2 Pituitary Adenoma 1 Neurinoma 5) total

81

1 2 3 4

5

r

(+)

B cells 5 (+) (+)

density of LC+ cells, classified according to Boker et al. (Clin. Neuiopathol. 3: 143-147, 1984) reI. density of OKT 8+ (T suppressor/cytotoxic) and OKT 4+/Leu 3a+ (T inducer/helper) cells reI. density of Leu 7+/Leu 11b+ (NK) cells reI. density of OKM It+/OKM 5+ (monocytic) cells reI. density of anti-Klanti-light chain+ (B) cells

++

++ not done

+

Cancer Remote Effects . 595

that 50-90% of Leu 7-positive cells have a common antigenic component with myeline-associated glycoproteine (MAG). Suggestions that here we are to deal with an approach to understand demyelinations in tumor patients are only speculative. A special form of vasculitis should also be mentioned here: it concerns inflammatory infiltrations of vessels of the basal ganglia, not to be mixed up with limbic encephalitis: the lympho- or granulocytically infiltrated vessel walls show seemingly insignificant gray depositions in normal light microscopy. But in polarisation one can observe an intensive double refraction. The crystaline structures thus demonstrable in polarized light are calcium oxalates. We were able to observe many such cases over the last few years in patients after treatment with xylitol or sorbitol, sometimes also after fructose infusions during intensive care. An altered metabolism of these polyols with conversion to oxalate would appear to be at work hereIo, 64, 100. Ad e) Metabolic and toxic lesions. One of the eldest known metabolic remote effects of malignant tumors is the ectopic production of hormones (Brown 1928) in tumors originating from neural crest. Only in two of our 21 cases of oat cell carcinoma was any hormonal activity registered by clinicians (one with ACTH, one with ADH). In a third case the patient revealed Klinefelter's syndrome. Nevertheless, this disorder does not belong to the CNSlesions proper. An important metabofic disturbance concerns Wernicke's syndrome and central pontine myelinolysis. In nine cases (or nearly 2% of the 456 tumor cases) Wernicke's encephalopathy was demonstrable by the characteristic pattern in corpora mamillaria (Tab. 12). It corresponds to the mean frequency of Wernicke's syndrome in large series of autopsies (1.76% Harper 1979, Peiffer 1982) resp. 1.97% in our controls. For this reason I cannot consider this disorder to be paraneoplastic. Nevertheless, among the Wernicke-afflicted cases, carcinomas are not distributed equally: In accordance with Victor and Laureno (1978) we found an overrepresentation of carcinoma of Table 12. Frequency of alcoholism and Wernicke's encephalopathy in malignant tumors Chron. Alcoholism Lung care. Mouth, larynx, pharynx c. Esophagus care. Stomach care. Liver care. Pancreas care. Kidney, bladder care. Non-Hodgkin lymphoma

n

n

%

Wernicke's Encephalopathy n % Ale.

63 23

7 7

11.1 30.4

5

2

3.1 21.7

5

8 32 19 11 25 44

4 2 5 1 3 3

50.0 6.2 26.3 9.0 12.0 6.8

1 1

4.0 2.3

1 1

9

1.97

2

Table 13. Frequency of central pontine myelinolysis in various malignant tumors Total

n

Lung care. Mouth, larynx, pharynx care. Esophagus care. Liver care. Kidney, bladder care. Female reprod. organ. care. Non-Hodgkin lymphoma CML Sarcoma

63 23 8 19 25 14 44 28 7

n 2 1 1 2 2 1 1 1 1 12

1 Alcoh. 1 Alcoh. 1 Alcoh. 1 Alcoh.

2.6%

the mouth, larynx, pharynx or tongue. In these carcinomas there was a high association with chronic alcoholism. But, as the comparison with esophagus carcinoma demonstrates, another additional factor may be important. We probably have to take into account the malnutrition caused by mouth and pharyngeal afflication. 12 cases showed central pontine myelinolysis (Tab. 13). Not only the characteristic center of the pons was involved. The lesions were extended over the whole brain stem and thebasal ganglia as in the cases just published by Okeda et al. (1986). The mean frequency of central pontine myelinolysis amon£ our whole autopsy material in an earlier examination98 0 er 99 was 0.9%, similar to the series of Shurtliff et al. (1966), but more than the 0.25% of Victor and Laureno (1978). In so far the frequency of 2.6% in our tumor series is higher, but in 4 of 12 cases the patients had been alcoholics. The other patients showed disturbances of electrolytes like those common in other perilous diseases. Such an electrolyte disequilibrium with hyponatremia or hypokalemia, occurring mostly in the terminal stages of the tumor disease, is the main pathogenic factor. Therefore, we do not class central pontine myelinolysis with real paraneoplastic syndromes or with remote effects, but with nosocomial metabolic disorders (see below). However, central pontine myelinolysis must no longer be regarded as an irreversible lethal disorder. We were able to observe several cases with reversibility of the clinical symptoms after cautious treatment of the metabolic disturbances: these are demonstrable also in computer tomographic pictures. Ad f) Anomalies nosologically difficult to classify. This group offers the highest number of problems, because we have to deal with pathogenetically least understood morphological patterns, involving either gray or white matter or altering the CNS by multifocallesions. - Among the gray matter alterations subacute cerebellar degeneration is the lesion reported most frequently. Nevertheless, we could observe it only in five cases, one case each of ovarial, prostate carcinoma and NH-Iymphoma, two cases of gallbladder carcinoma (Tab. 14) (Fig. 6). Henson and Urich (1982) remarked on such a

596 .

J.

Peiffer

Table 14. Review about the main groups of probably tumor-dependent (paraneoplastic) CNS lesions in various malignant tumors n=

Lung care. Mouth, larynx, phar. care. Esophagus care. Stomach care. Breast care. Liver care. Gallbladder care. Pancreas care. Intestin. tract. care. Kidney, bladder care. Male reprod. organ care. Female reprod. organ. care. Endocrine organ care. Hodking lymphoma Non-Hodgkin lymphoma Plasmocytoma AML CML ALL CLL Melanoma mal. Sarcoma

63 23 8 32 34 19 12 11 22 25 13 14 3 9 44 23 41 28 8 9 8 7 456

n= %

Diffuse Focal spong. Cerebellar Leukoencepha- axonopathic cortical lopathy Encephalopathy degeneration

3 = 4.8 1 = 4.3

1 (squam.)

1 (oat) 1

4 = 12.5

1

1

1 1

1= 3= 1= 2= 1= 6=

8.3 27.3 4.5 8.0 7.7 42.9

1

3

6= 4= 8= 6= 3=

66.7 9.1 34.8 14.6 10.7

2 2 1 1 1

2 2 4 3 2

1

1

1 = 11.1

1

24

5

6

1 1 1 1

2 2

1 1

1

1 = 14.3 51 = 11.2

11

discrepancy between the low real frequency of a symptom (PML) and the extent of its publicity: "this plethora of publications is perhaps a reflection of interest and theoretical importance rather than incidence". In our five cases Purkinje's cell layer was thinned out, but granular cell a)

Other neuronal affections

layers were atrophied, too. In the molecular layer there was a glial reaction, sometimes also observed in the dentate nucleus. This allowed the separation of subacute cerebellar degeneration from terminal acute granular cell necrosis 93 • On the other hand, the accentuation in both

.. . ..........

b)

• I

"

Fig. 6. a) Atrophy of cerebellar cortex (HE 1: 40); b) Loss of Purkinje and granular cells with glial reactions in molecular layer (HE 1: 100).

Cancer Remote Effects . 597

hemispheres allows also a differentiation from alcoholic cerebellar degeneration with its preponderance in the anterior vermis. In 5 further cases the alterations were restricted to the anterior vermis. All five had been chronic alcoholics as the tumor caSe reported by Meyer (1944). The tumor cannot be considered responsible for these alterations25 • 114 • But in the other 5 cases we may accept a remote effect, first discussed by Brouwer in 1919, resp. by Brouwer and Biemond (1938), later - but before the cytostatica-era - by Ziilch (1948) as well as by Croft and Wilkinson (1965). Henson and Urich emphasized the role of breast carcinoma, but we were unable to ascertain a preferable vulnerability of a special carcinoma type. The experience of reversibility of the cerebellar alterations 8• 69 could favour the remote effect conception, but is described in chronic alcoholism, too. The real importance of functional disorders of the cerebellar cortex was proved by Wessel et al. (1985) who used posturography. The authors found anomalies in 40% (10 of 25 of patients with bronchial carcinoma). - The cerebral gray matter, however, was not spared in all cases. In each one case of Hodgkin's disease as well as stomach carcinoma we found pseudolaminar ribbons with an intensive proliferation of astrocytes and small vessels as in Wernicke's disease. A further case showed spongious changes in neostriatum and thalamus (Fig. 7a). The rarity of such morphological patterns applies also to spinal gray matter lesiQns, especially to motor neuron diseases. Whereas Norris and Engel (1965) among 130 cases of ALS described 10% as tumor-associated, we were unable to find any case. In the same period of time, however, we observed 10 cases with ALS, all without tumoral diseases. Only in one case were the nerve cells of anterior horn swollen and tigrolytic, but we interpreted this altera-

Fig. 7. a) Spongious changes in putamen in a case with breast carcinoma (HE 1: 250); b) -Diffuse spongious changes in white matter (HE 1 :40).

tion as secondary to carcinomatous infiltrates in nerve roots (Fig. 2b). We are therefore not convinced that alterations of spinal gray matter are remote effects. - Alterations of gray matter are not restricted to a single system as e.g. the cerebellar cortex. Lesions in more than one system (multisystem atrophies) were reported by Verhaardt 1961, Vick et al. 1969 or Martinez-Lage et al. 1972. In our material two nonhereditary cases showed nerve cell loss and glial reaction also found in multisystem atrophy: Both cases, one with a phaechromocytoma combined with carcinoma of the prostate and the other with an ovarial carcinoma, revealed changes in inferior olives, substantia nigra, velum cerebellare superior, nucleus subthalamicus and putamen. Combinations of paraneoplastic cerebellar degenerations and lesions in inferior olives had been described by Schroeder and Kirschbaum (1928), as well as by Buchanan et al. (1947). Greenfield (1954) also mentioned spongious changes in the nucleus subthalamicus. It is very difficult to answer the question wether this is a casual coincidence of multisystem atrophies and tumor or wether this lesions have to be interpreted as tumor-dependent remote effect. In favour of the latter answer is the observation that at least cerebellar atrophies are reversible after excision of the tumor 8• 69. Multisystem atrophies and cerebellar degenerations throw up questions not only about the motoneuron system but also about lesions in the myelinated spinal tracts. - Our numbers of spinal cord lesions are limited because the spinal cord had been removed only in cases with spinal symptoms (Tab. 15). Only in 2 of our 456 cases was a myelomalacia observed, comparable to some earlier descriptions ll • 77• 125 • In one of the two AML patients the multifocal necrotic lesions showed lipophages and other intravital reactions combined with many focal spongious-axonal lesions in

598 .

J. Peiffer

Table 15. Spinal cord lesions in cases with malignant tumors Myelomalacia Oat cell lung care. Stomach care. Ovarial care. Kidney care. Non-Hodgkin lym. Plasmocytoma AML Sarcoma

Spinal traet- Surface-bound spinalNerve cell degeneration demyelination chromatolysis 1

1 1

2 2

Non-paraneoplastic old lesions

3

1

4

3

cerebrum and cerebellum (see below). There was no history radiation or cytostatica treatment. Necrotizing myelopathies, nevertheless, are a rare complication. Demyelination of the posterior resp. spinocerebellar tracts 87 • 134 could be demonstrated in 4 cases (Fig. 8) (one untreated lung carcinoma, three plasmocytomata, 2 of which had been treated with Alkeran resp. Vincristin). Two further untreated cases showed recent surface-bound demyelinations (Fig. 9a, 10). In the last-mentioned alteration a toxic influence via CSF appears suggestive (see below). However, the precondition for accepting a remote effect here is of course the exclusion of dorsal root tumor infiltration. This can be problematic in cases with only a few tumor cells between the nerve roots. Even cases with intensive demyelination of dorsal tracts have to be assessed with caution: thus, in three cases demyelination was not a remote effect, but the consequence of an older destructive process in the vertebral bone.

1

Spondylitis, Duralabscess Compression fracture Postmeningitic. (18ys ago)

The second group concerns cerebral white matter lesions. The literature offers a terminologically muddling picture of the demyelinating processes in malignoma (e.g. disseminated necrotizing leukoencephalopathy, subacute leukoencephalopathy, multifocal leukoencephalopathy, progressive diffuse leukoencephalopathy, neuroaxonal dystrophy, encephalomyeloneuropathy). I prefer the term diffuse leukoencephalopathy (DLE). We can observe here - as the term suggests - a diffuse demyelination, however, with various patterns concerning the glial reaction and the combination with spongious changes (Fig. 11, 7b). Sometimes there is only a rarefication of oligodendroglial cells and a light paling of the myeline staining. Rarely is the white matter spongiously altered. Glial reactions can be quite impressive, being well observable by GFAP immune reaction. In more acute cases the edematous myeline paling is often combined with some small axon swellings. Diffuse leukoencephalopathy involves not only the cerebral white matter but also the

Fig. 8. Systemic demyelination of spinal tracts (Kliiver-Barrera 1: 40).

Cancer Remote Effects . 599

Fig. 9. a) Surface-bound demyelination in spinal cord (Kluver-Barrera 1: 100); b) Focal spongious axonal myelopathy (van Gieson 1 : 250).

Fig. 10. Surface-bound focal spongiousaxonopathic lesions, a) Bodian 1: 40, b) Bodian 1: 400.

cerebellum (Fig. 12). Between the demyelinated fibres lipophages can occasionally be observed. In contrast to PML, neither abnormal blastoma-like astrocytic nuclei nor virus-suspicious particles belong to the pattern of DLE. Diffuse leukoencephalopathy or the more systematically accentuated lesions should be distinguished from focal lesions in which local spongious changes are usually associated with axonal swellings.

The focal spongious-axonopathic encephalomyelopathy (FSAE) is usually accompanied by a syndrome consisting of a light demyelination combined with spongious changes of the neuropile and axonal spheroids or wormlike swollen axons, mostly also of proliferated cytoplasma-rich astrocytes. Lipophages can only rarely be observed. Focal lesions prefer brain stem, peduncles and pontine fibres, more rarely the spinal cord (Fig. 4, 10, 14, 15). Occasion-

600 .

J. Peiffer

Fig. 11. a) Paling of myeline in cerebellar white matter (KluverBarrera 1: 40); b) Loosing of myline sheaths with light astrocytic reaction (HE 1: 250).

b)

Fig. 12. a) Diffuse demyelinated cerebellar white matter with rows of lipophages, Kluver-Barrera 1 : 40; b) Kluver-Barrera 1: 250.

ally, they can be ascertained macroscopically. One case yielded another focus within the pons similar to PML beneath its callosal lesion. Demyelination and glial proliferation were accompanied by slender plasmocytic infiltrates and by an intense astrocytic reaction demonstrable by GFAP antisera (Fig._.3, 4b). As Table 14 demonstrates, the highest percentages of diffuse leukoencephalopathy, focal spongious-axonopathic encephalopathy and spinal

cord lesions were found in Hodgkin's lymphoma, in overial carcinoma, in plasmozytoma, AML, CML as well as in stomach carcinoma. Focal spongious-axonopathic lesions are twice as frequent as diffuse leukoencephalopathy. The accentuation of some these lesions in the surface regions indicates possible relations to cytostatica treatment as an adverse drug effect. Indeed, most of our lymphoma and leukemia cases with CNS lesions had been

Cancer Remote Effects

601

a)

Fig. 13. a) Multifocal demyelination in metastatic-septic fungal encephalitis (HE 1: 40); b) Kluver-Barrera 1: 250.

b)

Fig. 14. Focal spongious-axonopathic encephalomyelopathy a) Axonal spheroids in cerebral white matter (HE 1: 400); b) Axonal spheroids in spinal cord (Bodian 1 : 400).

treated with Methotrexate, Phosphocyclamide or other cytostatica combined or not combined with radiation (15 cases). But it is important to point out that the same changes could also be observed in cases without any intrathecal, systemic or oral cytostatica-therapy (Tabble 16). This applies not only to diffuse leukoencephalopathy, but also to focal spongious-axonal encephalomyelopathy. Intrathecal methotrexat (MTX-)-ther'Wy can be followed by demyelination 1, 4~, 121, by gliosis 6, by tissue necrosis 76, 112, 117, 1~3 or by axonal swellings38 , 88,112,121. Most of the patients were leukotic children, often treated addi-

tionally with radiation. Sometimes the lesions had been combined with calcifications 38 , 40, 41, 106, 109. Not onJ;; in MTX, but also in BCNU71 or Cytosin-Arabinosid62 , 5,139 similar lesions have been described. In all these side effects the time-dosis-relation is an important factor in the toxicity of drugs. If the GSF outflow is inhibited e.g. by leukotic infiltrates or residues of hemorrhages in Paccioni's granulations CSF drug levels can reach toxic levels l9 , 76, 91. As in some of our cases, necrotic myelomalacies can be the consequence40 , 108. In lesions according to Vincristine treatmenrl 3 , 42, 45, 67, 78,118,128 secondary disorders by hyponat-

602 .

J.

Peiffer

Fig. 15. Field of axonal swellings in the pons (HE 1: 100). Table 16. Review about the frequency of cytostatica treatment in cases both with diffuse leukoencephalopathy and focal spongiousaxonopathic encephalomyelopathy. The cursively printed numbers concern cytostatica-treated cases n

Lung care. Mouth, larynx, pharynx care. Stomach care. Gallbladder care. Pancreas care. Intestin. tract. care. Kidney, bladder care. Female reprod. organ care. Hodgkin lymphoma Non-Ho.dgkin lymphoma Plasmocytoma

AML

CML CLL Sarcoma

63

23 32 12 11 22

Diffuse Leukoencephalopathy

Focal spongious-axonopathic encephalopathy/surefacebound

1

1

1

1 1 1 1

1 1

1

25 14

1

9

2

1

1 1

2 1+1

44

23

41

28 9 7

456

1

2

+

2

1

1

1 1

1 2 1 1

1

7+4=11

5

+ 10 = 15

4+5=9 24

remia, too have to be taken into account 111 • The list of dru~s with toxic side effects could be elongated to cisplatin 8 • Adriamycin-Doxorubicin 12 - 17, 141, Cyklosporine~' 70, and also to anticonvulsiva like DPH. As to these severe, partly necrotizing leukoencephalopathies or cerebellar degenerations it is obvious that all these lesions must be interpreted as drug-dependent. But, Mizutani et al. (1984) as well as Daniel et al. (1985), have reported equal lesions in untreated patients. This corresponds to our experience concluded from this material, that the same kind of CNS

lesions can also be observed in tumor patients without any radiation or cytostatica therapy. Even cases with very intensive alterations had never been treated with cytostatica. Therefore, it seems justified to assess at least some of these lesions as tumor-dependent remote effects. Over aed above this it should be noted that focal axonal swellings, often combined with spongious changes, are not at all specific for tumor patients, but can accompany traumata, metabolic disorders , avitaminoses 73 , 102, 105, 1116 or intoxication33 ,120.

Cancer Remote Effects . 603

Discussion

Table 18. Schematic review about the probability of pathogenetical tumor-association in different kinds of CNS alterations

Although our study was intended as an unbiased examination of CNS lesions in patients with malignant extracerebral tumors in an unselected material, some inevitable selection mechanisms, even in running series, cannot be avoided: - clinics may have different diagnostic, therapeutic or scientific interests, - in the agreement of patient's family to necropsy there are many imponderabilities - interesting cases are overrepresented in university clinics, - hence age distribution is atypical, - spinal cords are not available in all cases. Thus, the presence of a well known tumor centre in our medical school may explain that the percentage of patients with leukemia and lymphoma is relatively high. Nevertheless, the frequency of malignant tumors in our material corresponds with values given by other authors (Table 17). Table 18 summarizes the different categories of CNS-lesions and their frequency. As many cases had more than one lesion, the number of lesions (410) exceeds the number of the 262 cases with non-tumoral lesions. The percentages, however, are related to the whole 456 tumorbearing cases. Table 18 displays that vascular, resp. circulatory disorders represent the biggest part. But, the list does not answer the question wether there are lesions which are pathogenetically related to, or even dependent on, the basic tumoral disease. In our comments on the different kinds of lesions we explained our position. It was not difficult to give an answer to the two poles of possible tumor-relationship: Of course, malformations or traumata are obviously unrelated. Patterns like diffuse leukoencephalopathy or focal spongious-axonopathic encephalomyelopathies are probably related. The reason why we arrange the one or the other lesion between the poles depends particularly on our knowledge of other, better-known pathogenetic factors as electrolyte disturbances in central pontine myelinolysis. A main problem, is the terminology. What is the meaning of "paraneoplastic", tumor-related, tumor-associated or nosocomial? We prefer the last-mentioned term in cases Table 17. Comparison of the frequency of metastatic CNS alterations in different series of malignant extracerebral tumors n

metast.lmeningoses %

Gonzales-Vitale and Garcia-Bunuel 1976 Galluzzi and Payne 1956 Abrams et al. 1950 Miiller and Wochnitz 1961 Chason et al. 1963 Aronson et al. 1964 Peiffer 1986 (all tumors) Peiffer 1986 (only carcinoma)

2.227

18.0

647 1.000 3.239 200 2.406 456 279

21.0 17.6 9.8 18.3 16.5 31.6 14.9

a) Various well-defined impacts, diseases and genetical defects (29 cases = 6,3 %) - senile changes 12 - traumatic lesions 8 - malformations 7 - multiple sclerosis 2 b) Unspecific terminal resp. agonal changes (49 cases = 10.7%) 29 - acute granular cell necrosis - acute hypoxia and edema 15 - intravital brain death 5 c) Vascular or circulatory disorders includ. embolisation (217 cases = 47.6%) - hemorrhages (non-tumoral) 20 148 - infarcts - thromboses 22 - embolisation by endocarditis 6 - angiitis 3 18 - calcification of vessel wall d) Infections and other inflammatory alterations (38 cases = 8.3%) - of known etiology 18 - of unknown etiology 19 - by polyol-dependent oxalate cristals 1 e) Metabolic and toxic lesions (26 cases = 5.7%) - Wernickes encephalopathy 9 - alcoholic atrophy of vermal cortex 5 - central pontine myelinolysis 12 f) Anomalies nosologically difficult to classify (51 cases = 11.2%) - in gray matter - subacute cerebellar degenerations 5 - cerebral gray matter alterations 3 - motoneuron alterations 1 - multisystem atrophies 2 - in white matter 11 - diffuse leukoencephalomyelopathy - spinal tract degenerations 5 - multifocal - focal spongious-axonopathic encephalopathy 24

with infections of known etiology, here probably as an expression of an immuninsufficiency by tumor cachexia or by cytostatic treatment. Those conditions are neither paraneoplastic nor the sequences of specific organ destruction like in liver cell carcinoma or the neighbourhood reactions by space occupation. Here we should also take into account that most of the tumorbearing patients belong to the older people, who may also suffer from diabetes, atherosclerosis, hypertension or other diseases involving CNS. This explains the high percentage of circulatory lesions in our material. But even more psychosomatic factors like altered nutritional modes in tumor-bearing patients are able to influence the CNS~ Can those conditions therefore be called paraneoplastic? According to Gross (1984), one should reserve this term to the ectopic hormone production of tumor cells and its extratumoral consequences. We tried to classify the lesions found in our material according to pathogenetical conditions and with regard to

604 .

J.

Peiffer

the probability of their tumor-relationship according to the following scheme. Case numbers and percentages (related to 456) concern our material: I) Tumor-unrelated (casual coincidence) (197 cases = 43.2%) trauma (8) malformations (7) multiple sclerosis (2) senile changes (12) atherosclerotic infarcts (148) - hypertensive angiopathy with or without hemorrhages (20) II) Therapy-dependent (18 cases = 3.7%) radiation necroses - toxic side effects of drugs (e.g. cytostatica, anticonvulsiva) (16) - intensive care (polyol-infusions) (1) III) Agony-related (49 cases = 10.7%) - acute cerebellar granular cell necrosis (29) - brain edema (15) - intravital brain death (5) IV) Homoiogenic disorders (e.g. larynx carcinoma and Wernicke's encepalopathy by chronic alcoholism and nicotine abuse) (9 cases = 2.0%) V) Nosocomial disorders (diseases promoted or released by tumor) (59 cases = 12.9%) - infections (20) - metabolic disorders (17) - alterations of blood cells, blood viscosity; dysproteinemia (22)

I

/

/

/

/

/

/

/

/

,-

......

,-

L...--_r----...l' ....

....

....

"-

"-

"-

............

I~

I

'\.

\ \ \ \

'\

"

J

I

Toxic Side "- Effects .......

.... ......

......

\

\

....

-~ ,;

/1f

\\ \ //

Bone Marrow, / Blood Cell / Alterations ./ /

/ r-------,.., /

\

I

Immune Suppression

./

//

....... -

\

I

\

Diffuse Leucoencephalopathy Faciespong :"-axOilOpath rc Encephalomyelopathy -----------Neuronal alterations

\

'\

~

,

I

....

,;

I I I

I

....

-

?

Table 19

.......

Blood Cell Alterations r=IT""'hr-o"'mb"'o-s-es"'~

I Angiitis

\

VI) Tumor-dependent (tumor being the conditio sine qua non) - local neighbourhood effects - primary remote effects (79 = 17.3%) - specific functional anomalies by tumorous organ destruction (e.g. carcinoma of liver or thyroid gland) - remote effects of tumor cell-born (ectopic) release of hormones or hormone-like substances (so-called paraneoplastic) (2) - tumor antigen-dependent immune reactions (socalled paraneoplastic) (20) - pathogenetically yet uncleared mechanism (so-called paraneoplastic) (51) - secondary remote effects - embolisation in non-bacterial (so-called paraneoplastic) endocarditis (6) All these lesions are facultative. An overlap of some of these pathogenetical conditions is possible. The system restricts the term paraneoplastic to a small, but important and pathogenetically interesting group of tumor-dependent remote effects (17.3% of our material). We separate these lesions from local tumor-dependent effects and from nosocomial disorders. Summarizing the different pathogenetical factors and the results of our study in a diagram (Table 19), we find the last-mentioned therapeutic agents to influence either the metabolism of the brain tissue or the immune competence. The immune reactions, however, cannot only be influenced by therapeutic agents but also by the malig-

,,/

I /

/

Cancer Remote Effects . 605

noma cells themselves as antigen-active clones. The altered immune situation or the immune suppression are the cause of nosocomial infections, of arteritis, and inflammatory reactions. On the other hand, the malignoma cells primarily influence the metabolism by the production of ectopic hormones, by the disturbances of the electrolyte metabolism or by the consequences of malnutrition. Nevertheless, it seems to remain an immediate effect of the extracerebral malignoma cells on the central nervous system independent of toxic side effects. This effect concerns the last-mentioned group of remote effects and particularly the pathogenetically mechanism not yet cleared. These are diffuse leukoencephalomyelopathy, focal spongious-axonopathic encephalomyelopathies or neuronal alterations like subacute cerebellar cortical atrophy. All approaches to elucidate the responsible pathogenic conditions of this main group did not lead to a sufficient understanding. Nevertheless, to advance in this field we suggest to analyse all tumor-associated lesions in order to confine the pure, not otherwise interpretable disorders as a basis of further research. At the present time, however, we still have to accept the conclusion drawn by Henson and Urich: "Nothing is known about the pathogenesis of paraneoplastic cerebellar degeneration and all hypotheses advanced are purely speculative". The diagnosis of symptoms interpretable as remote effects of tumors, nevertheless, should be an admonition for the practician, a stimulance for medical research to further elucidate their pathogenesis. References 1 Allen JC, Thaler HT, Deck MDF, Rottenb,erg DA (1978) Leukoencephalopathy following high-dose intravenous methotrexate chemotherapy: Quantitative assessment of white matter attenuation using computed tomography. Neuroradiology 16:44-47 2 Aita JA (1972) Systemic and non-arteriosclerotic causes of cerebral infarctions. In: Vinken PJ, Bruyn GW (Eds) Handbook of clinical neurology, vol 11. North Holland Publishing Company, Amsterdam, pp 466-510 3 Arai S, Yamamoto H, hoh K, Kumagai K (1983) Suppressive effect of human natural killer cells on pokeweed mitogen-induced B cell differentiation. J Immunol 131: 651-657 4 Armstrong RM (1977) Effects upon the nervous system from remote tumors. In: Goldensohn ES, Appel SH (Eds) Scientific approaches to clinical neurology, vol 1. Lea & Febiger, Philadel-

~~

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Received November 26, 1986 . Accepted February 2, 1987

Key words: Paraneoplastic syndrome - Remote effects - Leukoencephalopathy - Cerebellar degeneration - Spongious changes - Axonopathy Prof. Dr.

J. Peiffer, Institut f.

Hirnforschung, Calwer Str. 3, 7400 Tubingen, FRG