Renal lesions associated with malignant lymphomas

Renal Lesions Associated with Malignant Lymphomas* JOHN RICHMOND, M .B ., CH .B ., f ROBERT S . SHERMAN, M .D ., HENRY D . DIAMOND, M .D . and LLOYD F . CRAVER, M .D .

New York, New York

I

N 1878 Sutton and Turner [1] presented to the

Ewing [2] has stated more recently that the kidney is a favorite seat of metastatic lymphosarcoma . Some idea of the incidence of renal involvement in the malignant lymphomas (which term for the purposes of this paper means

Pathological Society of London their autopsy findings in nine patients with "Hodgkin's disease and allied conditions ." Seven showed visceral involvement by the primary process . In five the kidneys were affected . Two of the latter patients, one a boy whose kidneys weighed 19 .5 and 19

Hodgkin's disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungoides) may be obtained from Table I which summarizes the main findings that have been reported by previous authors . It will be noted that the series of Barney, Hunter and Mintz [8] and of 1Nentzell and Berkheiser [9] have not been included because it was not possible, in these accounts, to separate malignant lymphoma from leukemia in

ounces, respectively, had not shown any increase in the number of "colorless corpuscles" in the blood during life and were stated to be suffering from Hodgkin's disease . They are believed to represent the first examples of malignant lymphoma in which involvement of the kidneys by the tumor was recorded .

TABLE I SUMMARY OF THE PREVIOUS LITERATURE REGARDING LYMPHOMATOUS INFILTRATION OF THE KIDNEYS

Authors

No. of Autopsy Cases

Diseases

Cutler [3] Lymphosarcoma (this included reticulum cell sarcoma and malignant lymphocytoma) Jackson, Parker [4] Hodgkin's disease and allied disorders

Symmers [5] Symmetric lymphosarcoma Watson, Sauer, Sadugor [6] . . . . Lymphoblastotna (which included cases of leukemia) Rappaport, Winter, Hicks [71 . . . Malignant lymphoma of follicular type

13

137

17 143 76

Incidence of Renal Parenchymal Involvement

46%

Hodgkin's disease, 18% of 97 cases ; lymphosarcoma 8% of 12 cases ; reticulum cell sarcoma, 21 % of 28 cases 18% Hodgkin's disease, 6 .6% ; lymphusarcoma, 61 .9 Hodgkin's disease, 33% of 3 cases ; lymphosarcoma, 4147c of 39 cases ; mixed lymphosarcoma and reticulum cell sarcoma, 32% of 28 cases ; reticulum cell sarcoma, 50%0 of 6 cases

• From the Lymphoma Service, Departments of Medicine, Memorial and James Ewing Hospitals ; the Department of X-ray Diagnosis, Memorial and James Ewing Hospitals ; the Lymphoma Section, Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research ; and the Departments of Medicine and Radiology, Cornell University Medical College, New York, New York. This work was supported by a grant from the Lloyd F. Craver Fund of the Memorial Sloan-Kettering Cancer Center, New York, New York . Manuscript received February 17, 1961 . f Present address : Department of Medicine, University New Buildings, Edinburgh, Scotland . 184

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the first and from multiple myelomaa and leukemia in the second . It would be misleading to draw firm conclusions from the figures quoted in Table i because of the small numbers involved in some of the reports and because of the different histologic classifications used by the writers . It appears, however, that the kidneys are involved much more frequently by tumor in the lymphomas than in most other forms of cancer . Whereas Abeshouse and Goldstein [70] could find an incidence of renal tumor in only 1 .5 per cent of a very large number of autopsied patients with miscellaneous diseases (56,252) and in only 4 .8 per cent of those known to have malignant disease (16,344), the incidence in the lymphomas is seen to range in one series from 6 .6 per cent in Hodgkin's disease to 61 .9 per cent in lymphosarcoma [6] . The incidence in other series lies between these extremes . In addition to these reports dealing with the frequency of involvement of the kidneys in malignant lymphoma, a number of isolated cases of unusual interest have been described . There are several accounts in which an unexplained abdominal tumor believed to be arising from a kidney has been found at surgical exploration to be due to lymphoma . In one [11], a three year old child who presented with hematuria, a lymphosarcomatous kidneyweighing 20 .5 ounces was removed . In another [12], the tumor was a huge mass of retroperitoneal lymphosarcoma which had engulfed and atrophied the kidney but which at autopsy could not be shown to have invaded the organ . 'he record for size probably belongs to the patient described by Freifeld [73] . This was a seventeen year old boy suffering from leukolymphosarcoma who had clinical features consistent with polycystic disease, namely, bilateral retroperitoneal tumors and mild impairment of renal function . At autopsy the tumors were lymphosarcomatous kidneys weighing 2,320 gm . on one side and 2,450 gm . on the other . As might he expected, reference to kidney metastases appears frequently in the literature, as for example in accounts of lymphosarcoma of the prostate [14], Hodgkin's disease of the mediastinum [75] and lymphosarcoma of the intestines [76] . It has been claimed by some that when kidney involvement occurs as part of a generalized process, it is associated, in most instances, with disease in the retroperitoneal space [17,18] . VOL . 32, FEBRUARY 1962

185

Yet Watson et al . [6], on the contrary, found that invasion of the kidneys from adjacent retroperitoneal disease occurred in only five of their 143 patients with lymphoblastoma who came to autopsy . It is uncertain whether primary lymphoma of the kidney occurs [2,19,20] . Nevertheless, renal involvement may be the only focus of clinical disease, at least for a time, as in the case described by Elmer and Boylan [21] in which the patient died of generalized reticulum cell sarcoma twelve months after nephrectomy . It has also been known for the kidneys and retroperitoneal tissues to be the main focus of disease in lymphosarcoma even at autopsy, as in the patient reported on by Davis and Olivetti [22] in whom the only other finding was a solitary lymphomatous nodule in the liver . In this regard a case recorded by Knoepp [23] deserves special mention since it concerns a patient who had a large lymphosarcomatous kidney removed, who was free of disease at a "second look" operation nearly two years later, and was without any objective evidence of disease five years after the original procedure_ Blatt and Page [241 described a patient in whom lymphosarcoma encased and involved the kidneys and markedly compressed the renal vessels, leading to hypertension and uremia . According to Wallach, Scharfman and Angrist [25], involvement of the renal parenchyma alone rarely has these effects . Kilburn and Brown 126] had an extraordinary patient in whom marked bilateral renal infiltration by reticulum cell sarcoma was found at autopsy, but in whom anasarca and hypoproteinemia not due to proteinuria remitted once spontaneously and once more after nitrogen mustard therapy . Sir James Galloway [27], in lecture notes published posthumously, described a patient with Hodgkin's disease who did have severe proteinuria due to a substance similar to but not identical with Bence Jones protein . Hyperuricemia may complicate malignant lymphoma and, as in leukemia [28,29], chemotherapy and radiation therapy may precipitate "uric acid ncphropathy ." Such a situation arose in a thirteen year old boy with leukolymphosarcoma following the administration of triethylene melamine (TEM) [30] . In this regard it is of interest that Weisberger and Persky [.31] in a series of ninety patients with malignant lymphoma found five with urinary calculi but none in 100 patients with other forms of cancer (e .g .,



186

Renal Lesions in Lymphomas-Richmond et al.

breast, lung, gastrointestinal tract, thyroid) who had also received radiation therapy . It is also apparent from a review of the literature that there is a marked discrepancy between the incidence of clinical recognition of renal lymphoma and its sequelae and the postmortem findings. In the series of 1,073 patients reported by Watson et al . [6] (which included 234 with leukemia), renal involvement was discerned antemortem in only 7 .5 per cent. Moreover, in the series of 618 patients suffering from malignant lymphoma reported by Gall and Mallory [32] only 10 per cent were found to have clinical involvement of any part of the genitourinary tract. Abeshouse and Goldstein [10] state that in none of their series of 1,461 patients with metastatic malignant tumors of the kidney from all causes was the diagnosis made antemortem . On the other hand, only one case was found recorded in the literature in which renal involvement by lymphoma had led to uremic coma and death [25] . This is in keeping with the experience of the same authors who found that of 300 miscellaneous autopsied patients dying of uremia in only one was death due to replacement of the renal parenchyma by tumor . With this background of the incidence and of the protean manifestations of renal involvement in the malignant lymphomas, it was decided to survey the series of patients studied at the Memorial Center for Cancer and Allied Diseases with the following objectives : (1) to establish the precise incidence and type of renal parenchymal involvement by malignant lymphoma in autopsied patients dying of Hodgkin's disease (HD), lymphosarcoma (LSA), reticulum cell sarcoma (RCS) and mycosis fungoides ; (2) to determine what renal parenchymal lesions other than lymphomatous deposits might be attributed to the primary disease and the frequency with which they occur ; (3) to estimate, in the whole autopsy series, how frequently renal lymphoma was the main cause of death ; and (4) to discover what particular clinical and roentgenographic features characterized those patients with renal involvement by lymphoma and to ascertain which findings had led or might have led to an antemortem diagnosis . The results of this investigation are discussed in the present paper . The data will be dealt with in two parts. Part I will contain an analysis of 696 consecutive cases of malignant lymphoma in which an unrestricted autopsy was performed between the years 1916 and 1958 ; in Part n will

be found a study of the clinical and roentgenographic records of those patients with renal involvement by lymphoma who were autopsied in the ten year period from 1949 through 1958 . It was realized that autopsy cases might constitute a selected group for study, but it was considered that histologic examination of the kidneys could be the only acceptable proof of their involvement in the lymphomatous process . It was also realized that a more refined classification of lymphoma than that stated, i .e., Hodgkin's disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungoides, might be desirable . However, it was appreciated early in the study that, as is well known, the histologic picture might vary in different tissues in the same patient and, indeed, in different parts of the same tissue . In the only compromise which was made, those cases of lymphosarcoma in which the marrow was found to be involved were, at times, treated separately . This was done in the belief that such a group would include all the cases of leukolymphosarcoma and that separate analysis of this group would distinguish the renal lesions of lymphoma from those described by other authors as occurring in leukemia [13,33-37] . Part I ANALYSIS AND DISCUSSION OF THE POSTMORTEM FINDINGS TN

696

PATIENTS SUFFERING

FROM MALIGNANT LYMPHOMA

Composition of the Group. The autopsy protocols of all patients with Hodgkin's disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungoides examined between the years 1916 and 1958 inclusive were studied . The total number of patients was 703 . In seven of these a restricted postmortem examination had been undertaken ; they were excluded from consideration . In eight others the final pathologic diagnosis was mycosis fungoides . In view of the nosologic difficulty which this condition sometimes presents, the histologic sections from this group were reviewed . In five patients the diagnosis was sustained, in one it was changed to lymphosarcoma, in one it was changed to reticulum cell sarcoma and in one the appearances were so bizarre that the condition could not be classified . The five patients with mycosis fungoides and the one patient with "malignant lymphoma, unclassifiable" did not show any peculiar feaAMERICAN JOURNAL OF MEDICINE



Renal Lesions in Lymphomas--Richmond cores in regard to the kidneys and will not be considered further . The number of the remaining patients in each disease group is shown in Table u . The Incidence of Involvement of Various Organs and Tissues by Malignant Lymphoma . Table iii summarizes the findings with regard to the incidence of involvement by the malignant lymphomas of all the important organs and tissues in the body . The criterion of "involvement" was microscopic evidence of infiltration . No attempt has been made to record the extent or nature of the lesion or to indicate whether it had been caused by invasion from contiguous tumor or spread from a distant site . It will be seen that when the hemopoietic and reticuloendothelial systems (lymph nodes, liver, spleen and bone marrow) are excluded, the genitourinary system is affected more frequently than any other . Moreover, apart from the relatively high incidence of lung involvement in Hodgkin's disease, the kidneys are infiltrated by the primary disease more frequently than any other organ or tissue . Attention is also drawn to the high incidence of involvement of the pelvic organs, gastrointestinal tract, heart and endocrine glands . The frequency with which the renal parenchyma is infiltrated by the disease in the different lymphomas is as follows ; Hodgkin's disease, 13 per cent : lymphosarcoma (with and without marrow involvement), 49 per cent ; and reticulum cell sarcoma, 46 per cent . In the lymphosarcoma group, 63 per cent of those with marrow infiltration had renal involvement, compared with 38 .5 per cent of the remainder . This difference indicates that leukemic transformation of lymphosarcoma increases the incidence of kidney infiltration ; study of Table iii suggests that this different behavior of leukolymphosarcoma compared with the other cases of lymphosarcoma affects the frequency with which many organs and tissues are infiltrated . In Table Iv an attempt has been made to show the incidence of involvement of the different systems in those patients who have lymphomatous infiltration of the kidneys compared with those who do not . Each system (in each disease group) has been affected much more frequently and disease tended to be more widespread in the patients with lymphomatous kidneys than in the remaining patients . No relationship could be established between any particular system involvement and the presence or absence of disease in the kidneys . VOL, 32, FEBRUARY 1962

et al .

187

TABLE IF NUMBER OF AUTOPSY CASES IN EACH DISEASE GROUP (Total, 690)

Disease Group

No .

Hodgkin's disease ' 272 l .ymphosarcoma 188 With marrow involvement 79 Without marrow involvement 109 Reticulum cell sarcoma 230

At the foot of Table rv it will he seen that the same trend applied, although to a lesser degree, in relation to involvement of the retroperitoneal tissues . In this regard it is interesting to note that there were some patients in each disease group (the incidence ranging from 6 to 14 per cent) in whom renal involvement was found to be the only evidence of lymphoma in the retroperitoneal space . In contrast, in 2 .5 per cent of all patients in the series, the kidneys were encased in a massive retroperitoneal tumor which had, however, failed to invade them . Involvement of the Kidneys by Lymphoma in Relation to Sex, Age and Duration of Disease . The composition of the cases analyzed for sex, age and clinical duration of disease is shown in Figures 1, 2 and 3, respectively . The over-all distribution of the patients in the different disease groups in respect to these factors is in agreement with the published statistics of others . It will be seen that neither sex, age nor duration of the disease appears to have an important influence on the finding of renal involvement at autopsy . However, although Hodgkin's disease and lvmphosarcoma occurred more frequently in the male than in the female in this series, the kidneys were found to be infiltrated in more females than males, in the proportion 1 .65 :1 and 1 .2 :1, respectively- The reverse appears to be true for reticulum cell sarcoma in which the incidence of disease in the sexes was equal but the kidneys were affected in 1 .4 :1 males to females . In lymphosarcoma and reticulum cell sarcoma, renal infiltration tended to be more common in the young (less than forty years) and elderly (more than seventy years) . In all groups, but particularly in the patients with Hodgkin's disease, the incidence of renal involvement was higher in those with a short history of disease (less than two years) than in the remainder . This last finding was considered to reflect the greater



188

Renal Lesions in Lymphomas-Richmond et al.

TABLE In THE INCIDENCE OF INVOLVEMENT OF VARIOUS SYSTEMS, ORGANS AND TISSUES BY MALIGNANT LYMPHOMA

(% in Each Disease Group)

Site Involved

Genitourinary system One kidney Both kidneys Total with kidney involvement (%) One pelvis and meter Both pelves and ureters Bladder One testis* Both testes One seminal vesicle and/or vas* Both seminal vesicles and/or vasa Prostate * One ovary* Both ovaries One Fallopian tube* Both Fallopian tubes Uterus*

Hodgkin's Disease

56 .5 5 .0 8 .0 13 .0 2,5 2 .0 4 .5 0 .5 0 .5 0 .0 0 .5 0 .5 4 .0 5 .5 2 .0 3 .5 9 .5 1 .0 Alimentary system 29 .0 Tongue 0 .0 Salivary gland 0 .0 Esophagus 2 .5 Stomach 12 .0 Pancreas 13 .0 Small intestine (including duodenum) 7 .0 Large intestine (including rectum) 7 .5 Peritoneum 7 .5 Gallbladder 3 .5 Respiratory system 50 .0 Nasopharyx 0 .5 Larynx 0 .5 Trachea 0 .5 Lungs 46 .0 Pleura 10 .5 Diaphragm 9 .0 Cardiovascular system 12 .0 Pericardium 10 .5 Myocardium 3 .5 Endocardium 0 .0 Aorta 1 .0 Inferior vena cava 2 .0 0 .5 Medium-sized vessels Nervous system 5 .0 Cranial meninges 3 .5 Cranial nerve tissue (excluding pituitary) 1 .0 1 .5 Spinal meninges 0 .0 Spinal nerve tissue 0 .0 Peripheral nerve roots or main trunks 99 .5 Hemopoietic system 99 .0 Lymph nodes Liver 57,0 Spleen 71 .0 Bone and bone marrow, diffuse involvement 32 .0 10 .5 Isolated lesions

Lymphosarcoma (with marrow involvement)

Lymphosarcoma (without marrow involvement)

Reticulum Cell Sarcoma

72 .0 10 .0 53 .0 63 .0 4 .0 8 .0 19 .0 19 .0 2 .0 0 .0 4 .0 23 .0 11 .5 31 .0 7 .5 15 .5 31 .0 11 .5 69 .0 0 .0 1 .0 7 .5 25 .0 33 .0 28 .0 26 .5 11 .5 9 .0 43 .0 0 .0 0 .0 0 .0 35 .0 16 .5 4 .0 24 .0 19 .0 16 .5 1 .0 1 .0 1 .0 0 .0 11 .0 6 .5 2 .5 6 .5 1 .5 0 .0 100 .0 97 .5 75 .0 75 .0 100 .0 0 .0

49 .5 8 .5 30 .0 38 .5 5 .5 7 .5 10 .0 4 .0 3 .0 1 .5 3 .0 12 .5 0 .0 24 .0 2 .5 8 .0 16 .0 0 .0 54 .0 2 .0 1 .0 1 .0 23 .0 18 .5 27 .0 26 .0 19 .0 9 .0 39 .5 6 .5 1 .0 1 .0 24 .0 8 .0 9 .0 20 .0 14 .0 9 .0 3 .5 2 .0 0 .0 2 .0 4 .5 1 .0 1 .0 0 .0 0 .0 1 .0 96 .5 94 .5 33 .0 39 .0 0 .0 3 .5

60 .5 13 .5 32 .5 46 .0 5 .5 4 .0 12 .0 9 .5 6 .0 0 .0 3 .5 11 .5 11 .5 13 .0 1 .0 7 .0 10 .5 1 .0 34 .0 0 .5 1 .0 7 .5 32 .0 29 .0 26 .0 21 .0 18 .5 8 .0 58 .5 3 .0 1 .5 2 .5 45 .0 18 .5 11 .5 22 .0 14 .0 10 .0 3 .0 1 .0 1 .5 2 .0 8 .0 4 .5 1 .5 1 .5 0 .5 1 .0 98 .0 96 .0 46 .5 48 .0 25 .0 12 .0

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TABLE III (Continued) THE INCIDENCE OF INVOLVEMENT OF VARIOUS SYSTEMS, ORGANS AND TISSUES BY MALIGNANT LYMPHOMA (% in Each Disease Group)

Hodgkin's Disease

Site Involved

Lymphasarcoma (with marrow involvement)

54 .5 34 .0 2 .5 1 .0 7 .5 12 .5 1 .5 O .D 11 .5 4 .5 15 .0 9 .0 See alimen ary system See genitourinary, system

26 .0 0 .0 3 .5 0 .0 5 .5 9 .0

Endocrine system Pituitary Thyroid Parathyroids One adrenal Both adrenals Pancreas Gonads Miscellaneous Skin Voluntary muscle One breast" Both breasts Thymus Tonsil

6 1 3 3 1 0

Lymphosarcoma (without marrow involvement)

.0 .0 .0 .0 .0 .5

6 10 7 4 4 0

.0 .0 .5 .0 .0 .0

Reticulum Cell Sarcoma

52 .5 1 .5 13 .5 0 .0 11 .5 17 .5

11 4 1 4 4 1

3 .5 4 .5 0 .0 0 .0 3 .0 2 .0

.0 .0 .5 .0 .0 .5

s Figures arc percentages of patients of the appropriate sex .

severity and dissemination of disease in the patients with short survival .

Nature of Kidney Infiltration .

It was found that

or isolated nodules (for the purpose of classification, two or less) or, as previous authors inn par-

in each of the diseases under consideration renal

ticular Puente Duany [38] have pointed out, the lymphoma might diffusely and symmetrically

involvement might be unilateral or bilateral . It

involve the kidneys, mainly in the cortices, with

was also found that the infiltration might take the form of a bulky single tumor, multiple nodules

great increase in size but with preservation

of

shape . In this last variety, microscopic examina-

TA13LE IV COMPARATIVE INCIDENCE OF VARIOUS SITES OF INVOLVEMENT BY LYMPHOMA IN PATIENTS WITH AND WITHOUT RENAL INFILTRATION

Incidence of Cases with Lymphomatous Involvement of the Kidneys (%)

Incidence of Cases without Lymphomatous Involvement of the Kidneys (7n )

Site of involvement HD

Genitourinary system excluding kidneys Alimentary system Respiratory system Cardiovascular system Nervous system Hemopoietic system Endocrine system Retroperitoneal glands

37 .0 57 .0 71 .5 25 .5 11 .0 100 .0 51 .5 91 .5

LSA*

LSA -

RCS

HD

64 60 66 32 14 100 70 94

50 74 57 31 7 100 59 86

51 69 69 32 11 99 62 90

8 .0 25 .5 47 .0 10 .0 4 .0 99 .5 22 .0 82 .0

.0 .0 .0 .0 .0 .0 .0 .0

.0 .0 .0 .0 .0 .0 .5 .0

Non : HD = Hodgkin's disease . LSA'' = Lymphosarcoma with marrow involvement. LSA- = Lymphosarcoma without marrow involvement . RCS = Reticulum cell sarcoma.

VOL . 32, FEBRUARY 1962

.0 .0 .0 .0 .5 .0 .0 .5

RCS

24 41 38 10 7 100 27 90

.0 .0 .0 .0 .0 .0 .5 .0

16 .5 45 .0 28 .0 13 .5 3 .0 94 .0 18 .0 76 .0

26 36 50 13 4 97 44 79

.5 .11 .0 .5 .5 .0 .5 .0





190

Renal Lesions in Lymphomas -Richmond et al . Hodgkin's Bp- disease

Lymphosarcoma

Ratio lum cell sarcoma

30-

d

d

0 Patients without

Percent at patients with HD

9

V

with 0 Patients kidney Involvement

HODGKIN'S DISEA

kidney involvement

0-9 10-19 20-29 30-39 4D-49 50-59 60-69 70-79 Age in years

9 / . D /

% .-1 :1 .65 1 2 1 .4 :1 Proportion of males to females with ® Patients with kidney involvement renal Involvement, Patients without kidney Involvement per cent of appropriate sex

Per cent of patients with LSA

0

FIG . 1 . Sex distribution of autopsy cases in each disease group .

20 -LYMPHOSARCOMA

0

%i// 1P OV/ /////// 0-9 1D-19 20-29 30 40-49 50-59 60-M 70-79 iI-89 Age in years

30 Percent u patients with RCS 0

RETICULUM CELL SARCOMA

s 'I 0-9 1D-19 20-29 30-39 40-49 50-59 60-69 70-79 OD-89 Age in years

tion usually revealed masses of tumor cells in the

FIG . 2 . Age distribution of patients at autopsy in different

renal parenchyma, with wide separation and

disease groups .

frequently atrophy of nephron units . In a proportion of cases, renal involvement appeared to have occurred from direct extension of neighboring disease in the retroperitoneal space . Finally, and in an important proportion of patients, lymphomatous infiltration could not be seen by

the naked eye at autopsy, but was evident on microscopic examination . The incidence of the various types of renal involvement in the different lymphomas is presented in Table v .

Patients with kidney involvement

0 30 Per cent of patients with NO

Patients without kidney involvement

HODGKIN'S DISEASE

U

j 0

<1

40 -

1-1 .9 2 2 .9 3-3 .9 4 4.9 5-5 .9 6-6.9 7-7 .9 8-8 .9 9 9 .9 )10 Years

LYMPHOSARCOMA

Per cent of patients 20 with LSA

(1

1-1 .9 2-2 .9 3-3 .9 44.9 5-5 .9 6-6.9 7 7 .9 8 8 .9 9-9 .9 s10 Years

(1

1-1 .9 2-2 .9 3-3 9 4-4.9 5-5 .9 6-6.9 7-7.9 8-8.9 9-9 .9 Years

Percent of patients 20

with RCS 0 )10

FIG . 3 . Clinical duration of disease at the time of autopsy .

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191

TABLE V INCIDENCE OF THE DIFFERENT TYPES OF RENAL INFILTRATION IN THE MALIGNANT LYMPHOMAS Infiltration

I I .ymphosarcoma Reticulum Hodgkin's Lymphosarcoma Cell (with marrow (without marrow Disease involvement) involvement) Sarcoma I Per cent of Total Number of Patients Showing Renal Involvement

Unilateral Bilateral

40 .0 60 .0

16 .0 84 .0

Total

21,5 78 .5

27 .0 73 .0

26 .0 74 .0

4 .0 4 .0 3 .0 62 .5 8 .0 18 .5

1 .5 7 .5 8 .5 52 .0 14 .0 16 .5

6 .0 6 .0 7 .0 61 .0 11 .0 7 .0

Per cent of Total Number of Kidney, Showing In It on Diffuse Bulky single tumor Solitary nodules Multiple nodules Invasion from perirenal disease Disease only evident on microscopy

7 .0 3 .5 12 .5 55 .5 5 .5 16 .0

12 .0 0 .0 2 .0 43 .0 2 .0 41 .0

Several observations are worthy of note . First, when the kidneys are involved by malignant lymphoma, multiple nodules of tumor is the most common type of presentation in all the diseases under consideration (61 per cent of all affected kidneys) . Secondly, in patients with lymphosarcoma and marrow involvement, infiltration was evident only on microscopic examination in 41 per cent of the affected kidneys . It was in this group also that bilateral involvement of the kidneys occurred most frequently (84 per cent of the patients with renal infiltration) and that the diffuse cortical type of infiltration, to which reference has already been

made, had its highest incidence (12 per cent of affected kidneys) . It is reasonable to believe that in many patients in this group the nature of the renal infiltration, by virtue of the features just outlined, frequently resembled that seen in leukemia 1381 . Thirdly, invasion from contiguous disease in the retroperitoneal space was the cause of infiltration in 14 per cent of the affected kidneys in the group of patients with reticulum cell sarcoma but a smaller proportion (2 to 8 per cent) in the other groups . Nodular infiltrates, diffuse infiltration and invasion from perirenal disease in some of the cases in the series are illustrated in Figures 4, 5, 6 and 7 . The Effect of Lymphomatous Infiltration on the Weight of the Kidneys Postmortem . The weight of

Fre . 4. Case 389 wenty-four year old man in whom the diagnosis was rcticulum cell sarcoma . Discrete nodules of lymphomatuus infiltration in both kidneys . VOL . 32 ; FLDRUARY 1962

Fse . 5 . Case 335 . A forty-six year old man in whom the diagnosis was reticulum cell sarcoma . Multiple nodules of lymphomatous infiltration in the kidney .

192

Renal Lesions in Lymphomas-Richmond et al .

Case 647 . A fifty-three year old man in whom the diagnosis was reticulum cell sarcoma . Massive infiltration of parenchyma of both kidneys (and adrenal glands) by lymphoma . The predominantly cortical distribution of disease in the sectioned kidney is well seen . FIG . 6 .

the kidneys at autopsy was studied to ascertain how frequently lymphomatous involvement caused enlargement of these organs . Information regarding the weight of normal kidneys in adults was obtained from Moell [39] . He quotes the weights given by Pourteyron [40], Thoma [41] and Roessle and Roulet [42] . Although according to these authors the kidneys of females tend to weigh less than those of males, and the left tends to be heavier than the right, it can be stated that at autopsy the average weight of a kidney from a normal adult ranges from 110 to 170 gm . Coppoletta and Wolbach [43] give the mean kidney weights at different ages for infants and children . It was decided to exclude patients under the age of twenty years from this analysis . In addition, all patients in whom the kidney weights were not stated or in whom only the combined weights of both organs were given could not be considered . The information which was obtained from the remaining patients (71 per cent of the total series) is presented in Figure 8 . From this diagram it can be seen that in the majority of adult patients in the study, lymphomatous infiltration of the kidneys did not increase the weight of these organs to an important degree over the weight of unaffected kidneys . However, of the kidneys showing involvement, 16 .5 per cent weighed 300 gm . or more whereas only 3 .5 per cent of the unaffected kidneys were so enlarged . Study of those patients in whom this degree of enlargement had been found revealed that when it was due to lymphomatous deposits it

7 . Case 500 . A fifty-nine year old man in whom the diagnosis was reticulum cell sarcoma . Both kidneys invaded by perirenal lymphoma (best seen in sectioned specimen) . FIG .

might be unilateral or bilateral and might occur with any of the different types of infiltration which have been discussed . When not due to deposits of malignant disease, it was caused most frequently by cysts, hydronephrosis, abscesses and hemorrhage in that order . Only on rare occasions did the kidneys weigh 500 gm . or more . In this series this was a unilateral finding in each instance and was due to lymphoma in five patients and cysts in two . Renal Lesions Other Than Lymphomatous Deposits .

Thirty per cent of the autopsied patients were found to have renal lesions other than lymphomatous deposits, which appeared to be due to the primary disease or to the therapeutic procedures used in its management . The total incidence of such lesions in the different disease groups was as follows : Hodgkin's disease, 29 .5 per cent ; lymphosarcoma with marrow involvement, 44 per cent ; lymphosarcoma without marrow involvement, 25 .5 per cent ; reticulum cell sarcoma, 28 per cent ; an incidence in the whole series of 30 per cent . The conditions which were ascribed to the malignant process were hydronephrosis, pyeloAMERICAN JOURNAL OF MEDICINE



193

Renal Lesions in Lymphomas-Richmond et al . ® Patients with kidney Involvement Patients without kidney Involvement

HODGKIN'S DISEASE 40

Per cent al patients with HD

20

0

, 0-99

Y///,1 100-149

150-199 200-249

250-299

300-349 350

and

over

Weight in gms LYMPHOSARCOMA WITH MARROW INVOLVEMENT 40

Per cent dpatlents with LSA+

20

p 0 0-99

100-149

150-199

200-249

250-299 300-349

Weight in gms 40-

Per cent d patients with LSA-

350 and

over

LYMPHOSARCOMA WITHOUT MARROW INVOLVEMENT

20

0-99

100-149

150 .199

200-249

250-299

300-349

Weight in gms

350

and

over

40- RETICULUM CELL SARCOMA

Per cent of patients with RCS

I0

20

0 0-99

100-149

w

150-199 200-249

Weight In gins

250 299

300-349

350 and

aver

Fm . 8 . The weight of the kidneys at autopsy comparing those which showed infiltration with those which did not .

nephritis or both due to ureteral obstruction, pelvic and ureteral calculi and macroscopic gravel, infarction of and hemorrhage into the renal parenchyma, hemoglobinuric and cholemic nephrosis, embolic abscesses in the kidney substance . nephrocalcinosis and amyloidosis . These various "secondary" lesions and their comparative incidence arc listed in Table vi . Since some of these conditions might be expected to give rise to clinical manifestations and some could seriously affect the course of the patient's illness, they merit brief discussion . Hydronephrosis and pyelonephritis : These conditions occurred singly or together in 16 per cent of the whole series . In 9 per cent of the patients (with the highest incidence in the group of patients with lymphosarcoma who had no marVOL, 32, FEBRUARY 1962

row involvement) the most important etiologic factor was believed to be ureteral obstruction as a result of compression by masses of tumor in the retroperitoneal space or actual lymphomatous infiltration of the ureters (see Table vi for respective incidence) . As will be seen later, this complication by leading to uremia was considered to be the main cause of death in twelve patients . It should be noted that in many other patients the ureters were described as being encased and often deviated by retroperitoneal tumor, but without being obstructed . Calculi and gravel: Urinary calculi and visible gravel occurred in 2 and 1 .5 per cent of the patients, respectively . The figure for calculi is only a little higher than that of 1 .2 per cent

194

Renal Lesions

in Lymphomas-Richmond et al . TABLE VI

RENAL LESIONS ATTRIBUTABLE TO THE PRIMARY DISEASE (OTHER THAN LYMPHOMATOUS DEPOSITS)

Incidence in Each Disease Group (%) I

Incidence of patients with a secondary lesion Ureteral obstruction causing Hydronephrosis One kidney Both kidneys Pyelonephritis One kidney Both kidneys Concomitant hydronephrosis and pyelonephritis One kidney Both kidneys Nature of ureteral obstruction Lymphomatous compression One side Both sides Lymphomatous invasion One side Both sides Pelvic or ureteral calculi One side Both sides Visible gravel or sand One side Both sides Infarction One side Both sides Hemorrhage, extensive One side Both sides Hemorrhage, petechial One side Both sides Hemoglobinuricnephrosis Cholemic nephrosis Embolic abscesses Bacterial Fungal Nephrocalcinosis Amyloid infiltration

Hodgkin's Disease

Lymphosarcoma (with marrow involvement)

Lymphosarcoma (without marrow involvement)

Reticulum Cell Sarcoma

Total

29 .5

44 .0

25 .5

28 .0

30 .0

2 .0 2 .0

1 .0 4 .0

4 .5 8 .5

5 .0 5 .5

7 .5

2 .0 0 .5

1 .0 1 .0

4 .5 6 .5

4 .0 1 .0

4 .5

0,5 0 .0

1,0 1 .0

4 .5 4 .5

2 .5 0 .5

3 .0

2 .0 1 .5

2 .0 1 .0

3 .5 5 .5

4 .0 4 .5

6 .0

2 .0 0 .5

1 .0 2 .0

7 .5 4 .5

5 .5 1 .5

5 .5

2 .0 0 .0

2 .5 1 .5

2 .0 0 .0

1 .0 1 .0

2,0

0 .5 0 .5

2 .5 4 .0

1 .0 1 .0

0,5 0 .5

1 .5

3 .5 0 .5

1 .5 0 .0

1 .0 1 .0

3 .5 0 .5

3 .0

0 .5 1 .0

1 .5 4 .0

1 .0 2 .0

0 .5 2 .5

2 .5

1 .0 3 .5 1 .0 8 .5

1 .5 10 .0 25 4 .0

1 .0 2 .0 2 .5 0 .0

1 .5 3 .0 4 .5 2 .0

4 .0 3 .0 2 .0 3 .0

1 .5 4 .0 7 .5 0 .0

0 .0 0 .0 3 .0 0 .0

1 .0 0 .0 3 .5 0 .0

which Weisberger and Persky [31] quote for the general population . It is, however, of interest that the incidence of calculi (4 per cent) and visible gravel (6 .5 per cent) was highest in the group of patients with lymphosarcoma and marrow involvement, a group of lymphomas in which hyperuricemia is encountered frequently . Cholemic nephrosis: In 3 .5 per cent of all patients (8 .5 per cent of patients with Hodgkin's disease) microscopic examination revealed

5 .0 1,5 3 .5 1 .5 1 .5 3 .5

changes in the kidneys consistent with cholemic nephrosis . All these patients were jaundiced in their terminal illness and all but one showed hepatic infiltration by the lymphoma at autopsy . One, a patient with Hodgkin's disease, had esophageal varices as a result of portal hypertension due to extensive periportal infiltration . This case has been reported elsewhere [44] . At the time of autopsy four patients had changes consistent with hepatitis ; another showed zones AMERICAN JOURNAL OF MEDICINE

Renal Lesions in Lymphomas-Richmond et al . of hepatic necrosis and another had biliary cirrhosis . In many patients there was a poor correlation between the extent of hepatic lymphoma and the severity of jaundice . Embolic abscesses : Approximately 2 .5 per cent of all patients were found to have abscesses in the renal parenchyma, distinct from those associated with pyelonephritis, at the time of death . In all but one patient there was antemortem or postmortem evidence or both that these abscesses were likely to have resulted from blood-borne infection . Twenty-three patients were so affected, eighteen being patients with Hodgkin's disease . In the main, organisms recovered from the blood during life or from the abscesses at autopsy were bacteria (Staphylococcus aureus, Escherichia coli, Bacillus proteus and Pseudomonas pyocyaneus) ; in three of these, bacterial endocarditis was also discovered . In ten patients the causative organism apparently was a fungus (Candida albicans, cryptococcus) and in two others bacteria and fungi were found concomitantly . Nephrocalcinosis : Nephroealeinosis occurred in twenty-three patients (3 .5 per cent of the series) . The highest incidence was in the group of patients with lymphosarcoma and marrow involvement (7 .5 per cent) . The severity of this lesion was graded arbitrarily as 1 plus, 2 plus or 3 plus, depending on the extent of calcification . The number so classified were 1 plus, fifteen ; 2 plus, four ; and 3 plus, four . Nephrocalcinosis was believed to be the sequel, most frequently, of lymphomatous infiltration of the osseous system, since skeletal disease was demonstrated at autopsy in all but two patients . Insufficient clinical and biochemical data were available for a satisfactory analysis of this group of patients . However, it is worthy of note that of the eight patients with 2 plus and 3 plus calcification, five had evidence of calcification in many other organs, hypercalcemia (more than 11 mg, per cent) was demonstrated in four of the five patients in whom the serum calcium was estimated, and in six (one with severe hypertension) there was compromise of renal function with nitrogen retention (blood urea nitrogen exceeding 25 mg . per cent) . Atnyloidosis : Sir Samuel Wilks [45] has been credited with the first description of the coexistence of Hodgkin's disease and amyloidosis . This appeared in a paper which he wrote in 1856 . Many years later, in opening a symposium VOL . 32, FEBRUARY 1962

195

on "Diseases of the Lymphatic System Including Lymphadenoma and Leukemia," he again raised the possibility of an association between Hodgkin's disease and lardaceous disease [4S] . Individual cases have been reported over the years, the most recent being that of Kilburn [47] . The latter concerned a young man in whom jaundice and hepatic failure developed apparently as a result of massive amyloid infiltration of the liver . Ewing [2] knew of twenty-two recorded examples and Wallace and his associates [48] were able to accept thirty-seven cases recorded in the previous literature at the time of their review, adding one of their own . In this last series no association could be established between the finding of amyloidosis and any histologic type of Hodgkin's disease, or with sex or age groups . The kidneys showed amyloid infiltration in about 50 per cent of the cases in which postmortem findings were given . In the present study the association of amyloidosis with malignant lymphoma was confined to Hodgkin's disease . In the series of 272 patients with Hodgkin's disease, eight had amyloidosis, an incidence of approximately 3 per cent . One of these patients had pulmonary tuberculosis and another terminal Listeria septicemia . Otherwise no possible etiologic factors could be identified other than the underlying lymphoma and the agents used in its management . The affected group contained three male patients and five female patients . The age range at the time of death was thirty-two to fifty-eight years . In two, the histologic picture was Hodgkin's sarcoma, in the remainder Hodgkin's paragranuloma . The extent of dissemination of the lymphomatous process was varied . The kidney glomeruli showed infiltration by arnyloid of varying severity in all eight patients ; in one, amyloid deposition was detected only in the kidneys . In the seven remaining patients amyloid was distributed in the organs characteristically most affected in "secondary amyloidosis," namely, spleen, seven patients ; adrenals, four ; lymph nodes, three ; liver, one ; and pancreas, one . The patient showing the most severe renal lesions had a nephrotic syndrome in the late clinical course and died of uremic acidosis (see Case 671) . No clue regarding etiology was forthcoming in these eight patients . The administration of nitrogen mustard has been shown to produce amyloid infiltration in healthy mice !49] and apparently to precipitate the lesions in Hodg-

196

Renal Lesions in Lymphomas-Richmond et al .

Cause of Death

No.

Uremia due to hydronephrosis and/or pyelonephritis consequent on lymphomatous obstruction of the ureters (three of these died in the postoperative phase of palliative nephrostomy) Uremia due to orate nephrolithiasis Uremia due to uric acid ncphropathy consequent on radiation therapy Uremia due to amyloidosis

critical study of the autopsy findings indicate that involvement of the genitourinary system was the main if not the sole cause of death . Extensive lymphomatous replacement of the renal parenchyma, leading to uremia, was implicated in only five of these (0.5 per cent), two of whom will be discussed briefly . The remainder may be summarized as shown in Table vii .

10 1

Part II

TABLE VII GENITOURINARY INVOLVEMENT BY LYMPHOMA AS CAIISF

OP DEATH

1 1

CORRELATION OF CLINICAL AND ROENTGENOGRAPHIC FINDINGS WITH AUTOPSY FINDINGS IN

142

PATIENTS WITH LYMPHOMATOUS

INFILTRATION OF THE KIDNEYS

kin's disease in man [501 . This drug was certainly given at some time in the management of six of the patients. However, it seems unlikely that it can be an important factor since nitrogen mustard and related compounds were used in the majority of patients in other disease groups in the series. It may be significant that in most of the patients with amyloidosis in whom information was available (seven of the eight patients) the duration of disease had been long : three, five, six, ten, eleven, fifteen and nineteen years . It should also be stated that in none of the patients with renal amyloidosis had the lymphomatous process infiltrated the kidneys. Miscellaneous findings: Renal cysts were encountered in 5 per cent of the patients in the series being unilateral in 40 per cent and bilateral in 60 per cent . Nine patients showed congenital malformations (ureteral abnormalities, four ; horseshoe kidney, two ; ectopic kidney, two ; aberrant renal artery, one) . Foci of tuberculosis were seen in two patients, one of whom had lymphosarcoma and the other reticulum cell sarcoma . This finding was due to miliary spread from the lung in each case . (Twenty-four patients had pulmonary tuberculous lesions at autopsy, healed in five ; sixteen of these patients were in the Hodgkin's disease group .) Implication of Genitourinary Involvement as a Cause of Death . As might be expected, genito-

urinary disease appeared to be a contributing cause of death in a considerable number of patients suffering from malignant lymphoma, e .g., extensive lymphomatous deposits in the kidneys and cholemic nephrosis . The incidence of this occurrence could not be evaluated . In only eighteen patients (2 .5 per cent) did

In order to determine which clinical and roentgenographic features might be diagnostic of infiltration of the kidneys in patients with malignant lymphoma a detailed analysis of the clinical records and roentgenograms was undertaken of all patients autopsied in the ten-year period 1949 to 1958 inclusive who had been found to have infiltration of the renal parenchyma . This ten-year period was chosen arbitrarily as one in which biochemical and roentgenographic investigation was known to have been extensive and of a constant standard . Approximately two-thirds (425) of the total patients in the series had been autopsied in the last ten years . Of these, the following numbers of patients were found to have lymphomatous involvement of the kidneys and were the subject of the special clinical and roentgenographic study : Hodgkin's disease, twenty-two ; lymphosarcoma with marrow involvement, forty-one ; lymphosarcoma without marrow involvement, eighteen ; and reticulum cell sarcoma, sixty-one . (Total number of patients : 142 .) Ten other patients had renal involvement at autopsy but could not be considered in the survey because their complete medical records were not available . Clinical and Biochemical Findings . The following symptoms and physical signs were thought to be relevant in patients with renal involvement by lymphoma : (1) pain or tenderness or both, particularly if in the loin or flank in a situation usually associated with renal or ureteric disease ; (2) a palpable mass in the renal areas ; (3) hypertension (diastolic blood pressure above 100 mm . Hg) ; (4) suppression of the flow of urine ; (5) macroscopic hematuria ; and (6) edema . The following biochemical changes were also considered : (1) albuminuria and/or AMERICAN JOURNAL OF MEDICINE



Renal Lesions in

197

Lymphomas-Richmond et al .

TABLE VIII INCIDENCE OF CLINICAL FEATURES AND . BIOCHEMICAL CHANGES BELIEVED TO BE DUE TO LYMPHOMATOUS INFILTRATION OF THE RENAL PARENCHYMA (GROUP A)

Incidence of Cases in Each Disease Group (%) Hodgkin's Lymphosarcoma (with marrow Disease involvement) Incidence of patients in group A Clinical features Pain Palpable mass Hypertension Oliguria Macroscopic hematuria Edema Biochemical changes Albuminuria, abnormalities in microscopic sediment Elevated blood urea nitrogen Hypercalcemia Hyperuricemia ----Hypoproteinemia

Lymphosarcoma Reticulum (without marrow Cell involvement) Sarcoma

Total

18 .0

24 .0

22 .0

24 .5

23 .0

9 .0 13 .5 4 .5 4 .5 4 .5 0 .0

0 .0 14 .5 14 .5 0 .0 5 .0 0 .0

0 .0 0 .0 10 .0 5 .0 0 .0 0 .0

3 .5 6 .5 5 .0 0 .0 0 .0 0 .0

2 .5 9 .0 8 .5 2 .0 2 .0 0 .0

9 .0 4 .5 0 .0 .0 0 .0

7 .5 10 .0 0 .0 2 .5 0 .0

0 .0 16 .5 0 .0 5 .5 0 .0

10 .0 15 .0 5 .0 8 .0 0 .0

7 .5 12 .0 2 .0 5 .0 0 .0

cells or casts in the urinary sediment ; (2) elevation of the blood urea nitrogen above 25 mg. per cent ; (3) hypercalcemia exceeding 11 mg . per cent ; (4) hyperuricemia exceeding 7 .5 mg. per cent ; (5) hypoproteinemia, the serum total protein level being less than 5 gm . per cent . Particular note was made of these various clinical and biochemical data from the 142 patients' records which were analyzed . The results fell into two groups . First, there were those patients in whom these clinical and biochemical findings could not be explained on any basis other than lymphomatous infiltration of the kidneys . Secondly, there were patients in whom the findings did not appear to be due to renal parenchymal involvement because they could be better related to other lesions . Table viii shows the frequency with which the various findings were believed to have resulted from lymphomatous infiltration of the kidneys (group A) ; Table ix shows the frequency with which the same clinical features and biochemical abnormalities were believed to be attributable to causes other than infiltration of the renal parenchyma (group B) . In almost all instances the clinical course and the autopsy findings clearly indicated to which group the patient should be assigned . It must be stated, however, that in a small proportion of cases, as in all retrospective surveys, an unVOL . 32, FEBRUARY 1962

desirable amount of judgment was required to close the gaps in the available data . Twenty-three per cent of the 142 patients in the clinico-roentgenographic survey had symptoms or signs or biochemical changes which were believed to have resulted from infiltration of the renal parenchyma (group A) . In 77 per cent of the 142 patients these same features were in part ascribed to lesions other than renal infiltration (group B) . Only 12 per cent of all the patients studied had no antemortem findings which might have suggested renal disease . (It will be noted that a proportion of patients were assigned to group A and to group B because in these patients some findings could be explained by renal infiltration while others could not .) Pain : Pain in one or the other flank or loin was noted in 6 .5 per cent of the patients in the series . In only one-third of these (group A) did it appear to result from renal lymphoma . In the remainder it was ascribed to disease in the spine or ilium or in the retroperitoneal space, or to enlargement of the kidney consistent with obstructive nephropathy . Palpable mass : A palpable mass in one or the other renal area was encountered relatively frequently, being recorded in 16 per cent of the patients . In approximately half of these patients the kidney was found to be large enough at autopsy, due to diffuse or multinodular infiltra-

198

Renal Lesions in Lymphomas-Richmond el al .

TABLE IX INCIDENCE OF CLINICAL FEATURES AND BIOCHEMICAL CHANGES WHICH MIGHT HAVE SUGGESTED LYMPHOMATOUS INFILTRATION OF THE KIDNEYS ANTEMORTEM BUT WHICH WERE BELIEVED TO BE ATTRIBUTABLE TO OTHER CAUSES (GROUP B)

Incidence in Each Disease Group (%) Hodgkin's Lymphosarcoma (with marrow Disease involvement) Incidence of patients in group B Clinical features Pain Palpable mass Hypertension Oliguria Macroscopic hematuria Edema Biochemical changes Albuminuria, abnormalities in microscopicsediment Elevated blood urea nitrogen Hypercalcemia Hyperuricemia Hypoproteinemia

Lymphosarcoma Reticulum (without marrow Cell involvement) Sarcoma

Total

73 .0

73 .0

83 .5

79 .0

77 .0

9 .0 13 .5 9 .0 13 .5 0 .0 27 .0

5 .0 5 .0 0 .0 29 .0 2 .5 39 .0

0 .0 11 .0 5 .5 16 .5 0 .0 55 .0

3 .5 5 .0 10 .0 11 .5 8 .0 35 .0

4 .0 7 .0 6 .0 17 .0 4 .0 37 .0

27 .0 27 .0 4 .5 4 .5 32 .0

27 .0 44 .0 10 .0 27 .0 14 .5

28 .0 45 .0 5 .5 22 .0 22 .0

23 .0 40 .0 3 .5 25 .0 15 .0

25 .0 40 .0 5 .5 22 .0 18 .0

tion or to invasion from perirenal disease, to make the clinical finding of a tumor very probable (group A) . In group B, hydronephrosis and massive retroperitoneal disease suggested the presence of a renal tumor on rare occasions . In most instances, however, the autopsy findings did not explain the clinical impression of a mass . Hypertension : Hypertension was a difficult feature to assess . In 6 .5 per cent of the patients elevation of the diastolic blood pressure was recorded only once or was a short-lived finding or was associated with nephrosclerosis (group B) . In the others (group A), 8 .5 per cent of the patients, hypertension was associated with extensive renal infiltration by lymphoma, the "diffuse" type of involvement being the most common . While it is not possible to prove an association between renal lymphoma and hypertension, the absence of other explanations in this group suggests a causal relationship, particularly as five of the nine patients so classified were under twelve years of age . Oliguria : Oliguria could rarely be ascribed to renal parenchymal lymphoma (group A) . It did, however, frequently result from other causes . In 17 .5 per cent of the patients (group B) the following etiologic factors were recognized : dehydration and vomiting (with improvement of urine flow following replacement therapy), uric acid nephropathy (clearly the sequel of radiation

therapy in one patient and chemotherapy in another), obstructive nephropathy and, in one patient, cholemic nephrosis . Macroscopic hematuria : Macroscopic hematuria occurred in 6 per cent of the patients . In the absence of causative factors other than renal lymphoma, one-third were placed in group A . The other two-thirds clearly belonged to group B because of thrombocytopenia (three patients), hemorrhagic cystitis (one patient), submucosal bladder hemorrhage (one patient) and renal infarction (one patient) . Edema, hypoproteinernia and renal loss of protein :

Although edema was observed in 37 per cent of the 142 patients in the survey and hypoproteinemia in 18 per cent, there was no instance in this series in which these findings could be attributed to albuminuria resulting from lymphomatous infiltration of the kidneys . In fact, in group B only 30 per cent of the large number of patients with clinical edema were found to have significant hypoproteinemia (a total protein level of less than 5 gm . per cent) . Compression of the venous return by nodal disease appeared to be the most frequent cause of fluid retention, particularly in the lower extremities . No explanation was available for the high incidence of hypoproteinemia . Abnormal findings in the urine : Reference has already been made to one patient with amyloid AMERICAN JOURNAL OF MEDICINE



199

Renal Lesions in Lymphomas-Richmond et al . nephrosis (see Part t) but albuminuria of more than a trace and attributable only to lymphomatous infiltration of the kidneys was excessively rare . In fact, only four patients (3 per cent) of the whole group could be assigned to group A for this finding . The urinary abnormality for which most patients were placed in group A was red blood cells in the sediment. Twenty-five per cent of the patients were assigned, however, to group B because of 1-plus albuminuria or because of red blood cells, pus cells or casts in the sediment . The underlying causes were hydronephrosis or pyelonephritis, or both, due to ureteric obstruction, cholemia, thromboeytopenia and hyperuricemia . Elevated blood urea nitrogen : Nitrogen retention (blood urea nitrogen exceeding 25 mg . per cent) occurred in 52 per cent of the patients . In approximately a quarter of these (group A), massive renal lymphoma was the only etiologic factor which could be identified . The types of infiltration implicated, in order of frequency, were "multinodular," "diffuse" and "invasion from perirenal disease ." As is seen in Table ix, other mechanisms were found for the production of azotemia in the remaining three-quarters of the patients . These were dehydration (in many instances in the terminal phase of the disease), obstructive nephropathy, hyperuricemia, cholemie nephrosis, renal vein thrombosis, calculi, nephrosclerosis and prostatic enlargement . Hypercalcemia and lryperurieemia . An elevated serum calcium level is most likely to be due, in the malignant lymphomas, to osseous involvement by the disease ; hyperuricemia (exceeding 7 .5 mg . per cent) was found in about 25 per cent of the subjects (see Tables viii and ix), being least common in Hodgkin's disease . Hyperuricemia and hypercalcemia were believed to have been aggravated by lymphomatous infiltration of the kidneys and renal insufficiency when these abnormalities were associated with azotemia . This occurred in 2 and 5 per cent of the patients, respectively (group A) . Roentgenographic Findings . The determination of the size and mass of the kidneys by roentgenology has been the object of many studies . However, despite a considerable amount of work, a situation similar to the present status of heart measurement exists . Instead of utilizing actual measurements in their routine work, most radiologists resort to a general appraisal of the size of the kidneys based upon knowledge of the normal gained by training and experience . In this judgment, the body build of the patient VOL . 32, FEBRUARY 1962

TABLE

x

TYPES OF ROENTGENOGRAMS wHiCH WERE AVAILABLE FOR STUDY

Type

Nn .

Scout film of abdomen, etc 52 Excretory pyelography only 27 Retrograde pyelography only 2 Excretory pyelography and scout film 7 Excretory pyelography and retrograde pyelogI 3 raphy Total

'

91

has obvious importance, but the known difference due to right- and left-sidedness and between the two sexes appears to be of little practical significance . The most reliable information regarding the size of the kidneys can be given when differences are evident in films taken at different periods of time or when one kidney is clearly larger or smaller than its mate . Because we had to deal with several types of roentgenologic examinations, not all of which were best suited to visualization of the kidneys, direct measurements were usually difficult or impossible to obtain . However, an estimate of the size and shape of the kidney could be attempted frequently . Besides this, many of the patients had several series of x-ray studies so that interval comparison was possible . In addition to the examinations directed to the urinary tract itself, such as excretory urography and retrograde pyelography, it was necessary to study scout films of the abdomen, lumbar spine, gastrointestinal tract, small bowel, colon and, in fact, any examination available that showed a renal outline . Fifty-one of the 142 patients known to have lymphomatous disease in the kidneys had to be excluded from the roentgenologic survey . The x-ray films of some patients could not be obtained . In a larger number no pertinent roentgenologic studies had been made whereas in others the time interval between the last examination and death was considered to he too long to make a satisfactory correlation possible . Ninety-one cases remained in which roentgenograms were suitable for study . The types of films which were available for review are shown in Table x . Listed under "scout film" are the various types of examinations mentioned, none of which is primarily directed to the visualization of the urinary tract.

200

Renal Lesions in Lymphomas-Richmond et al. TABLE XI

SCOUT FILMS : INTERVAL BETWEEN EXAMINATION AND TIME OF DEATH, AND SUITABILITY OF FILMS FOR VISUALIZATION OF KIDNEYS

Hodgkin's Disease

Lymphosarcoma (with marrow involvement)

6

16

9

28

59

4 2 0 0

10 5 0 1

4 4 0 1

13 9 4 2

31 (52 .5%) 20 (34 .0%) 4( 6 .75%) 4( 6 .75%)

1 5 0 0

4 6 3 3

4 4 0 1

8 12 2 6

17 (30 .0%) 27 (46 .0%) 5 (8 .0 %) 10 (16 .0%)

Patients with suitable films Time before death 1 mo 1-3 mo 3-6 mo More than 6 mo Quality of films Both kidneys seen well Right only seen well Left only seen well Neither seen well

Lymphosarcoma Reticulum (without marrow Cell involvement) Sarcoma

Total

TABLE XII EXCRETORY PYELOCRAMS : INTERVAL BETWEEN EXAMINATION AND TIME OF DEATH, AND SUITABILITY OF FILMS FOR VISUALIZATION OF KIDNEYS

Patients with suitable films, Time before death 1 mo 1-3mo 3-6 mo More than 6 mo Quality of films Both kidneys seen well Right only seen well Left only seen well Neither seen well

I

Hodgkin's Disease

Lymphosarcoma (with marrow involvement)

Lymphosarcoma Reticulum (without marrow Cell involvement) Sarcoma

5

11

5

16

1 1 1 2

5 4 2 0

1 2 1 1

6 7 3 0

13 (35%) 14 (38%) 7 (19%) 3( 8%)

3

10 0 0 1

3 0 1 1

14 2 0 0

30 (80%) 3 ( 8%) 1( 4%) 3( 8%)

Total

37

TABLE XIII CORRELATION BETWEEN ANATOMIC FINDINGS IN KIDNEYS AT AUTOPSY AND INTERPRETATION OF MOST RECENT ROENTGENOGRAMS

Type of Roentgenogram

Scout films All patients Patients x-rayed within 30 days before death . Pyelograms All patients Patients x-rayed within 30 days before death . .

Total Not Possible*

Good

Fair

Poor

6 (11 .5%) 3 (11%)

52 27

5 (9 .5%) 4 (15%)

24 (46%) 12 (44%)

17 (33%) 8 (30%)

39 15

0 (0%) 0 (0%)

28 (72%) 12 (80%)

9 (23%) 3 (20%)

2 ( 5%) 0(0%)

" The "not possible" group includes those patients in whom the appearance of the kidneys on ruentgenograms was so obscure as to make correlation unreliable or impossible . AMERICAN JOURNAL OF MEDICINE

Renal Lesions in Lymphomas-Richmond et

al.

Case 647 . A fifty-three year old man in whom the diagnosis was reiiculutn cell sarcoma . men showing typical bilateral diffuse enlargement of the kidneys .

Ftc . 9 .

Table xi presents details regarding the scout film group . One may justifiably question the value of those patients with x-ray coverage longer than three months before death since we have seen lymphomatous involvement of the kidneys appear and respond to treatment within that time interval . The scout film group of x-ray examinations naturally carried a high index of non-visualization and partial visualization of the kidneys . Table xii, which gives information regarding excretory pyelograms, shows that an improvement in the type of film coverage enhances one's ability to visualize the kidneys when compared with scout films . The time of pyelographic examination as related to the time of death showed a generally similar relationship with the scout film examinations . The number of retrograde pyelograms was too few to permit conclusions . 'Fable xm shows the correlation attained between the roentgenologic determination of the VOL . 32, FEBRUARY 1962

201

Scout film of

the abdo-

size and shape of the kidneys and the anatomic findings at autopsy . There was a good correlation in all cases in which roentgenograms were obtained within a month of death . The much better degree of correlation in the group in which pyelograms were obtained than in those in which scout films were obtained is also apparent . Finally, an attempt was made to estimate the potential value of pyelographic studies in view of the findings revealed at postmortem . It was considered that in about half of those patients in whom excretory pyelograms were not obtained, the examination might have served a useful purpose . In the remainder, it appeared unlikely that valuable information would have been obtained . A wider use of x-ray coverage would have undoubtedly increased the number of patients suspected of having renal involvement prior to death . No note was made roentgenologically of involvement of the lower urinary tract ur of extrarenal lymphomatous disease . Neither were

202

Renal Lesions in Lymphomas

Richmond et al.

Case 704. A forty year old woman in whom the diagnosis was reticulum cell sarcoma . Excretion pyelography showing diffuse bilateral kidney enlargement due to lymphomatous involvement . FIG. 10 .

instances of ureteral obstruction and displacement, extrarenal masses and distortions in the urinary bladder recorded . Calcification, as seen roentgenologically, did not occur . In the roentgenologic evaluation, the over-all size of the kidney was given special consideration in trying to determine whether or not tumorous disease was present . Next, the shape of the kidney outline, interval changes in size and, finally, the architecture of the collecting structures were appraised . The nature of the roentgenologic findings encountered can be surmised from the type of tumorous infiltration shown at autopsy . The most striking roentgenographic abnormality was symmetrical, bilateral enlargement of the kidney silhouettes . (Fig . 9 .) This enlargement is characterized by regular renal borders and seems to be accompanied by a relatively greater increase in the cortical zone of the kidney than in the medullary area . The urinary calyces are little affected except that their infundibula may be lengthened and there may be a slight

increase in the size of the calyces themselves . The renal pelvis may be somewhat fuller than usual . The development of these findings due to lymphomatous disease may take place in a period of a few weeks to a few months . If proper treatment is administered a regression and return to normal may occur in similar time . (Fig. 10 and 11 .) The second and less easily recognized roentgenographic change due to lymphomatous renal disease was the localized mass in some portion of an otherwise normal kidney shadow . (Fig . 12 .) This type showed a local bulge in the kidney outline and deformity of adjacent calyces or the pelvis . The roentgenologic appearance was indistinguishable from other forms of malignant tumor . Frequency with Which Lymphomatous Involvement of the Kidneys Was Recognized Antemortem . After

surveying all the clinical data which have been presented, it was considered that no single symptom or group of symptoms was diagnostic of AMERICAN JOURNAL OF MEDICINE

Renal Lesions in Lymphomas-Richmond et al .

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Fie . 11 . Case 704 . A forty year old woman in whom the diagnosis was reticulum cell sarcoma . Retrograde pyelography

showing return to normal after roentgen therapy . lymphomatous infiltration of the kidneys . The findings most frequently encountered (Table vnt) were a palpable mass in the renal areas (9 per cent), hypertension (8 .5 per cent) and azotemia (12 per cent) . The most favorable group for clinical recognition appeared to be children with lymphosarcoma and marrow involvement who had a palpable abdominal mass, roentgenographic visualization of enlarged kidneys and/or hypertension and/or nitrogen retention . Lymphomatous involvement of the kidneys was actually suspected antemortem in only 14 per cent of the 142 patients in the clinico-roentgenographic survey . The reasons for this very low incidence of clinical recognition appear to be several . First, the renal complications were frequently overshadowed, especially in the terminal illness, by the other features of generalized disease . This view is perhaps supported by the fact that only 0 .5 per cent of the patients died from the effects of lymphomatous invasion of the kidneys . Secondly, although one or more symptoms, signs or biochemical changes pointing VOL . 32, FEBRUARY 1962

to a possible renal lesion were found in 88 per cent of the patients, in three-quarters of these some other lesion, e .g ., dehydration, ureteric obstruction, thrombocytopenia or hyperuricemia, offered a more likely explanation for the findings than renal lymphoma . Thirdly, renal lymphoma rarely gave rise to massive enlargement of the kidney, but when it did the tumor was not always palpable, being frequently obscured by bulky paraortic or retroperitoneal disease or by ascites . SYNOPSES OF UNUSUAL CASES

596 . G . M . was a fifty-six year old man in whom a diagnosis of reticulum cell sarcoma was made . Six months before death urinary frequency developed . Investigation demonstrated a left-sided renal tumor . Nephrectomy was undertaken . Histologic examination revealed reticulum cell sarcoma . One month before death there was no clinical evidence of other lymphomatous lesions . Approximately three weeks later uremic acidosis and hypercalcemia developed, and the patient died . Autopsy revealed massive (80 per cent) replacement of the right kidney by lymphoma (weight 450 gm,) and infiltration of the CASE

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FIG . 12 . Case 233 . A forty-two year old man in whom the diagnosis was Hodgkin's disease . Excretion pyelography showing localized mass in the lower pole of the left kidney . right lung, myocardium, stomach, liver, adrenal glands, bone, dura mater and all the main nodebearing areas . CASE 200 . H . M-G . was a thirty-two year old man in whom a diagnosis of reticulum cell sarcoma was made. This Army officer's left kidney was removed two years prior to death following a bomb injury . Three months before death enlarged nodes, the first manifestation of malignant lymphoma, appeared in the neck. Thereafter the patient's condition deteriorated gradually with paraplegia developing due to spinal-dural involvement, concomitant difficulties in the bowel and bladder, and finally uremia . At autopsy the remaining kidney was found to be extensively replaced by tumor . It weighed 1,090 gm . (the largest kidney in the series) . Lymphomatous infiltrations were also found in the thyroid gland, myocardium, liver, pancreas, adrenal glands, testes, the main node-bearing areas and the lumbosacral plexuses . CASE 441 . A . D . was a thirty year old man in whom a diagnosis of lymphosarcoma was made . This patient had a slowly progressive course during two and a half years of clinical disease. Then, because of fever and probable para-aortic adenopathy, he was

given nitrogen mustard in a dose of 0 .2 mg . per Kg . His blood uric acid level, which had been 20 mg . per cent, promptly rose to 47 mg . per cent and the blood urea nitrogen from 10 to 80 mg . per cent. At this time pain developed in the right flank and lower quadrant of the abdomen, and oliguria occurred . Uric acid crystals and urates appeared in the urine . With conservative therapy (fluids, alkali), the blood urea nitrogen returned to normal levels and the uric acid to pretreatment levels . Autopsy examination revealed inconspicuous nodular infiltrates of lymphoma in the kidneys . CASE 251 . P . R . was a thirty-five year old man in whom the diagnosis of lymphosarcoma was made . This patient gave only a six-week history of indigestion prior to death . At autopsy he was found to have massive lymphomatous invasion of the stomach with extension to almost every viscus and tissue in the abdomen including the kidneys . During the last three weeks of life he had received 0 .4 mg. per Kg. of nitrogen mustard followed by radiation therapy through three large abdominal portals (the dose delivered through these was 1,200, 2,500 and 1,500 r, in air, respectively) . On the day following the administration of nitrogen mustard, the blood urea nitrogen AMERICAN JOURNAL OF MEDICINE



Renal Lesions in Lymphomas--Richmond et al . level increased from 13 to 43 mg . per cent and thereafter during the next three weeks to 81 mg . per cent . Urates appeared in the urine in large amounts . Uremic acidosis and uric acid nephropathy as a result of nitrogen mustard and radiation therapy appeared to be the main cause of death, which occurred three weeks after the start of treatment . Autopsy examination revealed a solitary microscopic focus of infiltration in one kidney . CASE 630 . H . R . was a fifty year old man in whom a diagnosis of lymphosarcoma was made . This patient gave only a four-month history of disease prior to death . Following the instillation of 0 .4 mg. per Kg . of nitrogen mustard into the pleural cavity the blood urea nitrogen was 41 mg . Per cent ; it rose gradually to 101 mg . percent three weeks later . At this time, hyperkalemia and acidosis were also present . Renal infiltration by lymphoma was suspected in this case because of tenderness in both renal areas . Accordingly, radiation therapy in a dose of 1,000 r (in air) was given to each lumbar area. Improvement in the blood urea nitrogen was evident on the day following the institution of radiation therapy and within five days it had returned to normal levels . Autopsy findings confirmed that renal parenchymal lymphoma was the only likely cause of azotemia. CASE 647 . J . S . was a fifty-three year old man in whom a diagnosis of reticulum cell sarcoma was made . This man had a clinical illness of sixteen months' duration. In his terminal two months of life, renal involvement by lymphoma was suspected in view of albuminuria (1 plus), microscopic hematuria, azotemia (blood urea nitrogen rising to 132 mg . per cent) and the finding of large kidneys on pyelography . Radiation therapy was prescribed but had to be discontinued after only 600 r had been delivered to each lumbar area because the blood urea nitrogen rose to 294 mg . per cent and hyperkalemia and hyperuricemia supervened . Death occurred approximately three weeks after the termination of radiotherapy during which time there had been persistent uremic acidosis . Autopsy examination showed the kidneys to be massively infiltrated by lymphoma ; the right and left weighed 320 gm . and 300 gm., respectively. (Fig . 6 .) CASE 373 . R . B. was a fifty-one year old man in whom a diagnosis of lymphosarcoma was made . This patient's duration of illness was ten months . The main features during life were extensive osseous infiltrates of lymphoma, hypercalcemia (15 .2 mg . per cent), azotemia (blood urea nitrogen 127 mg . per cent) and hyperuricemia (15 .2 mg . per cent) . Autopsy examination revealed only microscopic deposits of lymphoma in the kidneys ; death was due to renal failure as a result of nephrocalcinosis. CASE 671 . M . S . was a fifty-eight year old woman in whom a diagnosis of Hodgkin's disease was made . This patient had had clinical disease for nine years

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(treated by radiation therapy, nitrogen mustard and various steroids) when a nephrotic syndrome supervened . The clinical picture was one of generalized edema, hypoalbuminemia and gross albuminuria . Death resulted one year later from uremic acidosis . The main autopsy findings were Hodgkin's disease of the spleen (with known clinical involvement in neck nodes, mediastinum and perhaps the abdomen, at an earlier stage), amyloidosis involving the kidneys, liver, spleen and adrenal gland and uremic pericarditis . CASE 704 . R . L. was a forty year old woman in whom a diagnosis of reticulum cell sarcoma was made . This patient had a six months' history of nightly abdominal distress and vomiting, and had had an exploratory celiotomy in May 1956 at which time enlarged retroperitoneal nodes were found . A biopsy specimen was obtained and a diagnosis of reticulum cell sarcoma established . Soon after, cervical and mediastinal adenopathy developed . In January 1958, large globular masses felt in both flanks became palpable and easily ballotable and were thought, clinically, to represent enlarged kidneys . Intravenous pyelographic examination was performed in January 1958 and revealed diffuse enlargement of both kidneys with lack of filling of the inferior calyces, and more enlargement of the lower poles than the upper poles . The findings were consistent with diffuse involvement of the kidneys by lymphoma . (Fig . 10 .) There was chemical evidence of renal malfunction also . The patient was given radiation therapy to the kidneys, following a course of epoxypiperazine, through two posterior lumbar fields in a dose of 2,000 r (in air) to each field delivered in approximately two weeks . The kidneys became normal in size as seen on roentgenograms (Fig. 11), and all chemical aberrations of renal dysfunction were altered toward normal . This patient is still alive although she has evidence of reticulum cell sarcoma in bone and soft tissues . Presently, although nitrogen retention has recurred, her kidneys have not enlarged either clinically or roentgenologically . CASE 327 . M . C . was a thirty-four year old woman in whom a diagnosis of reticulum cell sarcoma was made. This patient had clinical disease probably of two years' duration . She presented with the features of superior vena caval obstruction, but in her last few weeks of life her main complaint was of severe polyuria . At autopsy, lymphomatous deposits were found in the spleen, liver, lungs and peritoneum . The kidneys were extensively involved but the patient's diabetes insipidus was almost certainly due to infiltration of the sphenoid bone and posterior pituitary gland . SUMMARY AND CONCLUSIONS

The literature relating to involvement of the kidneys by malignant lymphoma is reviewed .



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A study is made of 696 autopsy cases of malignant lymphoma (Hodgkin's disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungoides) to ascertain the nature and incidence of (1) renal infiltration by malignant lymphoma and (2) renal lesions other than lymphomatous deposits which appear to have arisen secondarily to the underlying malignant process . In addition, the relative incidence of involvement of all other tissues and organs in the body is determined . A separate analysis of those patients with lymphosarcoma showing marrow involvement is made since this group would be expected to contain all the patients with leukolymphosarcoma and might, therefore, help to distinguish the renal lesions which were more properly attributable to leukemia . The incidence of lymphomatous infiltration of the kidneys in the whole series is 33 .5 per cent . The incidence in the different disease groups is Hodgkin's disease, 13 per cent ; lymphosarcoma with marrow involvement, 63 per cent ; lymphosarcoma without marrow involvement, 38 .5 per cent ; reticulum cell sarcoma, 46 per cent . Except for the high incidence of lung involvement in Hodgkin's disease, the kidneys were found to be infiltrated by the primary disease more frequently than any other organ or tissue . The high incidence in the "lymphosarcoma with marrow involvement group" is due to the more frequent occurrence of a leukemic type of infiltration, apparent only on microscopic examination, than in the other groups . Only five patients with mycosis fungoides are available for study ; in none of these were the kidneys involved . Infiltration of the kidneys is unilateral in 26 per cent of affected cases and bilateral in 74 per cent . Lymphomatous deposits are most usually in the form of multiple nodules (61 per cent of all affected kidneys) . The other types of infiltration which were encountered were classified as "diffuse," "bulky single tumors," "solitary nodules," "invasion from perirenal disease" and, finally, that which could be detected only on microscopic examination . Widely disseminated disease appears to be more common in those patients with renal lymphoma than in the other patients . Age, sex and clinical duration of disease could not be shown to have an important influence on the incidence of renal involvement . The renal lesions other than lymphomatous deposits which could be attributed to the underlying disease process are hydronephrosis or

pyelonephritis, or both, due to ureteral obstruction ; urinary calculi and visible gravel ; infarction ; hemorrhage into the kidney substance ; hemoglobinuric and cholemic nephrosis ; embolic abscesses (bacterial and fungal) ; nephrocalcinosis and amyloidosis . The last occurred only in Hodgkin's disease in which group there was an incidence of one in thirty-five patients (a total of eight) . One of these had amyloid nephrosis . One hundred and forty-two patients (those who, at autopsy in the ten year period 1949 to 1958, were found to have lymphomatous involvement of the kidneys and for whom complete medical records were available) are the subject of special clinical and roentgenographic study . Only 23 per cent of this group had clinical features or biochemical changes which might have suggested renal involvement antemortem . The most frequent abnormalities are a palpable mass in the renal areas, hypertension and nitrogen retention ; the incidence of these findings in patients with renal involvement was, however, less than 10 per cent . In 75 per cent of the patients showing clinical and biochemical abnormalities which might have suggested renal lymphoma, the findings could be better explained by other lesions. Wider use of pyelographic examinations might have increased the number of patients suspected of having lymphomatous infiltration of the kidneys . The most common roentgenographic findings indicative of involvement are bilateral symmetrical enlargement of the kidneys, a localized mass or masses in an otherwise normal kidney outline, and an interval change in the appearance of the kidney due either to progression of the involvement or its response to treatment . In only 14 per cent of the 142 patients with renal involvement who received special study was the complication of renal parenchymal infiltration recognized antemortem . Possible reasons for this are discussed . In the entire autopsy series (696 patients), while infiltration of the renal parenchyma by lymphoma may have influenced the course of many patients, it could be accepted as the main or sole cause of death in only 0 .5 per cent . REFERENCES 1 . SUTTON, H . G . and TURNER, F . C . Drawings of organs with microscopical sections from cases of Hodgkin's disease and allied conditions . Tr. Path. Sac. London, 29 : 342, 1878 . AMERICAN JOURNAL OF MEDICINE



Renal Lesions in Lymphomas-Richmond et al . 2 . EWING,J .NeoplasticDiseases : A1'rcatiseonTumors, 4th ed. Philadelphia, 1940 . W . B. Saunders Co. 3. CUTLER, M . Lymphosarcoma . Arch . Surg ., 30 : 405, 1935 . 4 . JACKSON, H . and PARKER, F . Hodgkin's Disease and Allied Disorders . New York, 1947 . Oxford University Press . 5 . SYMMERs, D . Lymphoid diseases . Arch . Path ., 45 : 73, 19486 . WArsoN, E . M., SAUER, H . R . and SADUGOR, M. G . Manifestation of the lymphoblastomas in the genitourinary tract . J. [rd ., 61 : 626, 1949 . 7 . RAPPAPORT, H ., WINTER . W. J . and Htexs, E. B. Follicular lymphoma : a reevaluation of its position in the scheme of malignant lymphoma based on a survey of 253 cases. Cancer, 9 : 792, 1956 . 8 . BARNEY, J. D., HUNTER, F . T . and MINTZ, E . R . The ecological aspects of radiosensitive tumors of the blood forming organs . .. A . AL A ., 98 : 1245, 1932 . 9 . NVFNTZELL, R . A . and BERKHEISER, S . W. Malignant lymphomatosis of the kidneys . J. Urol., 74 : 177, 1955 . 10 . ABESioUSE, B. S . and GOLDSTEIN, A. E . Metastatic malignant tumors of the kidney : a review of the literature and report of 23 cases . Urol . & Caton . Rev ., 45 : 163, 1941 . 11 . PRICE, H . L . Lymphosarcoma of the kidney . Ohio M . J., 25 : 550, 1929 . 12 . MATHI, C . P . Retroperitoneal lymphoblastoma simulating kidney neoplasm . .1. Ural., 17 : 357, 1927 . 13. FREIFFLD, S. L . Lymphoblastoma of the kidney . Radiology, 46 : 507, 1946 . 14. FERGUSON, R . S . and STEWART, F . W . Lymphosarcoma of the prostate. J. Ural., 28 : 93, 1932. 15. Lvov, M . W. Case of mediastinal Hodgkin's granuloma with perforation of the chest wall . Am . J. M. Sc., 158 : 557, 1919 . 16 . ULLMANN, A . and AREsnousE, B . S . Lymphosarcoma of the intestine . Ann . Surg ., 95 : 878, 1932 . 17 . SIMONDS, J . P. Hodgkin's disease . Arch. Path . & Lab . Mod., 1 : 394, 1926 . 18 . ALLEN, D . H ., BERG, O . C . and ROSENBLATT, W. Lymphosarcoma of the kidney . Radiology, 55 : 731, 1950 . 19 . GIBSON, T. E. Lymphosarcoma of the kidney . J. Urol ., 60 : 838, 1948 . 20 . MILLER, C. O . Lymphosarcoma of the kidney . J. Ural., 62 : 439, 1949 . 21 . ELMER, R . F . and BOYLAN, C . E . Reticular cell sarcoma of kidney . Illinois M . J., 66 : 83, 1934 . 22 . DAVIs, F . M . and OLIVETTI, R. G . Primary lymphosarenmatosis of kidneys, adrenal glands and perirenal adipose tissue . J. Urol., 66 : 106, 1951 . 23 . KNOEPP, L . F. Lymphosarcoma of the kidney . Surgery, 39 : 510, 1956. 24 . BLATT, E. and PAGE, 1 . H . Hypertension and con striction of the renal arteries in man : report of a case . Ann . Int. Med ., 12 : 1690, 1939 . 25 . WALLACH, J. B., SCHARFMAN, W . B. and ANGRIST, A . A . Uremia due to replacement of renal parenchyma by tumor. J. Urol ., 67 : 623, 1952 . 26 . KILBURN, K. II . and BROWN, H . Anasarca and

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hypoproteinemia in reticulum cell sarcoma . Ann . Int . Med., 49 : 1257, 1958. 27 . GALLOWAY, J . Remarks on Hodgkin's disease . Brit . M . J ., 2 : 1201, 1922 . 28 . MF.RRILI, D . Uremia following x-ray therapy in leukemia . New England J. Med ., 222 : 94, 1940 . 29 . MERRILL, D . and JACKSON, H . The renal complications of leukemia . New England J . Med ., 228 : 271, 1943 . 30 . KR .AVITZ, 5 . ., C DIAMOND, H . D . and CRAVER, L . F. Uremia complicating leukemia chemotherapy . J . A . M . A ., 146 : 1595, 1951 . 31 . WEISBERGER, A . S . and PERSxv, L. Renal calculi and uremia as complications of lymphoma . Am. J . M. Sc., 225 : 669, 1953 . 32 . CALL, E . A . and MALLORY, 1'. B. Malignant lymphoma : a clinico-pathologic survey of 618 cases . Am . J. Path ., 18 : 381 . 1942 . 33 . W mra, P . J. and BuRNs, E . L . Fatal acute lymphoblastic leukemia with great enlargement of the kidneys in an infant 3 weeks old . Am . J. Dis. Child., 41 : 866, 1931 . 34 . MEYER, L. M. Pathology of the genitourinary tract in leukemia . Urol_ & Cutan . Rev ., 45 : 693, 1941 . 35 . KIRSImnuM, J . D . and PREUSS, F . S . Leukemia . A clinical and pathologic study of 123 fatal cases in a series of 14,400 necropsies . Arch, Int. Med., 71 : 777, 1943, 36 . BESSE, B . E ., LIEBERMAN, J . E. and LustED, L . B . Kidney size in acute leukemia . Am. J . Roentgenol ., 80 : 611, 1958. 37 . LUSTED, L . B ., BEssa, B. E . and FRITZ, R . The intravenous urogram in acute leukemia . Am . J. Roeatgenol ., 80 : 608, 1958 . 38 . PUENTE DUANY, N . Linfosarcoma y linfosarcomatosis de los rinones . Rev . Med. Trap . y Parasitol ., 6 : 117, 1940 . 39 . MoeLL, H. Size of normal kidneys . Acta Radial., 46 : 640, 1956 . 40 . POURTEYRON . Cited my MoeLL [39] . 41 . THOMA, R. Cited by MoeLL [.39] . 42 . ROESSLE, R. and ROULET, F . Cited by MoeLL [39] . 43 . COPPOLETTA, J . M . and WOLBACU, S . B . Body lengths and Organ weights of infants and children . Am . J. Path., 9 : 55, 1933 . 44. LEVITAN, R ., DIAMOND, H . D . and CRAVER, L . F . Esophageal varices in Hodgkin's disease involving the liver. Am . J. Med ., 27 : 137, 1959 . 45 . Wu .xs, S . Cases of lardaceous disease . Guy's Hosp . Rep ., 2(3rd s .) : 103, 1856 . 46. WILxs, S . Lyrnphadenoma and leukemia. Tr . Path. Sac . London, 29 : 269, 1878 . 47 . KILBURN, K . H . Secondary amyloidosis and hepatic failure in Hodgkin's disease . Am . J. Med., 24 : 654, 1958 . 48 . WALLACE, S, L., FELDMAN, D . J ., BERLIN, I., HARRIS, C. and GLASS, I . A . Amyloidosis in Hodgkin's disease . Am. J. Med., 8 : 552, 1950 . 49. TEILUM . G . Studies on pathogenesis of amyloidosis : effect of nitrogen mustard in inducing amyloidosis . J. Lab . & Clin. Med ., 43 : 367, 1954 . 50. SPAIN, D . M . Rapid and extensive development of amyloidosis in association with nitrogen mustard therapy ; report of a case . Am . J. Clin. Path ., 26 : 52, 1956 .