Carcinoma of Lung with Adrenal Hyperfunction and Hypercalcemia Treated by Parathyroidectomy
M. HENRY GAULT, M.D., M.Sc.º and T. DOUGLAS KINSELLA, M.D., F.R.C.P.[C],¡ Montreal
ABSTRACT
A case of severe hypercalcemia secondary to carcinoma of the lung is described in which hypokalemic alkalosis, renal failure and pancreatitis were also present. The relative importance of the few bone meta- stases found at autopsy is considered, and a probable endocrine-like effect of the tumour in the development of the hyper- calcemia is postulated. Treatment of the hypercalcemia included administration of corticosteroids and disodium EDTA, peri- toneal dialysis and subtotal parathyroid- ectomy; the most effective of these was peritoneal dialysis. Subtotal parathyroid- ectomy failed to produce a further decrease in serum calcium values. The occurrence of hypokalemic alkalosis in the presence of increased adrenocortical function and its relationship to the carcinoma of the lung are discussed. The possibility that this neoplasm produced two factors which caused systemic effects ordinarily associated with the func- tion of endocrine glands must be considered.
T THE hypercalcemia of malignancy frequently re- sponds to measures such as the administration of adrenocorticosteroids1-4 or chelating agents.7, 8 The present report of a case of carcinoma of the lung illustrates that correction of the hypercalcemia may be extremely difficult, if not impossible, and demonstrates the effects of two additional thera- peutic measures, namely, peritoneal dialysis and subtotal parathyroidectomy, in the management of the hypercalcemia.
Hypercalcemia associated with malignancy may occur with or without bone metastases.3, 4, 7-11 In some patients with bone metastases, the degree of hypercalcemia seems out of proportion to the extent of the metastases and may be due to a combination of bone destruction by the tumour and the effect of an unidentified humoral agent formed by the neoplasm. In view of the lack of radiological evi- dence of bone involvement and the relatively few metastatic deposits demonstrated at autopsy, the systemic effect of the tumour may have been domin- ant in the present case.
From the Departments of Medicine and Medical Chemistry, Queen Mary Veterans’ Hospital. Montreal, Quebec.
*Director, Department of Medical Chemistry, Queen Mary Veterans’ Hospital ; Research Associate, McGill University Clinic.
Clinical Fellow, Department of Medicine, Royal Victoria Hospital ; formerly, Resident in Medicine, Queen Mary Veterans’ Hospital.
SOMMAIRE
Les auteurs rapportent un cas d’hypercalcé- mie grave secondaire à un cancer pulmo- naire; coexistaient également une alcalose hypokaliémique, de l’insuffisance rénale et de la pancréatite. On a évalué l’importance relative de quelques métastases osseuses trouvées à la nécropsie et on invoque comme probable un effet endocrinoïde de la tumeur pour expliquer l’hypercalcémie. Parmi les moyens mis en œuvre pour traiter l’hypercalcémie figuraient l’administration de corticoïdes et d’EDTA disodique, la dialyse intrapéritonéale et une parathyroï- dectomie subtotale. Le moyen qui s’est révélé le plus efficace a été la dialyse intrapéritonéale. La parathyroïdectomie sub- totale n’a pas réussi à réduire davantage la calcémie. L’auteur étudie ensuite l’appari- tion d’une alcalose hypokaliémique en pré- sence d’un hyperfonctionnement de la fonction cortico-surrénale et sa relation avec l’existence du cancer pulmonaire. Il faut envisager la possibilité que ce néo- plasme a pu provoquer la genèse de deux facteurs qui ont entraîné des effets généraux relevant ordinairement de la fonction en- docrine.
Additional features of interest in this case were (1) severe hypokalemia with alkalosis in the pre- sence of elevated plasma and urine corticoids, (2) pancreatitis, and (3) renal failure. The latter was probably due to multiple factors of which the most prominent were hypercalcemia, hypokalemia and disodium EDTA therapy. Renal lesions shown at autopsy were similar in some respects to those re- ported by Dudley et al.6 as being due to disodium EDTA.
CASE REPORT
A 50-year-old white man was admitted to Queen Mary Veterans’ Hospital for the first time on November 5, 1961, complaining of anorexia, 20-lb. weight loss, increase in cough and sputum with hemoptysis, retro- sternal chest pain, shortness of breath on exertion and orthopnea. These symptoms had developed during the two months before admission.
Five years previously he had been admitted to another hospital because of anorexia, weight loss, cough and hemoptysis. Investigation at that time re- vealed a lesion which contained several small cavities in the right upper lobe. Although the diagnosis of
318 GAULT AND KINSELLA: CARCINOMA OF LUNG
tuberculosis was not confirmed bacteriologically, he was treated for three months with streptomycin and para-aminosalicylic acid and became asymptomatic. From 1955 until November 1961, he stated that he had been in good health, except for a chronic cough, until two months before admission. The patient had smoked two or three packages of cigarettes per day for many years.
Physical examination on admission was considered unremarkable except for evidence of recent weight loss.
On laboratory investigation, the hemoglobin was 13.2 g., hematocrit 42%, erythrocyte sedimentation rate 42 mm./hr .; blood urea nitrogen 10 mg./100 ml., and fasting sugar 76 mg./100 ml. Urinalysis, white cell and differential count, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum cholesterol, prothrombin time and seroflocculation tests were normal. Numerous sputa were negative for acid-fast bacilli on smear and culture, and several sputa showed cells suggestive of malignancy. Two sputa were negative for fungi.
Chest radiographs and tomography showed a diffuse increase in density in the region of the right upper lobe with cavitation, enlargement of the right hilar region and widening of the right superior mediastinum. Bronchography and bronchoscopy showed occlusion of the right upper lobe bronchus. Biopsies taken during two bronchoscopic examinations and a right scalene node biopsy failed to show malignancy or granuloma.
A diagnosis of carcinoma of the right upper lobe bronchus was considered probable and thoracotomy was recommended. However, the patient elected to delay surgery and was discharged from hospital on February 16, 1962.
Eleven days later, on February 27, 1962, he re- turned to hospital with all of his previous symptoms and, in addition, a four-day history of intractable con- stipation, with marked confusion and drowsiness for 24 hours.
Physical examination at this time disclosed a thin man with normal vital signs and no stigmata of Cush- ing’s syndrome. He was drowsy but oriented, and the neurological examination was otherwise within normal limits. Examination of the chest suggested right upper lobe consolidation. Rectal examination demonstrated hard impacted stool but a normal prostate.
Laboratory findings on this admission were as fol- lows: Urinalysis showed a specific gravity of 1.012, a trace of albumin, an alkaline pH, 3-4 white blood cells and occasional red blood cells per high-power field, occasional coarse and fine granular casts. The hemo- globin was 11.2 g., hematocrit 34%, erythrocyte sedi- mentation rate 29 mm./hr., and white blood cells 11,200/c.mm. with a normal differential count. The serum sodium was 136 mEq./1., chloride 87.8 mEq./1., potassium 2.2 mEq./1., CO2 combining power 43 mEq./1., blood urea nitrogen 18 mg./100 ml., arterial pH 7.52, serum creatinine 1.8 mg./100 ml., 24-hour creatinine clearance 26 ml./min., total protein 6.8 g./ 100 ml., albumin 46%, a,-globulin 8%, a2-globulin 13%, ß-globulin 11% and y-globulin 21%, serum glutamic oxaloacetic transaminase 15 units, lactic acid dehydro- genase 295 units, alkaline phosphatase 5 Shinowara units, serum calcium 16.6 mg./100 ml. (of which 45% was ultrafiltrable) and serum phosphate 2.5 mg./100 ml. Subsequent values for calcium and phosphate are recorded in Figs. 1 and 2 and Table III; BUN, serum creatinine and 24-hour creatinine clearance (retention
DISODIUM EDTA 150 mg/kg/24hr.
DEXAMETHASONE 9mg/24hr. P.O.
I.V. HYDROCORTISONE
240mg /24hr
201
PERITONEAL DIALYSIS
O.R.
18-
SERUM CALCIUM mg%
16-
14-
12.
10
Normal range
8-
DIALYSIS FLUID CALCIUM mg%
6-
M
4-
2
0
3500
3000
DIALYSIS
URINE
CALCIUM
2500
LOSS 2000
mg./ 24hr.
1500-
O.R.
1000
500-
0
1
2
3
4
5
6
7
8
9
DAYS of TREATMENT
10
13
14
15
catheter) are seen in Fig. 3. The electrocardiogram showed flattened T waves and a normal QT interval.
Because of the hypokalemic alkalosis, the diagnosis of hyperadrenocorticism secondary to the bronchogenic carcinoma was suspected. Plasma corticoids in a sample
DISODIUM EDTA 150mg/kg/24hr.
PERITONEAL .DIALYSIS
CORTICOSTEROIDS
WATER BALANCE 1./24 hr.
27
-1-
0
1-
2.
3
4
5
6
URINE
1.015
sp.gr.
1.010-
1.005
1.000
BUN mg%
100
75
50
25
0
SERUM CREATININE mg%
6
4
2
0
CREATININE
50-
CLEARANCE cc./min.
25
0
8
SERUM P mg%
6.
4.
O.R.
2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DAYS of TREATMENT
| Hospital day | Fluid-cc./24 hr. | Dialysate calcium | |||
|---|---|---|---|---|---|
| In | Out | Balance | mg./100 ml. | mg./24 hr. | |
| 6 (9 hr.) | 14,175 | 12,355 | +1800 | 5.7 | 704 |
| 7 | 20,330 | 21,520 | -1190 | 5.4 | 1162 |
| 8 | 41,700 | 41,975 | - 275 | 7.0 | 2938 |
| 9 (8 hr.) | 10,125 | 10,630 | - 505 | 4.7 | 500 |
| Totals (65 hr) | 86,330 | 86,480 | + 170 | 5340 | |
drawn at 4.00 p.m. on the day of admission were 28 µg./100 ml., and 24-hour urinary corticoids (Porter- Silber chromogen) were 14 mg. per 24 hours. Sub- sequent values are recorded in Fig. 3, together with serial values for serum potassium and CO2 combining power.
Additional laboratory findings included serum magne- sium 1.3 mEq./1., urinary 17-ketosteroids 10 mg., preg- nanediol 1.6 mg., pregnanetriol 0.7 mg., estrogens 64 ug. and aldosterone (low sodium intake) 15.8 µg. per 24 hours, all on Day 2. Spinal fluid cell count was normal, protein content 11 mg./100 ml., calcium 5.6 mg./100 ml. and lactic acid dehydrogenase 30 units, all on Day 10.
Management: Treatment will be considered under the following headings: (1) potassium replacement, (2) EDTA, (3) dexamethasone, (4) peritoneal dialysis, and (5) parathyroidectomy.
Intravenous potassium therapy was started one day after admission. The administration of 1000 mEq. over a four-day period was required before satisfactory serum levels and positive potassium balance were achieved (Fig. 3).
| Hospital day | Steroids (mg./24 hr.) | Disodium EDTA (mg./kg./24 hr.) | Potassium (mEq./24 hr.) |
|---|---|---|---|
| 1 | - | - | 20 |
| 2 | - | 50 | 400 |
| 3 | - | 150 | 300 |
| 4 dexamethasone | |||
| 9 mg. orally | 150 | 300 | |
| 5 | . | 150 | 150 |
| 6 | « | 150 | 80 |
| 7 | . | 150 | 80 |
| 8 | « | 75 | 100 |
| 9 | . | - | 100 |
| *10 | hydrocortisone | ||
| 240 mg. (i.v.) | - | 100 | |
| 11 | " | - | 200 |
| 12 | “ | - | 160 |
| 13 | .. | - | 170 |
| +14 | hydrocortisone | ||
| 80 mg. (i.v.) | - | 30 | |
*Subtotal parathyroidectomy.
+Eight hours of treatment.
Disodium EDTA in a dose of 150 mg./kg. intra- venously was given daily from Day 2 to Day 8 (Table II), with an increase in urinary calcium to four times the pre-treatment value (Fig. 1). On Day 8 this drug was discontinued because the urine output had dropped to 10 ml./hr. and the blood urea nitrogen had risen to 41.0 mg./100 ml. despite dialysis (Fig. 2).
Despite the four-fold increase in calcium excretion on EDTA therapy, the serum calcium had risen from the initial 16.6 mg./100 ml. value to 19.4 mg./100 ml.
DEXAMETHASONE 9mg/24hr.
I.V. HYDROCORTISONE
10mg/hr
-200
PERITONEAL DIALYSIS
-100-
0
K BALANCE
100
mEq/24 hr.
200
300-
400
6
SERUM K
-
4.
mEq/1.
2
0
40
CO2
30
COMB. POWER m Eq./1.
20
Art.pH
7.52
10
0
401
>100-67.0-64.0
PLASMA CORTICOIDS Mg-%
30
20-
10
URINE
0
17-OHCS .
17-KS
15
O.R.
C
10
mg./24 hr.
5
O
n
I
2
3
4
5
6
7
8
9
10
11
12
13
14
DAYS of TREATMENT
on Day 3. Accordingly, dexamethasone in an oral dose of 9 mg. per day was begun and continued to Day 10, when intravenous hydrocortisone was substituted in a dose of 10 mg./hr .; the latter was continued until the patient’s death (Table II).
In spite of combined EDTA and dexamethasone therapy which had resulted in a 10-fold increase in urine calcium excretion as compared to the pre-treat- ment value, the serum calcium on Day 6 was 18.2 mg./100 ml. Peritoneal dialysis was initiated at that time and was continued for a total of 65 hours until Day 9, when abdominal pain became severe. Prior to termination of the dialysis the serum calcium was 13.8 mg./100 ml .; total calcium removed during dialysis was 5.3 g. (Table I, Fig. 1).
By Day 10 the serum calcium had risen to 16 mg./ 100 ml., and deterioration of the patient’s neurological status was apparent. The persistent hypercalcemia, still of unproved etiology, was considered a threat to life. His poor general condition precluded the possibility of removal of what we considered to be the primary tumour, leaving parathyroidectomy as the sole practical possibility for effective control of the hypercalcemia. Subtotal parathyroidectomy was carried out on Day 10. Three normal-sized glands, in terms of the average dimensions of parathyroid glands indicated by Gray,12 up to 6 x 3 mm. and one slightly enlarged (11 mm. x 4 mm.), were found, all of normal histology. Three and two-thirds were removed, including the enlarged gland. While the patient withstood the procedure well, no sustained fall in serum calcium followed.
Clinical Course: Throughout these procedures the patient continued to have hemoptysis and the level of his awareness fluctuated considerably. He was fre-
quently disoriented, and his responses to auditory and tactile stimuli varied from reduced to exaggerated. On Day 14, he developed severe periumbilical pain; although physical examination of the abdomen at this time was unremarkable, the serum amylase was 534 units. In addition he had become stuporous, with hyper- active reflexes, and developed a fever of 103º F. in spite of antibiotic therapy. On Day 15, he developed pro- gressive, peripheral vascular collapse which did not respond to vasopressors.
Preterminally the serum calcium was 15.2 mg./100 ml., blood urea nitrogen 108 mg./100 ml., serum creatinine 5.6 mg./100 ml., creatinine clearance 5 ml./ min., serum phosphate 8.3 mg./100 ml., serum potas- sium 5.7 mEq./1., CO2 combining power 19 mEq./1. and serum sodium 138 mEq./1.
Analytical Methods: Biochemical determinations were carried out for the following values: serum and urine calcium;13 serum and urine creatinine as total chromo- gen;14 plasma 17-hydroxycorticoids15 except for initial value;16 urinary 17-hydroxycorticoids;17 17-ketoster- oids;11 aldosterone;19 estrogens;20 pregnanediol (preg- nane-3a,20a-diol) and pregnanetriol (53-pregnane- 3a,17a,20a-triol).21 Other determinations were by standard methods.
Autopsy Findings: On external examination the body was moderately well nourished and unremarkable ex- cept for healing cut-down and parathyroidectomy in- cisions. The significant findings on gross and microscopic examination were as follows:
(1) The tumour. The primary tumour originated from the right upper lobe bronchus and diffusely infil- trated the right upper lobe, which contained a 3 x 3 cm. cavity posteriorly and inferiorly. The tumour directly invaded the right pleura and the periosteum of ribs 1-3 in the mid and posterior axillary regions, and the bone of the first rib with adjacent muscle.
Grossly visible metastases were found in the right paratracheal and supraclavicular lymph nodes, in the liver (20 nodules, mainly a few mm. but up to 5 cm. in diameter), and the body of the first lumbar vertebra. Metastases of microscopic size were found in the second lumbar vertebra, one other vertebra, the right iliac crest and the left kidney (single parenchymal deposit and one arterial tumour embolus). Histologically, the tumour was predominantly of a moderately well-differ- entiated squamous type. It also contained some areas of somewhat undifferentiated epidermoid character.
(2) Endocrine system .- Only a small piece, 2 mm. x 1 mm., of the left upper parathyroid gland remained at autopsy. At the time of subtotal parathyroidectomy the four parathyroids were normal in size except for the slightly enlarged left lower gland which measured 11 mm. x 4 mm. The histology of all glands was con- sidered normal. The left and right adrenals weighed 7 g. and 6 g., respectively; evidence of cortical hyperplasia was absent on gross examination and with standard staining technique. The thyroid, testes and pituitary were unremarkable.
(3) The kidneys .- The left kidney weighed 400 g. and the right 350 g. On cut section the parenchyma bulged and was softer and paler than normal. Micro- scopically, there was interstitial edema, moderate vascu- lar congestion and a few focal accumulations of acute and chronic inflammatory cells in the interstitial tissues. The glomeruli appeared normal. The epithelium of the proximal tubules showed variable degeneration and
necrosis, frequently with severe degrees of desquama- tion; comparable changes of a lesser degree were noted in the distal and collecting tubules. In the lumina of many tubules there were numerous, mainly round acidophilic bodies, somewhat larger than red blood cells, some of which contained pyknotic nuclei; most did show nuclear material. Hyalin and cellular casts were common.
In addition, several small areas of cell vacuolization with distension were noted in the tubules, and focal tubular calcification was present. A number of proximal tubules were lined with a flat squamous type of epithe- lium which seemed to represent regeneration.
(4) Bones .- Fifteen sections of various bones, in- cluding skull, right and left humeri, right and left femora, right and left iliac crests and six vertebrae, were studied. Apart from sections of the first rib and the first lumbar vertebra which showed considerable in- vasion by tumour, other bony metastases were 1 mm. or less in size. One such lesion was seen in the second lumbar vertebra, one other vertebra and the right iliac crest. A postmortem radiological skeletal survey showed no evidence of bony metastases.
The bony trabeculae unrelated to tumour were of normal number and size and did not suggest osteitis fibrosa.
(5) Other significant findings .- The pancreas on gross examination showed numerous small, yellow foci of fat necrosis. Microscopically, there was focal fat necrosis with polymorphonuclear infiltration and some increase in fibrous tissue between and within the lobules, as well as infiltration by chronic inflammatory cells.
The prostate was slightly but symmetrically enlarged and microscopically showed slight glandular hyperplasia along with one small focus of localized adenocarcinoma which had not invaded the capsule.
The brain was normal on gross examination.
Both lungs (right 1200 g., left 800 g.) showed marked bronchopneumonia with microabscesses, con- gestion and edema. This infection appeared to be the immediate cause of death.
DISCUSSION Hypercalcemia
The hypercalcemia seen in association with malignant diseases may be due to either or both of the following mechanisms. The first is direct in- vasion and destruction of bone by tumour with the subsequent release of the bone calcium in excess of maximal excretion.3. 4, 9 The second mechanism, proposed as operating in neoplasms without meta- stases, is presumed to be mediated through some humoral agent elaborated by the tumour. The action of this hormone may be on bone directly, or indirectly through stimulation of the parathyroid glands. That parathyroid stimulation may occur has been suggested by the occurrence, in associa- tion with carcinoma, of parathyroid hyperplasia of the chief cell type,22, 23 by the response of the hypercalcemia to subtotal parathyroidectomy,23 by the low serum phosphate7, 8, 24 and reduced tubular reabsorption of phosphate25, 26 as seen with hyper- parathyroidism, and by the presence of osteitis fibrosa.23
While the substance responsible for the hyper- calcemia in carcinoma of the lung remains un- identified, it has been suggested that it is a para- thormone-like substance,4, 8, 27 a vitamin D-like sub- stance,28 citric acid4 or calcium-complexing sub- stance.29
A number of features observed in this patient suggest that hypercalcemia was due to the simul- taneous operation of a humoral substance elabor- ated by the tumour and the direct destruction of bone by metastases. The fact that this patient had no calcium intake other than tap water in small amounts during his second admission excludes the possibility that the hypercalcemia was related to increased absorption of calcium from the intestine.
Therapy of hypercalcemia (Fig. 1) was started on Day 2 with an increased calcium-free fluid in- take and disodium EDTA, 150 mg./kg./24 hours. At this time the serum calcium was 16.4 mg./100 ml. Even though the urine calcium was more than doubled to 500 mg./24 hours, the serum calcium continued to rise, presumably because of increased release from bone, and after 48 hours was 19.8 mg./100 ml. At this time, dexamethasone 9 mg./24 hours was administered orally. In spite of a con- tinued increase in urinary calcium excretion to almost 1 g. per day and a stabilization of the serum calcium between 18 and 19 mg./100 ml., no signifi- cant improvement in the patient’s clinical status was noted after 48 hours on the EDTA-dexametha- sone combination. Serum calcium values13 during the period of EDTA therapy included calcium bound to EDTA. A serum calcium measured using EDTA titration and including only the calcium free from EDTA was 13.2 mg./100 ml. on Day 7, compared to 15.7 by the Clark-Collip method.13 This indicates that about 2 mg./100 ml. was bound to EDTA at the time.
Because peritoneal dialysis had been reported to be an efficient method for correction of hyper- calcemia,30, 31 this form of therapy, in combination with EDTA and dexamethasone, was commenced on Day 6 with good results. Dialysis fluid calcium varied between 4.5 and 7 mg./100 ml., and a total of 5.3 g. of calcium was removed over a period of 65 hours (Fig. 1 and Table I). The result was a fall in the serum calcium to a level of 13.8 mg./100 ml. on Day 8. While this change in serum calcium coincided with a slight further rise in urine calcium from 1000 to a peak of 1250 mg. on Day 7, there was on Day 8 a marked drop in urine volume (and urine calcium) which necessitated cessation of EDTA therapy. On Day 9, because of severe ab- dominal pain, in retrospect probably due to pan- creatitis, peritoneal dialysis was discontinued. On Day 10 the serum calcium again reached 15.9 mg./100 ml., and the patient’s neurological status deteriorated.
At this time, because of the lack of clinical, radiological or biochemical evidence of metastatic disease, the initial low serum phosphate of 2.5 mg./ 100 ml. in the presence of diminished renal function
(which suggested the possibility of increased para- thyroid activity), and the hope that subtotal para- thyroidectomy might influence the course of the hypercalcemia of malignancy,23 three and two- thirds of the parathyroid glands were removed. A transient fall in the serum calcium followed, from 15.9 to 14 mg./100 ml., which was maintained for less than 24 hours; thereafter, the serum calcium stabilized around 15 mg./100 ml., approximately the preoperative level (Fig. 1). The urine calcium following operation averaged about 500 mg./day. The serum phosphate, which had rapidly risen to 7 mg./100 ml. preoperatively (Fig. 2), remained at about this level in spite of a continuous rise in serum creatinine and blood urea nitrogen.
Stone, Waterhouse and Terry23 reported the cor- rection of severe hypercalcemia following subtotal parathyroidectomy in a patient with bronchogenic carcinoma and parathyroid chief-cell hyperplasia; they believed that the hypercalcemia was due to a humoral agent elaborated by the tumour, acting on bone via stimulation of the parathyroid glands. The relationship of the fall in serum calcium to subtotal parathyroidectomy in this instance has been questioned4, 10 because of the 13-day delay before the serum calcium reached normal and the relatively terminal nature of the fall.
No definite conclusions can be drawn concerning the effect of parathyroidectomy on the hypercal- cemia in this patient because of (1) the fact that there was no adequate control period following cessation of EDTA therapy and peritoneal dialysis; (2) the concurrent adrenocortical steroid therapy which might have produced a significant although delayed suppression of the serum calcium; (3) the possibility that the major effect of parathyroid- ectomy on serum calcium did not become manifest during the five days of life following the operation; (4) the proximity of the operation to the patient’s death-serum calcium has been noted to fall termin- ally without therapy.4 However, in view of the fact that the serum calcium had risen from 13.8 to 15.9 mg./100 ml. during the 48 hours prior to para- thyroidectomy and at no time exceeded the latter level postoperatively, it seems quite likely that the operation had an ameliorating effect on the hyper- calcemia.
The following factors suggest, however, that the hypercalcemia was partly mediated by a humoral mechanism in this patient: (1) the paucity of bony metastases found post mortem despite the rapid re- lease of calcium from bone-13 g. of calcium was lost in urine and dialysis fluid in 12 days (Table III); (2) the initial serum phosphate of 2.5 mg./ 100 ml. in the presence of a creatinine clearance of 25 ml./min .; (3) the degree of the hypercalcemia, its persistence in spite of a variety of therapeutic regimens and its apparent stabilization following subtotal parathyroidectomy. While the levelling-off of the serum calcium under 16 mg./100 ml. follow- ing parathyroidectomy, compared to the rise from 13.8 to 15.9 mg./100 ml. during the 48-hour period
| Hospital day | Serum phosphate | Serum calcium | Daily calcium losst |
|---|---|---|---|
| 1 | 2.5 | 16.6 | 125 |
| 2 | 16.4 | 350 | |
| 3 | 3.1 | 19.4 | 484 |
| 4 | 18.6 | 942 | |
| 5 | 3.2 | 18.4 | 977 |
| 6 | 3.3 | 18.2 | 1871 |
| 7 | 3.8 | 15.7 | 2399 |
| 8 | 3.8 | 13.8 | 3226 |
| 9 | 14.8 | 1124 | |
| 10 | 7.8 | 15.9 14.6* | 490 |
| 11 | 7.5 | 14.2 | 662 |
| 12 | 7.8 | 15.6 | 567 |
| 13 | 8.2 | 15.9 | 440 |
| 14 | 8.3 | 15.2 | - |
*12 hours after subtotal parathyroidectomy.
+13-day total-calcium lost in urine and through peritoneal dialysis: 13,657 mg.
prior to surgery, suggests an ameliorating effect on the hypercalcemia, the evidence is not sufficient to establish that the mechanism of humoral action was chiefly through stimulation of the parathyroid glands.
NEPHROPATHY
The nephrotoxicity of disodium EDTA in the presence of renal disease when the recommended dose of 50 mg./kg./24 hours is exceeded is well established.6, 32 There is some evidence that renal damage can occur with conventional doses but in this instance the nephropathy is readily reversible.32 The dosage employed in this patient averaged 150 mg./kg./24 hours. At postmortem examination in two patients who died with renal failure after large doses of disodium EDTA, Dudley et al.6 found tubular necrosis (particularly proximal), internal hemorrhages and enlarged reticuloendothelial cells with coarse granules. At autopsy, the kidneys of the patient described in this report also showed patchy tubular necrosis, especially of the proximal tubules. In addition, in numerous areas convoluted tubular cells, each distended by a large single vacuole, were found, similar to those described by Dudley et al.6 There were some enlarged acidophilic-staining macrophage-like cells in the peripelvic tissues, but not in other organs. No hemorrhages were present. (Professor A. C. Ritchie, University of Toronto, compared the kidney sections of the present case with a section from the kidney of one of the cases reported by Dudley et al.6 and reported that they were very similar. He also pointed out that these changes are not specific.)
Disodium EDTA was discontinued on Day 8 of treatment because of reduction in urine volume to about 10 ml./hr. (Fig. 2); following this brief period of oliguria and the discontinuance of dialysis, there was a gradual rise in the serum creatinine and blood urea nitrogen, and a further fall in the already much reduced creatinine clearance, although a good volume of urine output returned (Fig. 2). The blood urea nitrogen and serum
creatinine levels would have been even higher if peritoneal dialysis had not been carried out for 65 hours. The pathological changes in the kidneys and rapid recovery of urine volume from oliguric levels after the discontinuance of EDTA emphasize its nephrotoxicity in this patient.
Severe hypercalcemia leads to moderate or marked impairment in renal function.5, 33, 34 The depression of renal function in this patient at the time of admission (Fig. 2) can be attributed to hypercalcemia and nephrocalcinosis, and an asso- ciated hypokalemic alkalosis. The significance of the hypokalemia is difficult to assess, since the lesions typical of this condition were not found at autopsy and the serum potassium level had been normal for eight days before death (Fig. 2).
PANCREATITIS
The occurrence of acute and chronic pancreatitis in patients with hyperparathyroidism has been well documented;35, 36 in addition, acute pancreatitis has been reported recently in association with the hypercalcemia of myeloma.37 The mechanism of the pancreatitis is not known, but it does not appear to be related to increased pancreatic excretion of calcium.38
In the present case there was clinical, bio- chemical and anatomical evidence of acute pan- creatitis. While the pancreatitis could have been due to peritoneal dialysis, evidence of a chronic process with superimposed acute changes makes this unlikely.
NEUROLOGICAL ASPECTS OF HYPERCALCEMIA
The level of serum calcium at which symptoms of hypercalcemia may occur varies a great deal from patient to patient, for reasons which are inade- quately defined.º Symptoms may be absent when the serum calcium is over 15 mg./100 ml. but may be marked at 13-14 mg./100 ml. Death may occur at 17-18 mg./100 ml.39, 40
This patient presented with symptoms of lethargy, drowsiness and inattention, and a serum calcium of 16.6 mg./100 ml .; he sank into stupor when this level approached 20 mg./100 ml. During the re- mainder of his life, there were wide fluctuations in the neurological manifestations, not always related to alterations in the level of serum calcium.
It is significant that at no time were his deep tendon reflexes depressed, and on several occasions they were found to be hyperactive when the serum calcium was 15 mg./100 ml. or higher. We have noted occasional hyperreflexia in four other pa- tients with serum calcium levels between 15 and 23 mg./100 ml.
ADRENAL FUNCTION AND HYPOKALEMIC ALKALOSIS
In bronchogenic carcinoma, adrenal function may be increased, with or without evidence of Cushing’s
syndrome. The manifestations of this increase in function may only be metabolic.41 The incidence of adrenal hyperfunction in bronchogenic carcin- oma can be judged by the increasing number of cases being reported+1, 43-47 and by the fact that four additional patients with lung cancer and features of Cushing’s syndrome have been seen in this hospital during the last two years.
Werk, Sholiton and Marnell+2 suggested that a spectrum of adrenocortical hyperfunction and altered cortisol metabolism exists in patients with progressively invasive bronchogenic carcinoma. These findings are most marked in patients with far-advanced oat-cell and undifferentiated tumours. There is evidence that the tumour itself may pro- duce an ACTH-like substance.46
That cortisol may not be the only significant adrenal hormone in these cases is suggested by the frequency and severity of the associated hypo- kalemic alkalosis which is often out of proportion to the other features of Cushing’s syndrome due to adrenal hyperplasia. Aldosterone is not con- sidered to be responsible,43, 47 and the initial value obtained in this patient probably lends support to this thesis. Cost,47 with direct evidence from one case, has suggested that very high values of corticosterone (not seen in the usual Cushing’s syndrome) may account for this metabolic ab- normality.
The present case appears to fall into the group with adrenal hyperfunction and metabolic evidence of Cushing’s syndrome, although there are aspects of it which are not typical of most of the other reported cases. The principal atypical features were (1) the histologic nature of the tumour-a moder- ately well-differentiated squamous cell carcinoma; (2) the partial though temporary suppression of plasma and urinary 17-hydroxycorticosteroids with dexamethasone-9 mg./day (Fig. 3); (3) the normal 17-ketosteroids and (4) the absence of adrenal cortical hyperplasia at autopsy. With regard to the latter, it should be noted that the patient had been on suppressive doses of corticosteroids for 12 days before death.
The features which favour adrenal hyperfunction and “metabolic” Cushing’s syndrome (Fig. 3) are: (1) elevated plasma and urine 17-hydroxycorti- costeroids; (2) hypokalemic alkalosis, which re- quired some 1000 mEq. of potassium for correc- tion, in the absence of other apparent cause for potassium or hydrogen ion loss; (3) the absence of diurnal variation; (4) the failure to achieve com- plete suppression of adrenal function with 9 mg. dexamethasone per 24 hours-actually, the fall in 24-hour urinary corticoids may have been due to declining renal function, for (when expressed as mg. per g. creatinine) values actually rose from 20 to 23 during the test.
While the plasma and urinary 17-hydroxycorti- coids in the range found in this patient and the absence of diurnal variation of plasma 17-hydroxy- corticoids were reported by Werk, Sholiton and
Marnell42 in patients with bronchogenic carcinoma without Cushing’s syndrome, the failure to achieve anything but a partial and transient suppression with dexamethasone provides good evidence for adrenal hyperfunction rather than merely altered metabolism of cortisol. The progressive decline in renal function and the institution of peritoneal dialysis increase the difficulty in interpreting this test.
The partial adrenal suppression and limited ele- vations in plasma and urine cortisol might be taken to provide support for the concept of a spectrum of disorders, in patients with bronchogenic carcinoma, starting with altered cortisol metabolism and pro- gressing to adrenocortical hyperfunction. However, in view of the severe hypokalemic alkalosis, a better explanation is that a corticoid, other than cortisol or aldosterone, was involved in the production of the hypokalemic alkalosis. Perhaps this was cortico- sterone, as suggested by Cost.47
With regard to the possibility that the hypo- kalemic alkalosis was secondary to hypercalcemic nephropathy, Ferris et al.48 found in this type of nephropathy an inability to excrete acid as well as an inability to conserve water and potassium. In their case, this resulted in hypokalemia with a systemic acidosis rather than an alkalosis. In ad- dition, Wrong and Davies49 reported decreased ability of the kidneys to excrete an acid load in hyperparathyroidism, and Heinemann50 found a defect in renal ammonium excretion in patients with hypercalcemia.
Alkalosis has been reported in association with hypercalcemia other than that due to the milk- alkali syndrome,3, 11, 51-53 but its cause remains un- explained.50 Thomas, Connor and Morgan11, 51 men- tion that alkalosis and hypercalcemia may be asso- ciated, but in any specific case reports that we have found, this has been due to vitamin D intoxica- tion,3, 52, 53 except for one case of carcinoma of the lung and another of carcinoma of the breast.52 Adrenal function studies were not reported in these cases, and as each had hypokalemia with alkalosis, adrenal hyperfunction should be considered a pos- sible cause of the hypercalcemia.
The production of two systemically active sub- stances by a single tumour of non-endocrine origin suggested by the hypercalcemia and abnormal adrenal function in this patient would be clearly unusual, but not unique. In 1957, Harrison et al.54 reported a patient with bronchogenic carcinoma and Cushing’s syndrome who had many features suggesting carcinoid tumour; however, the only tumour present was the bronchogenic carcinoma.
SUMMARY
A case of bronchogenic carcinoma is reported with biochemical evidence of adrenal hyperfunction, hypo- kalemic alkalosis, hypercalcemia, pancreatitis and renal failure. The severe hypercalcemia was treated with EDTA, dexamethasone, peritoneal dialysis and subtotal parathyroidectomy. Of these, peritoneal dialysis was
324 GAULT AND KINSELLA: CARCINOMA OF LUNG
the most effective form of therapy. The renal failure is considered in part related to the EDTA therapy. Although some bone metastases were present, it is suggested that the hypercalcemia and presumably the adrenal hyperfunction were at least in part due to a humoral factor produced by the tumour.
We are indebted to Drs. M. M. Hoffman, J. C. Beck and K. R. Mackenzie for their constructive reviews of the manuscript, to Dr. A. C. Ritchie for his evaluation of the kidney sections and to Dr. M. Aronovitch for the oppor- tunity to study this patient.
REFERENCES
1. MYERS, W. P. L. : Cancer, 11: 83, 1958.
2. CONNOR, T. B. et al. : J. Clin. Endocr., 16: 945, 1956 (abstract).
3. DAVID, N. J., VERNER, J. V. AND ENGEL, F. L. : Amer. J. Med., 33: 88, 1962.
4. MYERS, W. P. L .: Advances Intern. Med., 11: 163, 1962.
5. ZEFFREN, J. L. AND HEINEMANN, H. O .: Amer. J. Med., 33: 54, 1962.
6. DUDLEY, H. R. et al. : New Eng. J. Med., 252: 331, 1955.
7. SCHATTEN, W. E. et al. : Ann. Surg., 148: 890. 1958.
8. PLIMPTON, C. H. AND GELLHORN, A. : Amer. J. Med., 21: 750, 1956.
9. WARWICK, O. H., YENDT, E. R. AND OLIN, J. S. : Canad. Med. Ass. J., 85: 719, 1961.
10. Editorial : Ann. Intern. Med., 54: 1026, 1961.
11. THOMAS, W. C., JR., CONNOR, T. B. AND MORGAN, H. D. : New Eng. J. Med., 260: 591, 1959.
12. DAVIES, D. V. AND DAVIES, F., editors: Gray’s anatomy descriptive and applied, 33rd ed., Longmans Green & Co., Ltd., London, 1962, p. 1557.
13. CLARKE, E. P. AND COLLIP, J. B. : J. Biol. Chem., 63: 461, 1925.
14. BONSNES, R. W. AND TAUSSKY, H. H. : Ibid., 158: 581, 1945.
15. MURPHY, B. P., ENGELBERG, W. AND PATTEE, C. J .: J. Clin. Endocr., 23: 293, 1963.
16. NELSON, D. H. AND SAMUELS, L. T. : Ibid., 12: 519, 1952.
17. PORTER, C. C. AND SILBER, R. H. : J. Biol. Chem., 185: 201, 1950.
18. DREKTER, I. J. : J. Clin. Endocr., 12: 55, 1952.
19. NISHIKAZE, O. AND STAUDINGER, H .: Klin. Wschr., 40: 1014, 1962.
20. ITTRICH, G .: Acta Endocr. (Kobenhavn), 35: 34, 1960.
21. STERN, M. I. : J. Endocr., 16: 180, 1957.
22. MASSARO, D. J. AND OWEN, J. A., JR. : Amer. Rev. Resp. Dis., 85: 727, 1962.
23. STONE, G. E., WATERHOUSE, C. AND TERRY, R .: Ann. Intern. Med., 54: 977, 1961.
24. Case records of the Massachusetts General Hospital, Weekly Clinicopathological Exercises, Case 63, 1963 : New Eng. J. Med., 269: 801, 1963.
25. REISS, E. AND ALEXANDER, F .: J. Clin. Endocr., 19: 1212, 1959.
26. MYERS, W. P. L .: A.M.A. Arch. Surg., 80: 308, 1960.
27. CONNOR, T. B., THOMAS, W. C., JR. AND HOWARD, J. E. : J. Clin. Invest., 35: 697, 1956.
28. KABAKOW, B., MINES, M. F. AND KING, F. H. : New Eng. J. Med., 256: 59, 1957.
29. MARSH, E. B., JR. AND WALSER, M .: Clin. Res., 9: 205, 1961.
30. MAXWELL, M. H. et al. : J. A. M. A., 170: 917, 1959. 31. BURNS, R. O. et al. : New Eng. J. Med., 267: 1060, 1962.
32. FOREMAN, H., FINNEGAN, C. AND LUSHBAUGH, C. C .: J. A. M. A., 160: 1042, 1956.
33. EPSTEIN, F. H. : Univ. Mich. Med. Bull., 26: 266, 1960.
34. SANDERSON, P. H. : Brit. Med. J., 2: 275, 1959.
35. MIXTER, C. G., JR., KEYNES, W. AND COPE, O .: New Eng. J. Med., 266: 265, 1962.
36. STIEL, M. C. AND PIPER, D. W .: Amer. J. Dig. Dis., 7: 850, 1962.
37. MELTZER, L. E. et al. : Ann. Intern. Med., 57: 1008, 1962. 38. McPHERSON, R. C. AND PACE, W. G .: Surg. Forum, 12: 372, 1961.
39. OLIVER, W. A .: Lancet, 2: 240, 1939.
40. THOMAS, W. C., JR. et al. : Amer. J. Med., 24: 229, 1958.
41. HYMES, A. C. AND DOE, R. P. : Ibid., 33: 398, 1962.
42. WERK, E. E., JR., SHOLITON, L. J. AND MARNELL, R. T. : Ibid., 34: 192, 1963.
43. HILLS, A. G. AND WOEBER, K. A .: Ann. Intern. Med., 54: 1295, 1961.
44. LIDDLE, G. W. et al. : Arch. Intern. Med. (Chicago), 111: 471, 1963.
45. Editorial : Brit. Med. J., 2: 505, 1961.
46. MEADOR, C. K. et al. : J. Clin. Endocr., 22: 693, 1962.
47. COST, W. S. : Lancet, 1: 362, 1963.
48. FERRIS, T. et al. : New Eng. J. Med., 265: 924, 1961.
49. WRONG, O. AND DAVIES, H. E. : Quart. J. Med., 28: 259, 1959.
50. HEINEMANN, H. O .: Metabolism, 12: 792, 1963.
51. THOMAS, W. C., JR., CONNOR, T. B. AND MORGAN, H. G. : J. Lab. Clin. Med., 52: 11, 1958.
52. VERBANCK, M. et al. : J. Urol. Med. Chir., 66: 693, 1960.
53. FOLLIS, R. H., JR. : Some observations on experimental bone disease. In : Ciba Foundation Symposium on Bone Structure and Metabolism, edited by P. E. W. Wolsten- holme and C. M. O’Connor, J. & A. Churchill, Ltd., London, 1956, p. 249.
54. HARRISON, M. T. et al. : Lancet, 1: 23, 1957.
PAGES OUT OF THE PAST: FROM THE JOURNAL OF FIFTY YEARS AGO
THE THYMUS GLAND IN EXOPHTHALMOS
A few years ago we knew all about hyperthyroidism. The exophthalmic goitre was due to the excessive secretion and the opposite was due to insufficient secretion and operative work as a general rule confirmed this theory. When we think of a thousand cases a year that Mayo does and the results that he gets it seems to bear out this theory. But a part of our new view is that the results are not always satisfactory and it comes about that we have to select and differentiate these cases. The two most interesting features are, first, the sympathetic theory. It is an old theory. Trousseau thought that the exophthalmos might be very largely associated with sympathetic troubles but until Landstrom demonstrated his streaked microscopic muscle we did not seem to have a satisfactory working theory. This muscle is under the control of the sympathetic, its action is to pull the eyeball forward and the lids back and when the sympathetic is stimulated it contracts this muscle and pulls the eyeball forward and the lids backward. The removal of the superior sympathetic ganglion just above the bifurcation of the carotid relieves exophthalmos and does it quickly. Of course we have to suppose that the thyroid secretes something which stimulates the sympathetic to act on this muscle as described by Landstrom. Another point is extremely interesting. We have all seen cases where the tachycardia is extreme, the weakness is extreme, where the blood condition as described by Kocher is present in a well marked degree and with a small insignificant thyroid:
these are the worst cases, they give us the sudden deaths- die after the ligature of an artery. And now comes the thymus. So far as I know Garre and his assistant, Capelle, were the first to give us the theory that in the thymus substance there is a heart poison and that the tachycardia was due to something secreted by the thymus. His assistant in a case of well marked Basedow’s disease removed a part of the thymus and the patient experienced all the signs of well-being, the heart returned to a good beat and the lymphocytosis passed to 10 from 40 per cent, but the exophthalmos remained the same. Other cases gave the same results. One case, previously operated on by Kocher, later came to Haberer cyanosed, with bloody expectoration, his condition extreme and the physicians thought it im-
possible to do anything for him. He remained in hospital for some time under rest begging always for an operation which finally was done, a portion of the thymus being removed. The improvement in that man was remarkable and prompt and about a year afterwards he was perfectly well with a normal heart action. He had two other such cases. It would seem that in rare and exceptional cases par- tial thyroidectomy is not sufficient; we can lessen the exoph- thalmos in cases where the eyes do not recede after opera- tion by removal of the sympathetic ganglion and it may be shown that these extreme cases of tachycardia with very small thyroids may be better dealt with in the first instances by taking away a portion of the thymus .- G. E. Armstrong, Canad. Med. Ass. J., 5: 174, 1915.