So-called “metastatic” calcification of the lung

So-Called "Metastatic" Calcification of the Lung* H.

BENFER KALTREIDER, M .D ., GERALD

L.

BAUM, M .D ., GENE BOGATY, M .D .,

MICHAEL D . MCCOY, M .D . and MARGARET TUCKER, M .D . Cleveland, Ohio A case of rapidly progressive metastatic pulmonary calcification associated with a primary hepatic hemangio-endothelial sarcoma prompted study of the autopsy experience with pulmonary metastatic calcification . Twelve additional cases were found in a review of over 7,000 autopsies performed in a twenty year period . One surgical specimen was also studied . Chronic renal disease and primary parathyroid abnormalities accounted for seven of the cases, but the remaining seven were almost certainly due to malignant disease with destructive bone lesions .

1966, because of a two week history of physical and mental deterioration with weakness, lethargy, anorexia and emesis, incontinence of urine and feces, pain in the left shoulder and hip, and hoarseness . He was well and working until two weeks before admission . There was no history of antacid or vitamin D ingestion . Physical examination revealed a markedly cachectic, dehydrated, lethargic, disoriented, elderly man with a blood pressure of 100/60 mm . Hg, pulse 120 per minute, respirations 24 per minute and oral temperature 100 .4 ° E . A firm tender, smooth liver edge was felt 8 cm. below the right costal margin in the mid-clavicular line. Resistance to manipulation of the neck and left shoulder was noted . Initial studies revealed hematocrit 41 per cent ; white blood cell count 19,950 per cu. mm . with neutrophils 81 per cent, lymphocytes 6 per cent, monocytes 12 per cent and eosinophils I per cent ; urine specific gravity 1 .020 with 2+ proteinuria and 50 white blood cells per high powered field ; serum calcium 15 .3 mg . per cent and phosphorus 4 .1 mg . per cent ; twenty-four hour urine calcium excretion 437 mg . ; serum protein 7 .6 gm . per cent with albumin 3 .0 gm . per cent ; diffuse increase in gamma globulins on serum protein electrophoresis ; alkaline phosphatase 17 King-Armstrong units ; blood urea nitrogen 132 mg . per cent; creatinine 2 .5 mg. per cent ; twenty-four hour creati-

o-CALLED metastatic calcification is a pathologic entity, the presence of which is rarely apparent prior to death . We have recently seen an unusual case of this condition

S

which was characterized by the rapid development of bilateral patchy and confluent pulmonary infiltrates as observed on chest roentgenograms . The roentgenographic appearance of the lungs of this patient did not suggest metastatic calcification . Stimulated by this case, we reviewed the autopsy material of the Veterans Administration Hospital of Cleveland (7,221 autopsies, 1946-1966) in order to describe our pathologic, roentgenologic and clinical experience with this disease entity. We found eleven cases associated with characteristic groups of underlying diseases . Subsequent to our index case, two additional patients with metastatic calcification were seen . The diagnosis in one of these was established during life by means of open lung biopsy. One case, presented in detail, together with a summary of this additional experience, form the basis of this report. CASE REPORT

A fifty-seven year old Negro man was admitted to the hospital for the first time on November 17,

* From the Pulmonary Section, Medical Service, Laboratory Service and Radiology Service, Veterans Administration Hospital, Cleveland and the Departments of Medicine, Pathology and Radiology, Case Western Reserve University School of Medicine, Cleveland, Ohio . Requests for reprints should be addressed to Gerald L . Baum, MD ., Pulmonary Section B, Veterans Administration Hospital, 10701 East Boulevard, Cleveland, Ohio 44106. Manuscript received February 6, 1968 . 188

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Metastatic Calcification of the Lung-Kaltreider et al. nine clearance IS cc . per minute ; and blood sugar 150 mg. per cent . The bone marrow showed erythroid hyperplasia . The initial chest roentgenogram showed bilateral hilar prominence and a calcified primary focus in the lower right side of the chest medially (Fig. 1) . Electrocardiogram revealed nonspecific changes in the T waves consistent with right heart strain ; the Q-T interval was normal . The patient was treated with intravenous fluids, and daily administration of aqueous crystalline penicillin, 2 .4 million units, was begun on the third hospital day . On the seventh hospital day the patient's condition suddenly deteriorated ; he became febrile with temperatures to 101 ° F ., tachypneic and semiresponsive . There was diffuse, intense, bilateral bronchospasm. A chest roentgenogram revealed a dense, confluent, patchy infiltrate occupying the entire left upper lung field and at right mid-lung field (Fig . 2) . Routine blood studies were unchanged . Arterial blood revealed pH 7 .52, PCO, 80 mm. Hg and PO, 48 mm . Hg . The central venous pressure was 5 cm . of saline solution . Bronchoscopy disclosed no obvious obstruction of the tracheobronchial tree . The patient was given oxygen, aminophylline, massive doses of penicillin intravenously (60 million units daily) and hydrocortisone . Profuse widespread bleeding associated with an infinitely prolonged prothrombin time further complicated the course . This was controlled by the parenteral administration of vitamin K and whole blood transfusions. Tachycardia, fever, uncontrollable bronchospasm, progressive carbon dioxide retention, right-sided seizure activity and subsequent right hemiparesis supervened . The patient died on the morning of the twelfth hospital day . At autopsy the liver weighed 1,850 gm . It was almost entirely replaced by nodules of pale gray tumor with soft, hemorrhagic centers . Similar hemorrhagic tumor was found in tracheobronchial lymph nodes, right kidney, vertebral bodies, almost replacing both adrenal glands, and in the left frontal lobe. The right and left lungs weighed 1,250 and 900 gm ., respectively. The cut surfaces revealed many plaque-like, pale yellowish gray, dry spongy nodules, mottled with black, which measured up to 0 .7 cm . in greatest diameter . The air spaces in these nodules were empty and dilated . The alveolar septums stood out in bold relief . The heart weighed 370 gm . and was normal except for a small recent infarct of the anterior papillary muscle of the left ventricle . The bodies of lumbar and thoracic vertebrae were extensively replaced by numerous, soft discrete foci of metastatic tumor . Microscopically, the tumor was made up of spindle-shaped plump, ovoid, malignant-appearing endothelial cells which in some regions formed von . 46,

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1 . Postemanterior roentgenogram of the chest shortly after admission showing relatively clear lung fields . Fm .

vascular channels . At the periphery of the tumor nodules, the liver sinusoids were invaded by large, hyperchromatic tumor cells . Proximally, a few islands of intact cells were seen . At the center of some of the tumor nodules the channels were broad, lake-like and filled with blood (Fig . 3) . A diagnosis of hemangio-endothelial sarcoma (probably primary in the liver) was made .

Fro 2 . Posteroanterior roentgenogram o the chest . nine days later showing extensive bilateral disease suggesting alveolar distribution . This film was obtained two days before death .

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Ic . 3 . Photomicrograph of hemangio-endotheliosar . coma in liver showing spindle-shaped malignant endohelial cells with hyperchromatic nuclei lining vascular paces . A group of liver parenchymal cells is seen in one corner and a giant tumor cell near the adjacent comer . ematoxylin and eosin stain, original magnification 240 . m . 4 . Photograph of lower lobe of right lung showing he patchy raised, dry nodules with pale grey mottling . The dilated empty alveolar spaces are also seen . Ic . 5 . Photomicrograph of section through one of the raised lung nodules showing calcium in the walls of the empty, distended alveoli (darker grey and thickened) . The patchy heavy black flecks are anthracotic pigment . Hematoxylin and eosin stain, original magnification x 75 .

Microscopic sections of the lungs revealed the raised, dry nodules to be due to deposits of calcium in the alveolar walls, making them rigid (Fig . 4 and 5) . Except for a few patchy regions of pulmonary edema, the alveoli contained only scattered pigment-laden macrophages and a few red cells . No inflammatory cells were seen . Scattered throughout the lungs were microscopic foci of tumor in lymphatic channels and small vessels, but these were distinctly separate from the nodules of calcium deposition . Microscopic examination revealed foci of tumor in the mucosa of the stomach and the kidneys . In addition, the kidneys showed calcification of tubular epithelium . Adenocarcinoma of the prostate gland with no metastases was found . SUMMARY OF SALIENT FEATURES IN THE CASE MATERIAL During the twenty year period from 1946 through 1966, 7,221 autopsies were performed at the Cleveland Veterans Administration Hospital . Metastatic calcification of the lungs was found in thirteen cases (Tables I, it and in) . One of these (Case 12) is the patient just described. Another (Case 13) came to autopsy VOL .

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after the reported case and one (Case 14) had an open lung biopsy during the course of treatment for multiple myeloma . The focus of study in these fourteen cases is metastatic calcification of the lungs, although this process was also identified in other sites . Cases of metastatic calcification involving other sites, and not the lungs, were excluded . A review of this material revealed that the underlying diseases in these fourteen cases could be divided into three groups : chronic renal disease (primary), three cases ; destruction of bone by tumor, seven cases ; and excess parathyroid hormone activity, four cases (Table I) . The latter group was independent of renal disease as a cause of excess hormone activity . Underlying chronic renal disease was found in Cases 1, 8 and 11 . The pathologic diagnoses were marked chronic pyelonephritis, marked acute and chronic pyelonephritis with arteriolar nephrosclerosis, and marked diabetic glomerulosclerosis . Although metastatic calcification of the kidneys was also present in each case, it was not extensive andd was not regarded



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TABLE I CLINICAL, NONPULMONARY ROENTCF.NOGRAPHIC AND PATHOLOGIC CHARACTERISTICS IN FOURTEEN CASES OF METASTATIC CALCIFICATION OF THE LUNG

Evidence of Bone and Soft Tissue Involvement Case Age (yr .) Year of No . and Race Death

Primary Diagnosis

Pathological Evidence of Metastatic Calcification

Roentgenologic

Pathologic

1

59, W

1949

Chronic pyelonephritis, aplastic anemia cause unknown, exogenous hemoehromatosis

Lungs, kidneys

X-ray films not available

Renal osteo lystrophy

2

57, W

1953

Multiple myeloma

Lungs, kidneys

X-ray films not available

Mydomatous involve ment of vertebrae, rib . and .acrum

3

37, W

1956

Multiglandular tumors ; hyperparathvroidism due to adenomatous hyperplasia, nephrocaldnosis

Lungs, kidneys, stomach, hearq vessels, muscle

Spotty demineralization of skull ; osteoporosis, generalized soft tissue calcification of vessels ; renal scone, calcification in both shoulders

Osteitis fibrosa

4

41, W

1957

Lymphosarcnma, large cell Lungs, kidneys, vessels type

Osteolytic metastases to vertebrae

S.'emnal .m . involvement of lumbar vertebrae

5

53, N

1958

Reticulum cell sarcoma

Lungs, kidney, heart, vessels

Oateolysic lesions, left god rib ; multiple rarefactions in right ischium and skull ; calcification in shoulder bursa

Sarcomatous involvement of vertebrae and rib

6

35, W

1961

Multiglandular a lemmas, 2 parathyroid adenomas, nephrocaleinosis

Lungs, kidneys, heart, stomach, muscle, perineural sheath, vessels, snbcutanemrs tissue

None recognized

Osteids fibrosa

7

58,

w

1961

Carcinoma of the hypopharynx; metastatic car, cinoma in lung

Pancreas, lungs, heart, kidneys, stomach

None recognied

.stases ; osteoNo met porosis

8

40, W

1961

Acute and chronic pyelonephritis, arteriolar nephrmclerasis

Lungs, kidney, stomach

Vascular calcification, old fracture toe and pelvis

Renal osteodystrophy

9

67, N

1962

Carcinoma of lung

Lungs, kidney

Single lyric lesion seen on x- ray film of 8th rib ; oateoporcais

Single metastasis found in 8th rib ; slight osteoporosis

10

67, N

1963

Multiple mycluma; parathyroid adenoma

Lungs, stomach

Involvement of ribs, vertebrae, pelvis and femurs

11

49, N

1965

Diabetic glomerulosclerosis ; chronic pancreadtis

Lungs, kidneys

Pancreatic calcification, old fracture clavicle and pelvis ; ? osteomyelius finger

Mydomatous involvement of vertebrae and ribs Renal osteodystrophy with nsteosclerosis

12

57, N

1966

Iremnngio-endothelial sarcoma of liver

Lungs, kidneys

Metasentic lesions of vertebrae and pelvis

Metastatic lesions of vertebrae

13

44, N

1967

Carcinoma hypopharynx with metastases to lungs

Lungs, kidneys, heart

Nut recugnized (one month anmmortem)

Metastatic lesions of vertebrae

14

41, W

Lung biopsy 3/1/67

Multiple mvelorne

Lung (metastatic and dystrotrophic calcificadon)

Generalized demineralizaLion of bones, compres,ion fracture of 7th thorac overtebra ; "myeloma" hone lesions in ribs, skull, clavicle

as the primary cause of renal failure . One or more of the pathologic features of renal osteodystrophy [1] were present in each case . The blood urea nitrogen and serum inorganic phosphorus levels were markedly elevated in two of the three cases . In these same two cases, secondary hyperplasia of the parathyroids was diagnosed. No laboratory data were available and no parathyroids were recovered in the remaining case. Nine cases of metastatic calcification were associated with malignancies ; in seven of these

there was evidence of extensive, destructive bony lesions on roentgenograms and/or anatomic examination (Cases 2, 4, 5, 10, 12, 13 and 14) . The tumors resulting in bony destruction were multiple myeloma (three cases), and (one each) lymphosarcoma, reticulum cell sarcoma, hemangio-endothelial sarcoma of liver and squamous cell carcinoma of hypopharynx . Hypercalcemia was present in five (Table n) . Five of seven patients with malignancy in whom blood urea nitrogen data were available did have elevated levels . With one AMERICAN

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TABLE H SELECTED BLOOD CHEMISTRY STUDIES AND USE OF STEROIDS IN FOURTEEN CASES OF MET.ASTATIC CALCIFICATION OF THE LUNG

Case No. 1 2 3

Steroid Therapy

No

5

No

6

No

7

No

8

No

9

Yes

12

Serum Creatinine (0 .6-1 .5 mg ./100 ml .)*

Serum Calcium (9-11 .0 mg ./100 ml .)*

Serum Alkaline Phosphatase Serum (4-12 King- Phosphorus Armstrong (3-4 mg ./ units)* 100m1 .)*

Miscellaneous No chart available No chart available

No

10 11

Blood Urca Nitrogen (10-20 mg ./100 ml .)*

11 .8 13 .2 14 .4

132 136 151 16 21 20 24 32 68 58 66 180 194 112

15 30

10 .8 10 .8 10 .8

15

13 .3 13 .9 15 .5 15,5

7 23 40

7 .8 5 .9 6 .4 4 .6

9 .2 9 .8 9 .5 10 .9

6 .7 7 .7 6 .4 3 .6

83 86 116 120 35 78 9

176 180 160 168 180 196 12B 35 20

Patient worked up in hospital 6 mo . before death ; last admission short as death occurred before adequate workup 15 .9 18 .3 13 .4

"Normal" Yes (one day)

80 155

Yes

132 48 20 18 20 21

2 .5 1 .3

11 10 11 10 11

.0 .0 .1 .0 .1

9

10 .5 12 .2 9 .8 9 .9 10 .5

20 .2 15 .5 14 .1 9 .7 17 .4 14 .0 7 .5

21 30 37 23 24 16 .5

2 .3 3 .4 3 .2 2 .7 3 .2 4 7 .3

15 .3 12 .3 11,3 12 .2 12 .3

17 16 23 24 33

3 .9 4 .1 3 .9

AMERICAN

No chart available Admitted in coma and died in a few hours of pneumonia and acidosis Creatinine clearance 76 mm./1,400 ml . shortly before death ; urinary calcium 31 .2 mg ./100 ml . (reported in detail in paper)

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TABLE II (corsl'd.) SELECTED BLOOD CHEMISTRY STUDIES AND USE OF STEROIDS IN FOURTEEN CASES OF METASTATIC CALCIFICATION OF THE LUNG

Case No .

Steroid Therapy

Blood Urea Nitrogen

Serum Creatinine

Serum Calcium

(10-20

(0.6-1 .5

(9-11 .0

mg ./100 nil .)*

mg ./100 ml .)*

mg ./100 ml .)*

13

Yes

12 9 8 42 39 44 46 48 82

14

Yes

64 67 46 35 24 23 26 30 31

Serum Phosphorus (3-4 mg./ 100 ml .)*

Miscellaneous

.3 .0 .0 .4 .4 .6 .1 .6 .6

6 5 5 21 20 16 18 22 17

3 .5 4 .2 3 .9 4 .6

Received oral phosphate therapy shortly before death

14 .2 12 .0 9 .5 9 .6 8 .3 9 .0 10 .0 10 .6 9 .3

16 15 18 21 29 25 18 10 10

2 .3 2 .5

Case included since diagnosis rarely made antemortem ; lung biopsy no problem for patient

12 11 11 17 17 19 20 18 9 1 .8 1 .6 1 .7

Serum Alkaline Phosphatase (4-12 KingArmstrong units) *

* Normal values.

exception (a small parathyroid adenoma in Case 10) the parathyroids in these cases were normal . Two patients had malignancies without significant bony destruction . One (Case 7) had a squamous cell carcinoma of the hypopharynx with no bony metastases and the other (Case 9) had bronchogenic squamous cell carcinoma with a single small bony metastasis . No laboratory data were available in Case 7, but in Case 9 marked hypercalcemia was present . The parathyroids in these cases were normal . No other obvious cause of the hypercalcemia was found . In similar cases reported in the literature it is postulated that the tumor secretes a parathyroid hormone-like substance which results in hypercalcemia [2,3] . Such a mechanism was considered in these two cases . In addition to the two cases with malignancy and suggestive evidence of excess parathyroid activity, there were two cases of primary hyperparathyroidism . In one (Case 3) there was adenomatous hyperplasia involving four parathyroids and in the other (Case 6) there were adenomas of both inferior parathyroids . In both cases the patients presented with abVOL . 46, FEBRUARY 1969

dominal pain, abnormal calcium and phosphorus levels, and died with renal failure secondary to nephrocalcinosis . One of the difficulties encountered in this retrospective study was incomplete data concerning the parathyroids in some cases . No parathyroids were recovered in Cases 1, 2, 4, 12 and 13 . Four parathyroids were recovered in Cases 3 and 11 . One to three parathyroids were recovered in the remaining autopsy cases . Chest roentgenograms were available in six cases and reports of chest roentgenograms in six others (Table in) . For two patients (Cases 1 and 2), neither roentgenograms nor reports could be found . The periods of roentgenologic observation varied from ten years to less than one month . One patient (Case 14) is still under observation after two and a half years . Eight patients had definite pulmonary infiltrates . One manifested a lobulated mass density and one had increased markings . In two patients the chest roentgenograms did not reveal any abnormalities. Two others (Cases 11 and 12) had roentgenographic evidence of congestive heart failure. So-called metastatic calcification of lung was

Metastatic Calcification of the Lung-Kaltreider et at.

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TABLE III ROENTGENOGRAPHIC FINDINGS IN FOURTEEN CASES OF METASTATIC CALCIFICATION OF THE LUNG

Examined Film or Report

Time Antemortem X-Ray Film Taken

3

Nothing available Nothing available Report

?

4

Film

I me .

5

Film

2 days

6

Report

7 days

7

Report

8 9

Report Report

8 me . 7 days 1 me . 3 wk .

10

Report

6 days

11

Film

4 days

12

Film

1 day

13

Film

1 me .

14

Film

Case No . 1 2

in Case 11 pancreatic calcification was noted . In Cases 3 and 5 calcification was demonstrated in or near the shoulders . Roentgenograms in six cases showed bony malignant lesions . COMMENTS

Findings

Generalized increase in lung markings Lobulated Inass density, right hilum ; lungs clear Slight increase in lung markings ; pneumonitis left upper lung field Finely granular infiltrates, extensive, throughout both lungs Normal Normal Normal Infiltrates noted in both upper lungs, pneumonia in left upper lung Pneumonia, lower lobe of right lung Bronchopneumonia scattered throughout both lungs ; congestive heart failure noted Pulmonary congestion and patchy infiltrates bilaterally Soft nodular lesions throughout both lungs, probably metastatic nodules Nodular infiltrates in upper lobes of both lungs

not seen or reported in any of the cases in this series . After review of the available films (Cases 4, 5, 11, 12, 13 and 14), we are of the same opinion . Dystrophic calcification was evident on the films in five cases . No roentgenologic evidence of soft tissue metastatic calcification or calcinosis was noted on the roentgenograms available for review (Table t) . In Case 3 a renal stone was seen and

Pathologically, the most common sites of calcium deposition are in the kidney, lung and gastric mucosa . Mulligan [5] found the lungs to be the most common site of metastatic calcification, occurring in 75 per cent of the cases, regardless of etiology . In our series, by selection, there was lung involvement in all fourteen cases (Table I) . Of the thirteen autopsy cases, the kidney was involved in twelve, the stomach in five, the heart in five, the peripheral vessels in three, the muscle in two, and the pancreas, perineural sheath and subcutaneous tissue in one each . Grossly the lungs may be normal, with extensive involvement they may be heavy, tough and gritty . On cut surface, the involvedd areas with thickened alveolar septums may stand out from the retracted surrounding pulmonary tissue . Microscopically, calcium salts are most consistently observed in the alveolar septums with or without accompanying fibrosis . Less frequently, the vascular and bronchial walls are also involved . In contradistinction to other forms of soft tissue calcification, metastatic pulmonary calcifications are rarely observed roentgenologically antemortem [16,17] . In none of our fourteen cases were they recognized before autopsy or biopsy . However, in patients receiving massive doses of calcium parenterally, Cooke and Hyland [18], and Carter et al . [19] recently described cases in which metastatic pulmonary calcifications were visible on chest roentgenograms during life . We consider the case presented here to be a unique example of the exceptionally rapid evolution of metastatic pulmonary calcification . Roentgenographically the pulmonary calcifications appeared as acute, diffuse intra-alveolar infiltrates clearly developing over a twelve day period . Despite the roentgenographic impression of alveolar disease, the findings at autopsy were confined exclusively to the interalveolar septums . It seems most likely that the hepatic hemangio-endothelial sarcoma which was metastatic to bone was responsible for significant hypercalcemia which in turn predisposed to AMERICAN

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Metastatic Calcification of the Lung-Kaltrelder et al . the precipitation of calcium salts in the lung and kidney . In view of the significant bony lesions in this case there is little reason to postulate the presence of a parathyroid hormone-like substance, as has been suggested in other reported cases of this same malignancy [20] . Metastatic calcification, a metabolic disorder in which calcium salts are deposited in otherwise normal tissues was first described by Virchow [4] and extensively reviewed by Mulligan in 1917 [5] . The parameters pertinent to metastatic calcification including the blood pH, serum levels of calcium and phosphorus with their ion product, and tissue phosphatase activity can be measured or estimated. However, there is no clinical method to measure local pH of tissues or the mineralizing propensity of blood and tissue fluid. Thus, the precise mechanisms of metastatic calcification in most cases remain undefined. The role of increased serum phosphorus levels in metastatic calcification has been emphasized for many years [6] . Recently Walser [7] has shown that the ion product of calcium and phosphate is increased, often manyfold, in cases of renal failure [7] . Mulligan [5] in his review of the world literature concerning metastatic calcification found that over one fifth of the cases were associated with underlying chronic renal disease . In our series, three of the fourteen cases were associated with primary renal disease . Two other conditions with elevated serum phosphorus levels associated with metastatic calcification are hypoparathyroidism including its variants [18] and intravenous phosphate treatment for hypercalcemia [9] . Hypercalcemia is known to occur in sarcoidosis, the milk-alkali syndrome, prolonged immobilization, destruction of bone by tumor, primary hyperparathyroidism, vitamin D intoxication and hyperthyroidism [10] . Examples of metastatic calcification have been reported in each of those conditions except hyperthyroidism [5,6,11-15] . In our series, hypercalcemia was a relevant factor in the cases of destruction of bone by tumor and the cases of postulated excess parathyroid hormone secretion . Mulligan found that destructive bone disease was present in over one third of the cases he reviewed . In our experience, extensive bony destruction by tumor was present in seven of the fourteen cases . In five of these seven cases, vni.-

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the patients were known to have hypercalcemia . The malignancy most frequently encountered was multiple myeloma . This circumstance is perhaps related to the tendency of this tumor to cause both hypercalcemia and renal failure . Of the four cases in which excess parathyroid hormone secretion is postulated, two were associated with malignancies and two with primary hyperparathyroidism . One patient in each group was known to have hypercalcemia . Since there was no significant bony destruction in the two cases associated with malignancies, secretion of a parathyroid hormone-like substance by tumor is suggested . In both cases of primary hyperparathyroidism, superimposed marked renal damage was present . The previously cited study of Walser [7] demonstrated that the ion product of calcium and phosphate was not elevated in primary hyperparathyroidism or in hypercalcemia of malignancy until renal failure supervened . The precipitating factors responsible for the rapid deposition of calcium in the lungs are unknown . Five patients in this series received corticosteroid therapy, the role of which in this process is not clear. One patient received oral phosphate therapy shortly before death. Tissue injury, in the form of aspiration pneumonitis, is an attractive explanation for the massive calcium deposits in the lungs, but its presence is unsupported by histologic examination . The association between the use of steroids to lower serum calcium levels and the development of metastatic pulmonary calcification is provocative . Perhaps this is the reason that steroid treatment of patients with inoperable bronchogenic carcinoma results in decreased length of survival . Recently, Selye [21] has described in detail the phenomenon of calciphylaxis which has added immunologic considerations to the predisposing and precipitating factors involved in soft tissue calcification . Using this technic, Allegra [22] has been successful in experimentally producing alveolar septa] calcification indistinguishable from that seen in man . Despite anatomic similarity, this mechanism is not pertinent to our experience . The report of pulmonary alveolar microlithiasis by Sosman et al . [23], although representing a different type of disorder, points to genetic influences on the general process of tissue calcification .



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Metastatic Calcification of the Lung-Kaltreider et al. REFERENCES

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excessive milk and alkali intake . Am . J . Med ., 14 : 108, 1953 . 13 . CHFATLE, E . L . and SOMMERS, H . M . Metastatic calcification of the lungs . Quart . Bull . Northwestern Univ . M . School, 32 : 55, 1958. 14 . BAUER, J . M . and FREYBERO, R . H . Vitamin D intoxication with metastatic calcification . JA .M.A, 130 : 1208, 1946 . 15 . WILSON, C . W ., WINGFIELD, W. L. and TooNE, E . C ., JR . Vitamin D poisoning with metastatic calcification : report of a case and review of the mechanism of intoxication . Ain . J . Med., 14 : 116, 1953 . 16 . HILBISH, T. F . and BARTTER, F . C . Roentgen findings in abnormal deposition of calcium in tissues. Am . J. Roentgenol, 87 : 1128, 1962 . 17 . RUBIN, E. H . The Lung As A Mirror of Systemic Disease, p . 47. Springfield, Ill ., 1956 . Charles C Thomas . 18 . COOKE, C . R . and HYLAND, J . W. Pathological calcification of the lungs following intravenous administration of calcium . Am . J . Med ., 29 : 363, 1960 . 19 . CARTER, A . C., KAMAN, S. A ., DEMAYO, A, P . and ROSENBLUM, D . J . An unusual case of idiopathic hypoparathyroidism, adrenal insufficiency, hypothyroidism and metastatic calcification . J . Clin . Endocrinol., 19 : 1633, 1959 . 20 . Case Records of the Massachusetts General Hospital . Case 12-1967 . New England J. Med ., 276 : 629, 1967 . 21 . SELYE, H . Calciphylaxis. Chicago, 1962 . University of Chicago Press . 22 . ALLEGRA, L . Experimental pulmonary calcification . Exper. Med . & Surg., 23 : 227, 1965 . 23 . SOSMAN, M . C ., DODD, G . D ., JONES, W. D . and PILLMORE, G . U . The familial occurrence of pulmonary alveolar microlithiasis . Am. J . Roent . genol, 77 : 947, 1957 .

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