CHLOROMA 997

the exophthalmometer reading on the lefteye was 15 and on the right eye 13. Theonly possible indication of the etiologywas that the X-ray examinations showedan elevation of the outer table of thefrontal bone, and there was a densenessin both antra, thus suggesting the possi­bility that an inflammatory granulomahad extended from the sinuses into theorbit and over the frontal bone.

DR. PHILIP M. LEWIS, closing: I wishto thank the gentlemen for their diSC11$­sion. There is just one thing I want tosay. I believe that, in these cases, evenif we are suspicious that they are ofchronic inflammatory origin, we shouldgive the patient the benefit of a biopsy,rather than wait to see what may happen,because the condition might not be ofinflammatory origin.

CHLOROMA*

REPORT OF A CASE WITH HEMATOLOGIC STUDY

ALBERT D. FROST, M.D.Columbus, Ohio

Since exophthalmos is usually the firstsymptom of chloroma, a discussion ofthese cases deserves a place in ophthalmicliterature, even though the subject re­mains primarily in the realm of thehematologist. A complete review of theliterature would be superfluous at thistime, since this has been done so recentlyby Gump, Hester, and Lohr."

The gross anatomic features ofchloroma were first described by Burns"in 1823, who noted the green orbitaltumors and fatal outcome. King" was thefirst to use the name chloroma in 1853.Von Recklinghauserr' in 1885 mentionedthat the histologic pictures of chloromaand leukemia were similar but made nocorrelating blood studies. In 1893 Docksdiscussed the relationship between chlo­roma and leukemia, and in 1904 he andWarthin6 definitely established this rela­tionship. In 1910 Lehndorff" reviewed the73 cases which had been reported andconsidered 56 of these to be of lymphoidorigin. Inferior hematologic methods and

*Presented before the American Academyof Ophthalmology and Otolaryngology atChicago, in October, 1937. '

the generally accepted lymphoid natureof chloroma were probably responsiblefor the slow recognition of the myeloidnature of the disease. At the present time,most hematologists agree that the processis myelogenous.

In many of the cases that have beenreported as chloroma, the diagnosis maybe considered doubtful. In several in­stances there was neither biopsy norautopsy; hence the green color and othercharacteristics of the tumor were notdisclosed. This is particularly true of thecases reported by Gould and Le'Wald" inwhich the separation of the suture linesof the skull was stressed as an importantdiagnostic sign. Although this is evidentin some cases, it is a rare finding. Theirdiagnosis may be questioned also becausethe blood examinations did not showleukemia, the biopsy of the lymph glandsdid not show the green color, and autopsywas not performed. True aleukemicforms of the disease are rarely en­countered, but relatively aleukemic stagesmay be present.

Brannan's" review in 1926 left littledoubt of the myelogenous nature of the

998 ALBERT D. FROST

process and suggested that many casespreviously reported as chloroma were ofdoubtful authenticity. Nevertheless, ofseven cases reported by Feer'" as late as1927, three were classed as lymphoid, butone of these was diagnosed as lympho­sarcoma at autopsy. His second caseshowed leukopenia and nearly 90 percentlymphocytes. In none of these cases wasoxidase or supravital-staining techniqueused. Even the oxidase reaction does notdifferentiate lymphocytes from myelo­blasts, and it is easily seen that immaturemyeloblasts may have been mistaken forlymphocytes.

As yet there have been no cases ofdefinitely proved chloroma in which theoutcome was not rapidly fatal. Wash­burn'" in 1930 reported a case with cureby roentgen therapy two-and-one-halfyears after appearance of the tumor.This patient had a definite but moderateleukemia with an abnormal number ofimmature cells of the myeloid type (rnye­locytes) ranging from 5 to 26 percent.A green tumor of the frontal region wasfound at biopsy. According to a recentcommunication from the author, the childis still living. Distinguished pathologistsin various parts of the country recentlyhave examined sections of tissue from thetumor, but they have failed to agree onthe diagnosis. Some have called itxanthoma, some chloroma, and othershave been unwilling to classify it. Wash­burn says, "My own feeling is that inreferring to the case it should be men­tioned that the diagnosis of chloroma isopen to question in spite of the fact that Istill believe it is the most plausible diag­nosis." This is the only case in whichroentgen irradiation was administered ina relatively long course of small dosesrather than in full erythema doses. Itmay be significant, also, that the treat­ment covered practically the entire bodyand was not confined to the visible man i-

festations of the tumor. In 24 treatmentsover a period of six months, the entirebody was irradiated except for the handsand feet. Washburn was unable to findin the literature that similar treatmenthad been used in any other case of thistype, nor was 1. At the conclusion ofthe treatments, the blood count was nor­mal and no immature forms were evi­dent.

Several other writers, including King-"and Merculov.P have reported apparenttemporary benefit from local irradiation.On the other hand, Gamble" and otherobservers have reported rapid progres­sion of the disease in spite of roentgentreatment.

In many of the articles on chloroma,too much stress has been laid on so­called characteristic findings such asseparation of sutures, involvement of thebones of the skull, papilledema, sub­conjunctival hemorrhages, which reallyrepresent individual manifestations thatmayor may not be present. This has ledto considerable confusion, in that theabsence of these conditions may tend tolead the observer away from the diag­nosis. Why make it hard? The subjectiveand objective signs and symptoms aredependent merely on the situation of thetumor, which may be at any place in thebody.

It is necessary, then, that a clear defini­tion of chloroma be made, if possible.Localized growths of myeloid elementsanywhere in the body, as demonstrated bybiopsy or autopsy, and myelogenousleukemia, progressing rapidly to a fataltermination, are the outstanding featuresof the disease. It appears more often inchildren. When adults are affected, thecondition seems to occur more frequentlyafter the fourth decade. The underlyingpathologic change consists of a primaryhyperplasia of bone marrow which mayproduce masses of immature white blood

CHLOROMA 999

cells beneath or in the periosteum of theflat bones with metastasis through theblood stream to distant tissues. Thehyperplastic areas in the bone marrow in­crease in size and the bony trabeculaebecome rarefied. I f they break through,they produce flattened greenish tumorsover the inner surface of the skull, thevertebrae, and the ribs. The diagnosiscannot be made by roentgenographic orblood studies alone. The green colorshould be present if the term chloromais to be employed. However, Gump, et aPstate that the tumors may not be green.

Thus far the cause of the green colorof the tumors has not definitely beendetermined. It is assumed that it is boundup in some way with the metaplasia ofthe myeloid cell which is peculiar to thistype of leukemia, but this color is notnecessarily characteristic of the color ofbone marrow in other types of leukemia.Boots" showed that the color fadesrapidly on exposure to light and air andthat formalin specimens become greenagain in hydrogen peroxide. He alsofound the green color in the buffy coatof the white cells in a case of myelog­enous leukemia, but not in the cellsfrom a patient with lymphatic leukemiawhose white count was equally high.

Chloroma is definitely a leukemic dis­ease and may be considered as an un­usual form of myelogenous leukemia. Inthis sense it is a distinct entity. Its neo­plastic properties cannot be questioned,and chloroma in myelogenous leukemiamay be a counterpart of lymphosarcomaseen in lymphatic leukemia.

CASE REPORT

A white boy, aged four years, was ex­amined on November 23, 1935, becauseof a swelling in the left upper lid. Thishad appeared about two months before

.and had increased in size, gradually atfirst, but for the last two weeks had dis-

played rapid growth. The child felt per­fectly well and had no other complaints.Except for whooping cough a year be­fore the child had had no illnesses, andhis birth and development had beennormal in every way.

Physical examination revealed that theboy was well nourished and of normaldevelopment. He weighed 32 pounds. Ex­cept for a few palpable posterior cervicaland axillary lymph nodes, exophthalmosand downward displacement of the lefteye were the only abnormal findings. Theexophthalmos was caused by a circum­scribed hard tumor mass slightly visible,somewhat nodular, between the globe andthe lateral portion of thesroof of theorbit. It apparently extended far back inthe orbit and was somewhat adherent tothe periosteum, causing proptosis of8 mm. and downward displacement. Therewas no edema of the conjunctiva, thecornea was clear, the pupil round andequal to that of the right eye and normal­ly active. No lagophthalmos, loss ofmotility, nor diplopia could be demon­strated. The vision was normal, as far ascould be determined by illiterate tests,and the fundus showed normal findings(fig. 1).

The family physician reported thatexamination of the urine and blood hadshown nothing abnormal. A roentgeno­gram of the skull and orbit revealed nobone change nor destruction.

The patient was admitted to the Uni­versity Hospital on December 2, 1935. Inthe interval since examination there hadbeen a noticeable enlargement of thetumor of the left orbit, and, in addition,another tumor ·had appeared in the sameposition in the right orbit. This was notdetected until the child was anesthetizedfor operation. The blood count at thistime showed 32,000 white cells, with ap­proximately 82 percent myelocytes.

Operation was performed on December

1000 ALBERT D. FROST

5, 1935. Incision through the skin andfascia of the upper lid exposed a cir­cumscribed tumor mass of distinctlyolive-green color. The mass was easilyseparated from the surrounding tissues

on the left, and did not include any ofthe lacrimal-gland area. Palpation of theorbit through the incision revealed noevidence of other tumor masses fartherback in the orbit, and when the sutures

Fig. 1 (Frost). Photographs of patient showing supraorbital tumor andexophthalmos (December I, 1935).

(fig. 2). It was somewhat adherent tothe periosteum of the roof of the orbitand the supraorbital ridge, but not apart of it. It was not adherent to the

were in place, there was little displace­ment of either eyeball.

The tumor from the left orbit measured3 x 3 x 1 em., was convex against the roof

Fig. 2 .(Frost). Tumor removed from the left orbit(December 5, 1935).

sheath of the superior-rectus muscle. Thelatter portion occupied the normal situa­tion of the lacrimal gland. The tumor inthe right orbit was also removed. Thiswas less than half the size of the one

of the orbit, and somewhat concave in itslower part to fit the contour of the globe.The gross examination of the tumor andfrozen sections established the diagnosisof chloroma (fig. 3). It was firm and of

CHLOROMA 1001

a dirty-green color. It had an elasticitysuggestive of fibrous-tissue proliferation.Its contour was fairly smooth, but themass was not covered with a membrane,nor was it encapsulated. Section of thegrowth showed a fibrous-tissue back­ground infiltrated with round cells. Therewas a large portion of lacrimal glandattached to and associated with one mar­gin of the tumor. The glands were quitenormal in appearance, with only slightcloudy swelling presumably caused bysome vascular disturbance. The processappeared to be one of extension into,rather than of primary involvement ofthe lacrimal gland.

After the operation, the child's generalcondition was satisfactory except for aslight elevation of temperature daily inthe afternoon to l00.5°F. There was con­stant drainage of blood and serum fromthe incisions which required changing ofdressings each day, but there was no in­fection in the wounds. Nevertheless, thechild displayed progressive weaknesswith a rapid drop in the number of redblood cells and in hemoglobin content. Atransfusion of 250 c.c, of citrated bloodsix days after the operation was fol­lowed by a chill with a rise of tempera­ture to 104.5°F. Later the temperaturefluctuated between 99 and 100°F. Theoozing from the wounds ceased, theyhealed promptly, and there was much im­provement in the patients general condi­tion, except for an occasional complaintof pain in the eyes. By December 18th,the boy was able to be up and about theward, at which time the admission weightof 32 pounds was still maintained.

On December 24th, he was allowed toleave the hospital for the Christmas holi­days, on condition that he return. Exceptfor weakness and anemia, his generalcondition was good. There was no evi­dence of recurrence or new tumors. Be­tween January 14th and January 22d, the

patient received a course of roentgentherapy over the parietal regions. A totalof 2,400 roentgen units was administeredin eight applications. There was littlechange in his appearance and conditionduring the month of January. His ap­petite was good and his weight was

Fig. 3 (Frost). Section of tumorremoved from the left orbit, showinginvasion of the lacrimal gland. X 150.

maintained. He did not return to thehospital until January 27: 1936.

Following a transfusion, on February5th, of 375 c.c, of citrated blood into thejugular vein, the child contracted chicken­pox and was transferred to the IsolationHospital where he remained until Febru­ary 18th. On February 14th a mass waspalpated beneath the lower lid of theright eye. This grew rapidly. A smallermass also was palpated in the same posi­tion in the left orbit (fig. 4). Right facialparalysis and deafness, along with someswelling in the right temporal region andcheek were discovered, but these symp­toms improved after irradiation therapy.

At about this time the patient began tocomplain of severe epigastric pain which

1002 ALBERT D. FROST

was relieved only when he sat upright.The tumor mass in the right orbit en­larged rapidly. Because of increasingexophthalmos and severe pain, the masswas removed through an incision in the

continuous. The patient's temperaturerose to 105 degrees and death was ex­pected. The day after the operation, 150c.c. of blood was withdrawn and 350 C.c.of the father's citrated blood immediately

Fig. 4 (Frost). Photographs of patient (February 14, 1936). Noteright facial paralysis.

lower lid on February 20th. This growthmeasured 3 x 2.0 x 2 em., and waspathologically identical with those that

Fig. 5 (Frost). Tumor removed from the floorof the right orbit (February 20, 1936).

were removed earlier (fig. 5). Bleedingand oozing through the dressings were

supplied. The next day the condition ofthe patient was so much improved thatthe procedure was repeated three dayslater. A single treatment with roentgenrays (600 r) was administered on Febru­ary 29th.

The tissues about the wound becameswollen and edematous from a largehematoma. There was no healing norgranulation and the tissues becamegangrenous beneath the skin of the cheekand temple. About two weeks after opera­tion, the patient was taken to the operat­ing room and the wound was thoroughlycleansed and irrigated. His condition im­proved after this and his temperaturedropped to between 99 and lOO°F. Therewas less discharge from the wound, andthe patient was much more comfortable.

The tumor mass previously palpated inthe floor of the left orbit had disappeared,probably as the result of irradiation, butthe exophthalmos increased gradually.Numerous lesions then appeared in theform of skin nodules which later broke

CHLOROMA 1003

down into abscesses of the chin, forehead,and outer canthus of the left eye. At firstthese appeared to be firm and nodular,but rapidly became necrotic, punched-outulcers discharging foul, purulent material.No biopsy or cultures were made ofthese, but they probably were not chloro­ma. There was marked swelling of bothanterior and posterior cervical lymphnodes; one of these nodes was removedfor biopsy.

The right temporoparietal region dis­played increased thickening, apparentlydue to elevation of the periosteum andincreased thickness of the bone, but re­peated roentgenograms showed no evi­dence of bone change throughout thepatient's entire course.

About three weeks after the last opera­tion (March 12, 1936) the patient com­plained of severe pain in the abdomen,and the next day there was marked ab­dominal distention which was not relievedby an enema or other measures. The out­put of urine was scanty and there wereno stools. Four days later the distentionwas somewhat relieved by involuntarystools and urination. This was accom­panied by rectal prolapse and bleeding.Coughing increased, the child's breathingbecame labored and his temperature roseto 104 degrees. His condition became pro­gressively worse during the few daysuntil his death on March 19, 1936.

Necropsy. The child's body was ex­amined after death and revealed the fol­lowing abnormal findings: The soft tis­sues around the right eye were ecchy­motic, swollen, ulcerated, and injected.There was slight edema and ecchymosisof the cornea. No nodules were palpableon the bones. The mesenteric lymph nodeswere slightly enlarged. The left thoraciccavity contained a slightly increasedquantity of fluid. There were adhesionsbetween the posterior surface of the leftlung and the vertebral column. They

were firm and represented the growth ofa tumor from the vertebral column intothe thoracic cavity with extension to thelung. The sternum showed a slight bluishnodularity on the left side, extendingfrom the first rib into the first interspaceand adjacent to the periosteum in thisregion. The spleen weighed 110 grams,and there were some small accessoryspleens at the hilus. The left kidneyweighed 110 grams and the right kidney80 grams, but neither showed anythingremarkable on cut section. The peripan­creatic lymph nodes were markedly en­larged.

The bone marrow in the left femurwas examined; it was hyperplastic,grayish-red in color, and of a seminecrotictype. There was a heavy infiltration of agreenish-yellow tumor over the vertebralperiosteum at the approximate level ofthe third thoracic vertebra, with exten­sion downward to the mid-lumbar region.The growth extended over the left borderand the side of the vertebra and into thethoracic region and stood out over theadjacent portions of the ribs. On cutsection the tumor was very firm, andof a dirty yellow-green color with focithat looked to be hemorrhagic andnecrotic. The appearance of this tumorwas identical with that primarily removedfrom the left orbit and also the rightorbit. The dissected vertebrae showedapparent extension through the neuralforamina into the vertebral canal withcompression of the spinal cord. This pres­sure was exerted from a posterior posi­tion, since none of the tumor tissue wasanterior to the cord. The dura of thecanal appeared to be intact and showedno evidence of penetration by the malig­nant growth into the subdural space.

Microscopic examination of tissues.The characteristic feature of the case wasthat of subacute myelogenous leukemia,with marked primary hyperplasia of the

1004 ALBERT D. FROST

bone marrow and infiltration or hyper­plasia of primitive cells of the granu­locytic series, particularly in the peri-

kidneys, and pancreas. The peculiar dirtygrayish-green character of the tumor, itspredilection for periosteum, and the es-

Fig. 6 (Frost). Sections of: a, lymph node; b, periosteum; c, lung;and d, spleen. X 150.

osteum, to a moderate degree in thelymph nodes, and with no infiltration intoorgans most commonly involved in my­elogenous leukemia, such as the liver,

tablished myelogenous leukemia placed itin the class of tumors called chloroma(fig. 6).

The patient's symptoms were directly

CHLOROMA 1005

dependent upon the disturbance of func­tion by growth of the tumor in organsin immediate proximity to the sites ofinvasion of the periosteum in the orbitsand spinal column. Death was due to dis­turbance of metabolism, paralysis of com­pression myelitis, terminal septicemia,and lobar pneumonia.

Hematologic study. After the diag-

time to time and in response to varioustherapeutic procedures, for the most partmyelocytes of the very young, or "A"type represented about one half of thecirculating white cells. Unlike most casesof acute myeloid leukemia, however, my­eloblasts in large numbers appeared onlyinfrequently and did not tend to increaseeither in relative or absolute numbers as

Fig. 7 (Frost). Chart showing complete blood picture during patient'sentire course. Note particularly the fluctuations following blood transfusionsand roentgen therapy.

nosis was established by the blood countand the biopsy of the orbital tumors, thepatient was placed under the care ofDr. B. K. Wiseman, of the Departmentof Medical Research, who made a thor­ough study and has tabulated the bloodfindings in the accompanying chart (fig.7).

In common with most of the previouslyreported cases of chloroma and of acutemyeloid leukemia, the blood picture ofthis patient shows the dominance of rela­tively immature cells of the myeloidseries. While the white blood cells of thevarious types fluctuated in numbers from

the disease progressed. In common withleukemia in general, a marked anemia andthrombopenia were shown throughout thecourse of the disease.

The response of these circulating ele­ments to certain therapeutic proceduresand circumstances that supervened dur­ing the course of the study of this patientare shown in figure 7. On December11th, after transfusion of 250 c.c, of ci­trated blood, there was a gradual butdefinite fall in the total white-blood-celllevel from more than 20,000 to approxi­mately 8,000. The reduction in cells con­sisted chiefly of the young myeloid cells.

1006 ALBERT D. FROST

The fall in the myelocyte A, B, and Ctype, and particularly in myeloblasts, wasoutstanding. With the diminution inyoung myeloid cells, there was a gradualrise in mature neutrophiles and lympho­cytes. This remission lasted until approxi­mately January 6th, at which time therewas an increase in the total number ofwhite blood cells and in immature my­eloid cells.

On January 13th, deep irradiation wasadministered over the right parietal re­gion, with reduction in total white bloodcells and myelocytes of much less mag­nitude than that following the bloodtransfusion. Immediately after discon­tinuance of roentgen therapy, the whitecount began to climb, with a particularlyprominent increase in immature cells ofthe myeloid series.

The patient contracted a mild case ofchickenpox on February 6th. Littlechange in the blood picture followed thisinfection, which is of interest since in­fections in the course of myeloid leuke­mia often are followed by temporarymarked remissions in the basic leukemicstate.

Following exsanguination transfusionswhich were given on February 21st and24th, the white-blood-cell count fell grad­ually from about 20,000 to an approxi­mate level of 5,000, with a markeddiminution in young myelocytes and my­eloblasts. About March 10th, there wasa recrudescence in the activity of the dis­ease, with accompanying rise, particu­larly in myelocytes A, until death super­vened.

The type of cell involved in this casehad the usual characteristic signs of im­mature myeloid cells. Some of the my­elocytes had two nuclei and many hadmultiple nucleoli, often of very largesize. A large proportion of these cells con­tained hyalin rods, known as Auer bodies,in the cytoplasm, some of which took

the neutral-red stain; others rejectedthis dye. In the preparation stained byWright's technique, these rods stained tothe same quality and color as the gran­ules of the neutrophils. The significanceof these bodies is not clear, but it is ap­parent that they occur only in the my­eloid cells of the myelogenous type ofleukemia. They are never seen in infec­tious states nor in blood dyscrasias otherthan myeloid leukemia, in which there isa severe shift to the left in the myeloidseries. The Auer-body phenomenon per­sisted during the entire course of obser­vation of this patient. The lymphocytesand monocytes showed no qualitativechanges except a mild shift to the left.The total number of lymphocytes andmonocytes was, for the most part, al­ways within the range of normal.

Oxydase stain upon the cells of theperipheral blood showed a positive re­action in 85 percent; negative, in 15 per­cent. A supravital differential count doneat the same time upon the blood showed84 percent granule-containing cells and16 percent nongranule-containing cells.The latter group consisted of 15 percentlymphocytes and 1 percent monocytes.Hence the differentiation of cells in theperipheral count checked very closelywith the number which theoretically areoxydase positive, and further substan­tiated the classification of cells.

The blood studies in this case weresupplemented by study of a section of alymph node from the right cervical re­gion. This showed that some of the nodesin this chain had the cellular content with­in the capsular borders almost completelyreplaced by immature myeloid cells. Onesmall node, however, showed only aminor degree of infiltration of the abnor­mal cells. There was no change in thereticuloendothelial structures of theselymph nodes nor any alteration in lym­phocytes.

CHLOROMA 1007

Repeated examination of the urine forBence-jones bodies (five observations)yielded negative results. Several observa­tions on the fragility of the red blood cellsshowed a very slight increase in resist­ance to hemolysis by hypotonic solutions,a finding which has been consistent inthe studies of myeloid leukemia in thehematologic laboratory of this hospital.

SUMMARY AND CONCLUSIONS

A typical case of chloroma in a boy,aged four years, is reported. These caseshave a place in ophthalmic literature onlybecause exophthalmos is so often the firstsymptom to bring the patient to a physi­cian. Hence ophthalmologists must be fa­miliar with the condition but should seekthe collaboration of the hematologist, inwhose domain this disease properly lies.

It is evident from the lengthy discus­sions in ophthalmic literature of the na­ture of chloroma that some authors havebeen led far afield in the emphasis on so­called characteristic symptoms such asseparation of the suture lines, which rep­resent merely secondary manifestationsdependent on the situation of the tumorgrowths. At the same time there has beenexhibited a failure to emphasize and evena lack of understanding of the underly-

ing pathology of the disease, which is aparticular type of myelogenous leukemia.

The diagnosis is made on the blood pic­ture and the presence of tumor massesof a greenish color which contain embry­onic myeloid cells.

Roentgen irradiation is the most satis­factory treatment, for it causes a reduc­tion in the size of the tumors and reliefof pain. If the total white cell count ishigh the spleen and lymph nodes as wellas areas with pronounced symptomsshould be irradiated, as is done in casesof leukemia. Replacement transfusionsalso are of value in relieving the symp­toms and reducing the number of ab­normal cells in the blood. Surgery shouldnot be attempted (except for biopsy) un­less roentgen therapy has failed to de­crease the exophthalmos, or the eye 'mustbe preserved from destruction.

In the presence of exophthalmos withor without palpable orbital tumors, espe­cially in children, a complete blood studywith supravital-staining methods shouldbe made by a competent hematologist, inorder to establish the diagnosis. A routineblood count may fail to reveal the true na­ture of the condition.

150 East Broad Street.

REFERENCES

J Gump, M. E., Hester, E. G., and Lohr, O. W. Monocytic chloroma. Arch. of Ophth., 1936, v. 16,Dec., pp. 931-949.

e Burns, A. Observations on the surgical anatomy of the head and neck. First Amer. Ed. by G. S.Pattison. Baltimore, Lucas, 1823,p. 386.

• King, A. Case of chloroma. Monthly Jour. Med. Sci., 1853,v, 17, pp. 97-104.• Von Recklinghausen. Ueber Chlorome. Tagebl. d. Verso deutschen Naturf. u. Aerzte, 1885,

v, 58, p. 421.• Dock, G. Chloroma and its relation to leukemia. Amer. Jour. Med. Sci., 1893,V. 106,pp. 152-185.0 __, and Warthin, A. S. A new case of chloroma with leukemia, with a study of cases re­

ported since 1893. Med. News, 1904, V. 85, pp. 971,1025,1078,1118.'Lehndorff, H. Zur Kenntnis des Chloroms (Chlorleukamie, Chlorleukosarkomatose). jahrb,

f. Kinderh., 1910, v, 72, pp. 53-77.• Gould, E. yv., and LeWald, L. T. Chloroma: A report of two cases, together with the roent-

genologic findings. Amer. Jour. Obst., 1916, v. 73, pp. 1159-1162. Also, Arch. Ped., 1916, v. 33,pp.417-433.

• Brannan, D. Chloroma: The recent literature and a case report. Bull. Johns Hopkins Hosp.,1916, v.38, pp. 189-216.

t. Feer, E. Zur Kenntnis der Chloroleukamien im Kindesalter, J ahrb, f. Kinderh., 1927, v. 116,pp. 155-164.

1008 ALBERT D. FROST

11 Washburn, A. H. Chloroma: Report of a case with recovery following roentgentherapy witha review of the literature. Amer, Jour. Dis. Child., 1930, v. 39, pp. 330-348. '

l2 King, C. Case of chloroma with orbital involvement locally benefited by X-ray therapy. Trans.Amer, Ophth, Soc., 1934,v. 32, pp. 340-353.

11 Merculov, I. I. Chloromatous neoforrnations and their roentgenotherapy. Russkii Ophth,Jour., 1928,v. 7, pp. 621-630.

"Gamble, R. C. Chloroma. Illinois Med. Jour., 1927, v. 52, pp. 466-471.,. Boots, R. H. Chloroma with. report of a case. Jour. Lab. Clin, Med., 1916-17, v, 2, pp. 622-631.

DISCUSSION

DR. T. L. TERRY, Boston: Exophthal­mos is almost invariably present in chlo­roma and it is often the first symptom,as the essayist has stated. Granting thatleukemia is relatively rare, it is very im­portant that leukemia with or without thegreen tumor should be considered in thedifferential diagnosis of unilateral or bi­lateral exophthalmos. There is very littlereference to chloroma or leukemia as acause of exophthalmos. In Spaeth's recentarticle (Arch of Ophth., 1937, v. 18, pp.107-148), chloroma is mentioned, but inthe symposium before the Academy in1934 Plummer and Wilder state that ex­ophthalmos in myelogenous leukemia isalmost unknown.

That leukemia must be considered inthe differential diagnosis of the causes ofexophthalmos is stressed in my mind bythe following case:

The patient was referred to me by aninternist. The internist had already madea careful examination including bloodstudy, X rays, and basal metabolism. Theblood study showed a mild anemia, 8,000white blood cells, and a normal differ­ential count. The left eye was 7 mm.more prominent than the right. Therewere some small bright-red rounded hem­orrhages in the retina near the disc ineach eye. Because of the bilateral retinalhemorrhages it seemed that the cause ofthe trouble must be a general disease. Irepeated the blood count and found manyimmature granulocytes and 16,000 whiteblood cells per cubic millimeter of blood.

From subsequent studies the white bloodcount was found to have increased rap­idly to 49,000 within a week. It was evi­dent that the blood picture was rapidlychanging from an aleukemic phase tomarked myelogenous leukemia. The ex­ophthalmos disappeared almost com­pletely in two days following X-ray ther­apy to the orbit (2/3 erythema dose).In spite of a great reduction in the whitecount by general X-ray treatment, thepatient became weaker and died withinthe month. Since no biopsy was done andno post-mortem examination was made,the color of the orbital tumor was notdetermined, and for that reason a posi­tive diagnosis of chloroma is impossible.

Had it been suspected that the ex­ophthalmos might have been due to aleukematous disease during the aleukemicphase, very diligent and repeated bloodexaminations with supravital stain mighthave given the diagnosis much earlier.According to Isaacs and Danielan (Amer.Jour. Med. Sci., 1927, v. 174, p. 70), theabnormal white cells are largely thrownout of the body into the intestinal tractrather than left to meet destruction inthe body, and it follows that the ratio ofnormal to abnormal white cells in theblood and in the saliva is inversely re­lated. Use may be made of the saliva cellcount in relation to the blood count indetecting leukemia during the aleukemicphase. Allen and Dickey (Amer. Jour.Roentgenol., 1937, v. 38, p. 57) considerthe correlated study of saliva cells and

CHLOROMA 1009

blood cells of value in regulating thedosage of X-ray therapy.

The great difference between chloromaand myelogenous leukemia is the de­velopment of a green tumor in theformer. The significance of the greentumor may not be known until the causeof the green color is fully understood.There have been many attempts to ex­plain the color, as the essayist has men­tioned. Thomas and Bigwood (Compt.rend. Soc. de Biol., 1935, v. 118, p. 381)thought that the green color is due toporphyrin, since they have shown byspectroscopic study the presence of freeporphyrin in the tumor. They have re­covered porphyrin from the tumor by ex­traction with glacial acetic acid and ether.

Why do these green tumors have a pre­dilection for growth in orbital tissue?The orbit is remarkably free from lymphnodules. The orbit must certainly havelymphatic channels which have little orno connection with the lymphatic chan­nels of the face and neck. It is possiblethen that the very lack of free communi­cation of lymph channels to the face andneck may tend to produce a physiologicallymph stasis in the orbit. Such a condi­tion would favor development of my­elogenous, chloromatous, or lymphoma­tous nodules.

The appearance of white centers, inretinal hemorrhages is presumably diag­nostic of leukemia, although it is not in­variably present. It is due to accumula­tion of abnormal white blood cells in thecenter of the hemorrhage. I should liketo ask Dr. Frost if this is also observedat times in chloroma?

DR. GEORGIANA DVORAK-THEOBALD,

Chicago: Dr. Frost's study of this casehas been most complete, and his bloodfindings and histologic pictures are ofgreat interest.

Chloroma is a rapidly growing malig­nant neoplasm involving the hemato-

poietic system, with metastases of cellsto distant organs, and associated with aleukemic blood picture. It is almost in­variably fatal, with a duration of threeto five months following recognition.

Up to the present time, about 200 caseshave been reported in the literature.

The most characteristic sign is the pre­dilection of the tumors for the perios­teum of the cranial bones, especially ofthe orbit.

The rapidity of growth and extent ofthe orbital tumors may give rise to anumber of ocular symptoms; namely, ex­ophthalmos, drying of the cornea (dueto extreme proptosis), optic neuritis, reti­nitis, sluggish reactions of the pupils,anisocoria, mydriasis, conjunctivitis, cat­aract, exotropia, and nystagmus. In onetype of chloroma the aural structureswere affected.

Etiology: The tumors apparently arisefrom localized growth of leukemic depos­its or metastases, and the tumor cellsmetastasize in the blood to produce leu­kemia.

In about half of the cases the perios­teum of the orbital bones is the site ofpredilection. Why this is so is not known.

Differentiation between chloroma andmyeloma is based on the usual blood pic­ture of leukemia and the green-coloredtumor in chloroma, and the tendency tospontaneous fracture in myeloma. As arule the Bence-jones type of protein ispresent in the urine of myeloma patientsand only rarely in chloroma patients.

It is thought that the green color ofchloroma is due to a lipochrome, or thatit is due to a blood pigment; but nothingis definitely known. Roehn and his asso­ciates say that it is due to phagocytosisof the blood in obstructed capillaries byendothelial cells.

Histologic pathology: The tumor cellsare usually large, undifferentiated mono­nuclears, designated as myeloblasts or

1010 ALBERT D. FROST

lymphocytes. Indeed, in the past, patho­logic differences of opinion have cen­tered around the lymphatic or myelogenicorigin of the neoplasms. In a case re­ported by Roehn, Riker, and Olsen (Ann.Inter. Med., 1937, v. 10, jan., p. 1054),pathologic examination of the tumor byDr. C. V. Weller of the University ofMichigan showed that it was neithermyelogenic nor lymphatic in origin, asthe tumor cell is a primitive blastomawhich might conceivably differentiate in­to either a lymphocyte or myelocyte.

The possibility of tumor cells having adouble potentiality of development is wellbrought out in Berger's theory of the"double potentiality of development" of asingle neuropigmental blastoma. That isto say, the cells of the blastoma are capa­ble of evolving either as elementary gan­glion cells or Schwannian melanic ele­ments, "for the Schwarm nerve cells andthe melanic cells there is a common pri­mary blastoma the elements of which be­come neoplastic."

Gump, et al (Gump, Hester, andLohr") treat of monocytic chloroma,which they say is usually classed as a dis­tinct entity; but the origin of the mono­cyte, whether from reticulo-endothelialelements or not, is doubted. In their case,autopsy sections of the tissue showedcells of the neoplasm in a connective­tissue reticulum, satisfying the criterionfor true blastomatous neoplasm of the en­dothelial system.

In an early article, more than 20 yearsago, Dock and Warthin,? who made anexhaustive study of chloroma, concludedthat "cholororna is a tumorlike hyper­plasia of the parent cells of the leuko­cytes primarily in the red marrow, theperiosteum being involved."

I have seen two cases of choloroma;one with Dr. Cupler at St. Anthony'sHospital. This patient had a blood picturesimilar to that described by Dr. Frost.

The orbital contents were sent to meafter death of the patient, but are notready for study. The second case is be­ing successfully treated by irradiationover a period of several years by Dr.Poucher. The eyes are proptosed, but thelids have grown sufficiently to protectthem properly. The proptosis is not dueto a shallow orbit. The vision is normal,and the fundus shows no changes.

DR. ALBERT D. FROST, closing: I thankthe discussants for their interesting re­marks.

Relative to the saliva count, question­ing hematologists, I believe they considerthis to be a very noteworthy observationbut as yet a scientific curiosity, never­theless it may be a valuable diagnosticpoint and should be done.

I think it unwise to indulge in alengthy discussion of the difference inthe color, since this is a much-disputedpoint even among hematologists, whofind, for instance, a decomposed productof red cells which seemingly are rapidlydestroyed in this disease. The definiteanemia present, therefore, seems to bea satisfactory explanation of the phe­nomena. However, it is also plausible thatthe reaction may be due to the granulecontent of the predominating myelocytes,such as was mentioned by Boots.

I have not observed retinal hemor­rhages in this case, nor do I find any dis­cussion of. such in the literature. Mostmyeloid leukemias, as I understand it, donot show the characteristic retinal hemor­rhages, and they are prevalent in thelymphatic leukemias. A probable explana­tion may lie in the fact that in lymphaticleukemia there is more definite throm­bopenia than there is in the myeloid type.

I might add that the autopsy did in­clude a rather thorough examination ofthis boy's one eye, and we have neverhad a better section of a normal eyethroughout.