Primary neurogenic sarcoma of the gallbladder

PRIMARY NEUROGENIC SARCOMA OF THE GALLBLADDER* JACOB RABINOVITCH, M .D. AND SALVADOR TRINIDAD, M .D. Brooklyn, New York HE commonest malignant tumor of the gallbladder is carcinoma . Primary sarcoma of the gallbladder is a very rare occurrence . The total number of cases reported in the literature to date is probably not more than forty . The occasional observation at operation or autopsy of a sarcoma of the gallbladder usually evokes little comment or surgical curiosity and writers who have reported single cases have discussed the subject from a rather narrow angle . The object of this article is to summarize the principal observations in a pathologic study of a case of neurogenie sarcoma of the gallbladder which has been observed at the Jewish Hospital, and to present for convenience of reference a summary covering the subject .

T

CASE REPORT

A . S . (No . 277974), a white woman, aged sixty-three years, entered the Jewish Hospital on September 21, 1944, complaining of severe pain in the right upper quadrant of the abdomen . The onset of the present illness she dates back to thirty-three years ago when she was operated upon for removal of gallstones . She was in good health since then until four months prior to the present admission to the hospital when intermittent attacks of right upper abdominal pains developed . The pain was usually relieved by vomiting or alkalies . In recent weeks the pain occurred more frequently and was precipitated after partaking of a fatty meal. The patient was also known to suffer from hypertension and had a repair of the pelvic floor performed three years ago . She lost fourteen pounds in weight since the onset of the present illness . The physical findings on admission to the hospital were briefly as follows : A well developed woman with a questionable jaundice of the skin and scleras . The heart was enlarged to the left . The lungs revealed a few dry Tales over both bases posteriorly . The blood pres-

sure was 21o/To5 . The abdomen was soft but tender over the right upper quadrant . The liver edge was palpable 2 to 3 cm . below the right costal margin . The gallbladder could not be definitely palpated . Laboratory findings revealed the following : the urine showed a faint trace of albumin ; red blood cells numbered 4,280,000, the white blood cells 8,400 and the hemoglobin 84 per cent . The sedimentation rate was 66 mm . The total blood cholesterol was 216 mg . per cent of which 69.5 per cent was free cholesterol . The icterus index was 5 .4 ; van den Bergh direct was negative and indirect o .6 . The serum phosphatase was 2 .3 units ; blood sugar 97 mg . per cent and urea 18 .9 mg . per cent . The cephalin flocculation test was 2 plus . Cholecystography revealed non-visualization of the gallbladder . Roentgenograms of the gastrointestinal and urinary tracts proved negative . Operation was performed on September 25, 1 944 . A right subcostal incision was made to explore the gallbladder . The latter was found enlarged and its wall thickened . No calculi were palpable within the gallbladder . Near the ampulla of the gallbladder was a firm mass which appeared malignant . After ligating and cutting the cystic duct and artery the gallbladder was removed together with a rim of attached normal looking liver tissue . A diathermy cutting needle was used in the resection of the gallbladder because of the malignant nature of the lesion . The abdominal wall was then closed in layers . Pathologic examination of the gallbladder revealed a somewhat enlarged organ measuring 8 em . i n length . The serous surface was ragged and the wall considerably thickened ; it measured 1 .2 cm . in thickness . When the gallbladder was opened the cavity was found to contain yellow-grey, soft and necrotic tissue, but no stones . The mucous surface presented a greenyellow discoloration . Areas of necrosis and softening were found in the much thickened

* Prom the Departments of Surgery and Pathology, Jewish Hospital, Brooklyn, N . Y .

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Rabinovitch, Trinidad-Sarcoma of Gallbladder figures were rather few in number, indicating a low grade malignancy. (Fig . 2 .) We find therefore in this gallbladder several interesting changes resulting probably from a common etiologic cause. In the first place, there is the presence of chronic inflammation with no stone formation . The inflammatory process is apparently of long duration judging from the increased thickness and pathologic changes in the wall Second, there is the presence of a neurogenic sarcoma, the latter being completely differentiated from the surrounding inflammatory process . COMMENT

Fit ; . i . Appearance of gallbladd removed at operation- Note the thickened wall particularly in the region of the fundus where a sarcomatous change has taken place in the wall .

wall . One large lymph node was found near the neck of the gallbladder . (Fig . i .) Microscopic sections taken from the inflamed areas of the gallbladder distant to the tumor revealed the following changes : The surface epithelium was for the most part denuded ; and where it was still intact, it was one layer deep . The wall was considerably thickened because of a chronic inflammatory reaction . There was wide spread necrosis of the mucosa ; the latter was replaced by granular debris and ghosts of pre-existing cellular structures . Beneath this was a wide spread inflammatory process consisting of an abundant round cell infiltration and fibroblastic proliferation . The inflammatory process involved all the coats of the gallbladder including the serosa . Sections taken from the wall of the gallbladder involved by the tumor growth showed in addition to the inflammatory reaction described new growth formation . The tumor was very cellular, not encapsulated and was essentially limited to the submucosal and muscular coats of the organ . The neoplastic cells were elongated, narrow, spindle shaped and arranged in interlacing bands . The nuclei were also narrow, elongated and hyperchromatic and were frequently arranged in palisades pattern, an architecture reminiscent of and peculiar to tumors of neurogenic origin . Mitotic

Sarcoma of the gallbladder affects mostly the older age groups ; the average age of the patients reported by Thompson and Bostick' from a survey of the literature was fifty-eight years ; our patient was sixty-three years old . It is also noted that women are more commonly affected than men ; this is probably due to the fact that cholecystitis is more prevalent in females . The clinical picture presented by our patient followed the pattern previously described by other authors and requires little comment . Analysis of the diagnostic facts relating to this disease shows that pain is the most constant subjective symptom . The pain is usually severe and may vary in duration from weeks to months . Anorexia, nausea and vomiting are frequent complaints and loss of weight is only moderate in degree. Our patient lost fourteen pounds within four months . The outstanding physical findings consist of tenderness in the right upper quadrant of the abdomen . A tender mass is usually palpable although it was not felt in our patient . Jaundice, whenever present, is usually a late manifestation of the disease . The laboratory data, although helpful, are by no means pa .hognomonic of the disease . The incidence of sarcoma of the gallbladder in general is remarkably low . and that of ncurogenic sarcoma is so rare that whenever found, it is regarded as a pathologic curiosity . Erdmanns in a study of 525 patients with gallbladder disease found one sarcoma and six carcinomas . Ragiust found two sarcomas of the gallbladder in a series of 8,534 autopsies . Ours is the first case of sarcoma of the gallbladder seen in the Jewish Hospital among several thousands of gallbladders removed at operation and autopsy . American Journal of Surgery



Rabinovitch, Trinidad-Sarcoma of Gallbladder

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FIG . 2 . Photomicrograph of neurogenic sarcoma of the gallbladder . Note the palisading of the elongated, narrow tumor cells and the inflammatory cell reaction . Ifematoxylin and eosin stain, X 8o .

The gross appearance of these tumors show great variations and depends largely on the character of the cell composing the tumor and their rapidity of growth . These tumors are notable for their variation in growth rate which at times is very rapid and at other times exceedingly slow. Between these extremes there are all grades of variations with the greater number exhibiting rapid growth and with a relatively large number spreading by metastasis . The tumors show a frequent tendency to grow expansively in the connective tissue and vascular framework of the organ rather than to grow by infiltration as in the case or carcinoma . Usually the rapidly growing tumors are associated with degeneration, necrosis and hemorrhage which may take place within the tumor itself or the gallbladder cavity . The direction of the growth is usually intramural as was the case in our patient . The intramural forms grow more slowly and tend to be delineated from the surrounding structures of the gallbladder wall ; this again is well exemplified in our case . Of the various forms of sarcoma of the gallbladder described in the literature, the spindle cell type is most commonly encountered . It must be noted however that in many instances the spindle cell sarcomas display cellular characteristics and structural patterns that closely simulate fibrosarcoma . We are of the opinion that a number of these growths heretofore described as spindle cell sarcoma are in reality fibrosarcomas . The neurogenic sarcomas, on October, 1952

the other hand, present a unique anatomic picture which at once distinguishes them from the other forms of sarcoma . Sarcomatous growths of neurogenic origin are very rarely found in the gallbladder . To the best of our knowledge no instance of neurogenic sarcoma . of the gallbladder has been heretofore reported in the literature . Since nerve tissue is normally present in the wall of the gallbladder, one should expect to find a cholecystic form of ncurogenie sarcoma . Very little is known about the etiology and pathogenesis of sarcoma of the gallbladder . Since the true etiology of the disease is not determined, one is reduced to speculations regarding the mode of dependence of the tumor process upon the irritant . It is almost an undisputed fact that irritation resulting from chronic inflammation, stones, or both, plays a very important role in the development of carcinoma of the gallbladder . 4 Very little has been said about the relationship existing between chronic inflammation of the gallbladder and sarcomatous formation . Theoretically, it is conceivable for fibrosarcoma to develop as a result of chronic inflammation of the gallbladder, because the latter condition stimulates considerable and prolonged fibroblastic proliferation . Peculiarly enough, fibrosarcoma is far less frequently associated with chronic cholecystitis than carcinoma . So far as neurogenie sarcomas are concerned, it is very questionable whether the development of these tumors is induced by the existing inflammatory

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Rabinovitch, Trinidad-Sarcoma of Gallbladder

process . Since inflammatory reactions are commonly associated with neoplastic formations, especially with malignant tumors, one cannot exclude the possibility that these inflammatory changes are secondary to the malignant process . Allowing for these reservations it is most likely that the development of a sarcoma of the gallbladder on the basis of an existing inflammatory process is the exception and not the rule. The histopathologic findings presented in this case show two distinct morphologic changes ; first, a chronic inflammatory process of the gallbladder characterized by necrosis of the mucosa and wide spread inflammatory cell reaction of the remaining coats of the organ ; second, the formation of a malignant neoplasm of neurogenic origin . The growth pattern of the tumor is quite distinctive . Although a direct transformation of nerve tissue to tumor could not be observed, such an origin seems most likely . These growths arc fully capable of stimulating epithelial neoplasms and other forms of spindle cell sarcoma and fibrosarcoma . A rather striking growth characteristic was manifested by the cellular grouping of the tumor that produced distinct nuclear palisading when the cells were of the elongated variety and produced a picture which is unique of tumors of neurogenic origin . In few focuses the tumor cells lay directly upon the endothelium of thin blood vessels, but in no place could the tumor cells be seen to invade these vascular structures . Furthermore, there were very few mitoses, thus indicating a low grade malignancy . Another manifestation of the growth characteristic of this tumor was the alignment of the cells in interlacing bundles and whorls, thus retaining the fundamental property of neurogenie tumors . It has been generally stated that malignant changes develop in a certain per cent of patients with chronic cholecystitis . It is likely, therefore, that in some instances chronic inflammation of the gallbladder may be considered the pathologic connecting link between benign inflammatory lesions on the one hand and malignancy on the other, but it is in the small proportion of cases in which chronic cholecystitis develops that malignancy is likely to occur . The practical implication of this does not need stressing, for if one can identify inflammatory changes which are not yet malignant but are likely to proceed in that direction,

early removal of the lesion will save the patient front the terrors of cancer ; this represents prophylactic surgical intervention in the best sense. Our patient had a previous operation for the removal of stones, but the gallbladder was left in situ . The present trend in surgery is to remove the gallbladder with stones even in the presence of acute inflammation . Needless to say, had the gallbladder been removed in this case during the first operation thirty-three years ago, it would have prevented the subsequent development of sarcoma . So far as treatment of the malignant lesion is concerned, early thorough operation offers perhaps the best chance of complete cure . When the tumor is still in the localized stage and metastasis has not already taken place, complete resection of the entire growth gives the best results . A common source of failure in surgical procedure is the surgeon's inability to recognize at operation the malignant character of the neoplasm . In cases of nodular thickening of the gallbladder in patients of the cancer age in which there is some doubt as to the malignancy or non-malignancy of the tumor, the operation must be radical to the extent of removing every portion of the involved tissues, including if necessary adjoining liver tissue . The pathologist must be on the alert to distinguish these proliferating tumors from ordinary slow growing neoplasms or from more common inflammatory processes of the gallbladder . SUMMARY

A case is presented in which a neurogenic sarcoma of the gallbladder was found and removed . In addition to the tumor of the gallbladder evidence of old standing chronic inflammation in that organ was found . The pathology and pathogenesis of neurogenie sarcoma of the gallbladder is generally discussed . To the best of our knowledge this is the first case of neurogenic sarcoma of the gallbladder. REFERENCES

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