Primary signet ring cell carcinoma of bladder exemplifying vesical epithelial multipotentiality

PRIMARY

SIGNET

CARCINOMA VESICAL

OF BLADDER

EPITHELIAL

F. A. DE TURE, R. DEIN,

RING CELL EXEMPLIFYING

MULTIPOTENTIALITY

M.D.

M.D.

R. L. HACKETT, D. M. DRYLIE,

M.D. M.D.

From the Division of Urology, Departments of Surgery Pathology, University of Florida College of Medicine, Gainesville, Florida

and

ABSTRACT - The eighth reported case of primary signet ring cell carcinoma of the urinary bladder is described clinically and pathologically. It is unusual because of complete replacement of the transitional epithelium by squamous and glandular metaplasia. The latter was particularly striking, demonstrating “normal” colonic mucosa, cystitis glandularis, well-diff erentiated adenocarcinoma, poorly differentiated adenocarcinoma, and the rare signet ring cell carcinoma variant. The possible origin of such changes is discussed.

Primary signet ring cell carcinoma of the bladder is a rare entity. Detailed case reports have been described only seven times previously.1-5 In addition, Mostofi, Thompson, and Dean’ alluded to 2 other cases, without detail, in a review of 44 cases of adenocarcinoma of the bladder. The theory of the pathogenesis of adenocarcinoma of the bladder and the multipotentiality of the urothelium have been well reviewed. 6-1o We report the eighth case of primary signet ring cell carcinoma of the bladder. Furthermore, the theorized multipotentiality of the urothelium is lent credibility by the pathologic demonstration of discrete areas of glandular metaplasia, well-differentiated metaplasia, squamous adenocarcinoma, poorly differentiated adenocarcinema, and signet ring cell carcinoma with areas of intimate admixture. This case is compared with those previously reported. Case Report The patient, a sixty-two-year-old black male, had worked as a farmer and gardener all his life.

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He had progressively severe, postprandial nausea and nonbilious vomiting for several weeks. For several days prior to admission, the patient had dull, aching, intermittent right upper quadrant pain that radiated to his right costovertebral angle; this usually precipitated nausea, with bilious vomiting, followed by ebbing of the pain. There was no history of intolerance to fatty food, and no other gastrointestinal symptoms. He had been afebrile, his strength was good, but he had lost ten pounds in the month prior to this admission. Review of systems revealed a six- to eightmonth history of decreased urinary stream, hesitancy, straining, and nocturia two to three times. There was no history of urinary tract infection. Past history revealed that the patient had smoked one pack of cigarettes per week for forty-five years. The patient was admitted for evaluation of suspected gastric outlet obstruction. Findings on physical examination revealed a thin black male in no acute distress. Blood pressure was 2001110 mm. Hg. Bilateral arcus senilis was present, as

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was grade 2 hypertensive retinopathy. There was a grade 2/6 holosystolic murmur heard best at the apex. Right dorsalis pedis pulse was absent. Prostate was symmetrically enlarged, of rubbery consistency, and not nodular. Results of abdominal examination revealed moderate right upper quadrant and epigastric tenderness, without guarding or rebound; no organomegaly was present. Moderate right costovertebral angle tenderness was present. The remainder of the physical examination was normal. Abnormal admission laboratory values included: hematocrit 38; hemoglobin 12.5 Gm. per normocytic peripheral 100 ml. ; normochromic, blood smear; amylase 360 Somogyi units; blood urea nitrogen 138 mg. and creatinine 12.1 mg. per 100 ml.; serum carbon dioxide 10 mEq. per liter. Additional liver function studies and serum electrolytes were normal. Total protein was 8 Gm. per 100 ml. Serum protein electrophoresis demonstrated a moderate polyclonal elevation of beta and gamma globulins with reduced albumin. Urinalysis consistently showed microscopic hematuria, gross pyuria, and 1 plus proteinuria. Initial urine culture grew > 100,000 colonies per milliliter of Escherichia coli. Twenty-four-hour creatinine clearance was < 5 ml. per minute. Findings on urine cytologic examination were reas were stool guaiac tests. peatedly negative, Gallbladder x-ray films were normal. An upper gastrointestinal series revealed pyloric narrowing without evidence of active ulcer or tumor; the remainder of the stomach and duodenum were normal. Upper gastrointestinal series was repeated but did not clarify the pyloric findings. Small bowel x-ray films, barium enema, and sigmoidoscopy were normal. Initial gastric analysis revealed basal and posthistolog stimulation achlorhydria. Repeat gastric analysis showed acid secretion within the very low normal range. Serum B12 values were normal. Gastroscopic examination was negative for tumor and ulcer disease. After infusion nephrotomography failed to define the renal anatomy, cystoscopy was performed, and an extensive, fungating, exophytic lesion involving the trigone, posterior bladder wall, and dome was seen. The remainder of the bladder mucosa was smooth, shiny, and pearly in appearance. Neither ureteral orifice could be identified as the tumor overgrew them. The prostatic urethra was patent and had a normal mucosal lining. No distal urethral obstruction was present. Multiple transurethral biopsies

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were performed; all showed adenocarcinoma of varying degrees of differentiation, but with predominance of neoplastic signet ring cells. Bimanual examination of the bladder under anesthesia indicated absence of perivesical thicktumor was ening or fixation. The intravesical without fixation, of the palpable. Induration, posterior bladder wall was present. This was interpreted as a clinical stage B2 lesion. The patient was placed on an anephric diet, methyldopa (Aldomet), and hydralazine (Apresoline), with stabilization of blood urea nitrogen and creatinine but poor control of his hypertension. Because the patient required urinary diversion and the signet ring cell carcinoma was not believed to be of bladder origin, exploratory laparotomy was performed. No intraperitoneal, gastrointestinal, or retroperitoneal evidence of tumor was found. Specifically, the common sites of origin of signet ring cell carcinoma, the stomach, colon and gallbladder, were normal.” No enlarged lymph nodes were found. The bladder was mobile. Findings on random frozen iliac node biopsies were negative. Bilateral end cutaneous ureterostomies were performed for urinary diversion. The postoperative course was unremarkable. Two weeks postoperatively, with the wound healing well, the patient received 2,000 rads tumor dose to the bladder over a four-day period, followed in four days by radical cystoprostatectomy. Again, his postoperative course was uncomplicated, and he was discharged on the tenth postoperative day. At this time the blood urea nitrogen was 25 mg. and creatinine 2.4 mg. per 100 ml. Electrolytes including carbon dioxide were normal. Twenty-four hour creatinine clearance had improved to 27 ml. per minute. Blood pressure was 110/70 mm. Hg. Medicine at discharge was 250 mg. methyldopa twice a day. Pathologic examination of the specimen was as follows: the resected specimen consisted of a 12 by 8 by 4 cm. bladder with attached prostate, seminal vesicles, distal ureters, and membranous urethra. Nothing to suggest a urachal remnant was found. Two fungating papillary tumors arose from the bladder mucosa. One, on the posterior bladder wall adjacent to the trigone, measured 5 by 5 by 1 cm., was poorly differentiated adenocarcinoma with primitive, mucinproducing glands lined by a pleomorphic, poorly differentiated epithelium (Fig. 1). Pools of mucin were found associated with clusters of signet

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FIGURE 1. Gross frontal section of bladder and prostate. Posterior half of bladder is on left and anterior half on right. Posterior wall tumor obliterates ureter-al ori$ces. Demarcation between two _abnormal types of bladder eithelium is best seen on posterior dome of hemibladderonleft. Opaque, pearly, gray-white keratinizing squamous epithelium over right anterolateral and posterior wall is clearly different from more extensive, translucent, glistening, colonic-like mucosa over left anterior and lateral wall.

ring-type cells with eccentric, flattened, hyperchromatic nuclei and foamy, mucin-filled, vacuolated cytoplasm (Fig. 2A). These signet ring cells invaded lymphatic channels and bladder muscle and extended into the adventitia. The second tumor was at the bladder dome and measured 4 by 3 by 0.7 cm. (Fig. 1). This was papillary adenocarcinoma which was better differentiated than the first tumor. Malignant glands were lined by cells with basal nuclei and abundant apical, mucin-containing cytoplasm, reminiscent of primary colonic adenocarcinomas (Fig. 2B). This tumor invaded muscle, but did not extend to the adventitia. No foci of transitional cell carcinoma or squamous cell carcinoma were present in either tumor. The remaining bladder mucosa was highly abnormal (Fig. 1). Most was translucent, gray, and glistening. These areas had metaplastic colonictype mucosa with benign gland formation (Fig. 2C). In addition, beneath this colonic luminal lining, cystitis glandularis was present, with many glands connecting to the bladder surface. No Brunn’s nests or cystitis cystica were found. The remainder was opaque, pearly, and graywhite, and represented metaplasia to a benign, keratinizing, squamous epithelium. No normal transitional epithelium could be identified. The ureters, seminal vesicles, prostate, and urethra were not involved. Subsequently, the patient’s blood urea nitrogen, creatinine, and blood pressure remained stable at the above levels. Intravenous pyelography revealed stable, bilateral, grade 3 pyelocaliectasis.

Adenocarcinoma of the bladder, of which signet ring cell carcinoma is a rare type, may arise de novo from urothelium, in urachal remnants, or by metastasis. We are confident that this case did not represent adenocarcinoma metastatic to bladder. Exhaustive radiologic and endoscopic examinations, as well as negative results in three abdominal explorations, would eliminate an extravesical primary. The patient’s tumor-free course to twenty-eight months is inconsistent with metastatic signet ring cell carcinoma. Lastly, the complete replacement of the normal urothelium by

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Fourteen months after cystoprostatectomy, an ileoconduit was constructed because the cutaneous ureterostomies could not be adapted to a leak-proof appliance. At this time, no evidence of tumor recurrence could be found. Eight months later, a left nephrostomy was required for obstruction at the left ureteroileal anastomosis. For the next twenty-eight months there was no evidence of tumor recurrence. The patient was vigorous, with good appetite, stable weight, and normal findings on physical examination. Renal function and anatomy were stable, and hypertension was well controlled. Thirty months postdiagnosis, the patient died of a clinical myocardial infarction. Although an autopsy was not authorized, the patient was asymptomatic prior to the sudden development of crushing chest pain and severe dyspnea, which suggests death unrelated to tumor. Comment

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FIGURE 2. (A) Predominant cells of posterior wall tumor were signet ring cells; they are characterized by eccentric, flattened, hyperchromatic nucleus and foamy, mucin-filled, vacuolated cytoplasm. (B) Dome tumor predominantly comprised of cells shown here; malignant glands are lined by cells with basal nuclei and abundant, apical, mucin-staining cytoplasm. These type cells are reminiscent of those seen with colonic adenocarcinoma. (C) Representative area of benign metaplasia to colonic-type mucosa.

metaplastic and neoplastic epithelium appears to be inconsistent with a metastatic lesion. Adenocarcinoma arising in an urachal remnant classically occurs in the dome or anterior wall of the bladder. The tumor is predominantly intramural with an intact or ulcerated transitional epithelium over the tumor. Cystitis cystica and cystitis glandularis are absent6,10 Although one of the lesions in this patient arose in the bladder dome, none of the other criteria for urachal origin were met. The entire vesical epithelium was abnormal; in particular, the epithelium over the tumor mass was neoplastic. Cystitis glandularis was present. Although both lesions extended deeply into, and in one case through, muscle, the bulk of both tumors was intraluminal. Susmano et al., 7 Melicow,a Mostofi,g Wheeler and Hill,‘O and Edwards, Hurm, and Jaeschke” have described the probable development of adenocarcinoma of the urinary bladder. They agree that primitive cells, harbored in cloaca1 rests persisting after development of the septum between the primitive bladder and rectum, are a possible source of a glandular epithelium. More

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likely is a metaplasia of the urothelium induced by chronic irritation. This metaplasia may be predominantly to a squamous epithelium, with or without keratinization, or to a glandular epithelium. Melicow’ believes the latter is best termed retroplasia to underscore the urothelial ancestry. Glandular differentiation is proposed to occur as follows: irritation of the urothelium produces cellular proliferation manifest as Brunn’s nests. These represent “protective” epithelial nests within the lamina propria, which may remain solid or develop a lumen and produce mucin.7 The proliferative buds may stabilize as Brunn’s nests; become increasingly cystic (namely, cystitis cystica); differentiate into true glands (namely, cystitis glandularis) with distinct lumen, radially aligned cells about the lumen and mucin production;g or undergo varying degrees of hyperplasia or neoplasia. 6 Albarran’s13 theory that the trigone and vesical neck normally contain glandular epithelium has not been confirmed and is generally not considered to be an etiologic factor in bladder adenocarcinoma.

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This case presents an etiologic dilemma because of the absence of any normal transitional epithelium, as well as the absence of the usual benign proliferative changes described previously. There was, however, extensive replacement of the bladder epithelium by a mucinproducing mucosa similar to the “intestinal-type glands” described by Emmett and McDonald.14 This mucosa was remarkable in that not only did the surface epithelium contain numerous goblet cells but also simple glands lined by similar epithelium extended into the lamina propria, mimicking colonic mucosa (Fig. 2C). The remaining bladder, not involved in neoplasia, was replaced by a benign keratinizing squamous epithelium. Bothsquamousmetaplasiaandformation of “intestinal-type glands” have been described in chronically inflamed bladders, usually associated with calculi and infection. The history in the present case offers no suggestion of chronic cystitis or bladder calculi. No explanation is available for the extensive abnormal vesical changes. However, the diffuse involvement would appear to favor a metaplastic process. The spectrum of the changes remains dramatic. None of the changes noted were thought to be secondary to irradiation. The benign nature of the squamous changes with absence of cellular atypia and dyskeratosis mitigate against radiation effect. Seven cases of primary signet ring cell carcinoma of the bladder have been previously reported. Of these, 6 had associated transitional cell carcinoma, l-5 4 had cystitis glandularis, l-3 and 2 had Brunn’s nests.1,3 None of the previously reported cases had benign squamous metaplasia present. Our patient’s relatively long survival without clinical evidence of recurrence to twenty-eight months is unusual. The previously reported survival rates for primary signet ring cell carcinoma of the bladder has ranged from four to fifteen months. This patient’s course would refute Cor-

1. SAPHIR, 0.: Signet-ring cell carcinoma of the urinary bladder, Am. J. Pathol. 31: 223 (1955). 2. PAYAN,H. M., MENDOZA, C., JR., CABINUM, D., and GERWIG, W. H.: Primary signet-ring cell carcinoma of the urinary bladder, Arch. Surg. 92: 958 (1966). 3. ROSAS-URIBE, A., and LUNA, M. A. : Primary signet ring cell carcinoma of the urinary bladder, Arch. Pathol. 88: 294 (1969). 4. CORWIN, S. H., TASSY, F., MALAMENT, M., and GRADY, H. G.: Rare signet-ring cell variant of mutinous adenocarcinoma of the bladder, J. Urol. 106: 697 (1971). 5. NAEIM, F., SCHLEZINGER, R. M., and de la MAZA, L. M.: Primary signet ring cell carcinoma of the bladder: report of a case and review of the literature, ibid. 108: 274 (1972). 6. MOSTOFI, F. K., THOMSON, R. V., and DEAN, A. L., JR. : Mucous adenocarcinoma of the urinary bladder, Cancer 8: 741 (1955). 7. SUSMANO, D., RUBENSTEIN, A. B., DAKIN, A. R., and LLOYD, F. A.: Cystitis glandularis and adenocarcinema of the bladder, J. Urol. 105:671 (1971). 8. MELICOW, M. M.: Terminology in uropathology: a plea for consensus, including a discussion of retroplasia versus metaplasia, ibid. 105: 714 (1971). of bladder epithelium, 9. MOSTOFI, F. K.: Potentialities ibid. 71: 705 (1954). 10. WHEELER, J. D., and HILL, W. T.: Adenocarcinoma involving the urinary bladder, Cancer 7: 119 (1954). 11. SAPHIR, 0. : Signet-ring ,cell carcinoma, Mil. Surg. 109: 360 (1951). 12. EDWARDS, P. D., HURM, R. A., and JAESCHKE, W. . Conversion of cystitis glandularis to adenocarznoma, J. Urol. 108: 568 (1972). 13. ALBARRAN, J.: Les tumeurs de la vessie, Paris, G. Steinheil, 1892, p. 78. 14. EMMETT, J. L., and MCDONALD, J. R.: Proliferation of glands of the urinary bladder simulating malignant neoplasm, J. Urol. 48: 257 (1942).

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win’s implication that surgery, chemotherapy, and radiotherapy are of little avail in the treatment of this disease.4 Department of Surgery Gainesville, Florida 32610 (DR. DE TURE)

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