The 96th Clinico-Pathological Conference of the Odawara Municipal Hospital, The 9th Joint CPC of the Odawara Medical Association and Odawara Municipal Hospital, held on December 9 1996


SN-816 OOOO, XXXX 69 y. f. Date of Autopsy; 1996.6.14. (1.5 hrs. p. m.)

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Clinical Diagnosis by Dept. Urol.
1. Cancer of unknown primary site
2. DIC

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Patho-anatomical Diagnosis by Dr. Hasegawa of Dept. Pathol. :
1. Carcinoma of the urinary bladder, involving liver, bone marrow, spleen, pancreas, kidney, lungs, and lymph nodes
2. DIC with fat necrosis of the pancreas

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A. Cancer of the urinary bladder:

1. A flatly elevated multinodular tumor located at the anterior wall of the neck of the urinary bladder, fairly well-demarcated, grayish white at cut surface, measuring circa 7 x 7 x 2 cm in dimension. The bladder wall deeply infiltrated by the tumor into the perivasicular fat tissue, while bilateral ureteral orifices not involved. Histologically, diffuse and rather monotonous proliferation of small cell undifferentiated carcinoma cells with high nuclear/cytoplasmic ratio, consisting of oval to polygonal shaped nuclei containing coarse chromatin and showing nuclear molding, and scant cytoplasm (intermediate type), and focally accompanying keratinizing squamous cell carcinoma component at the luminal surface (composite small cell and squamous cell carcinoma). Immunohistochemically, cytoplasms of the small cell carcinoma cells positively stained with antibodies for cytokeratin and NSE (DAKO-EPOS anti-NSE/HRP), and negative for vimentin, ECG (endocrine granule component), and S-100. Electron microscopically, sparse dense-core secretion granules, measuring about 300 nm in diameter, in addition to well-formed and frequent desmosomes, mitochondria, rough surfaced endoplasmic reticula and dense bodies, measuring up to 300 nm in diameter, in the cytoplasm of the tumor cells.

2. Metastasis of the cancer to;

a. the liver (2,030 g), forming innumerable tiny nodules, grayish white, measuring up to 2.0 cm in greatest diameter, scattering over both lobes. Yellow, slightly turbid ascites (1,100 ml). Histologically, nodular growth of small cell carcinoma with extensive sinusoidal infiltration.

b. the vertebrae, Th-L5, and the sternum, diffuse and massive.

c. the spleen (200 g), diffuse and solid.

d. the pancreas head and body, multinodular and diffuse, up to 0.7 cm in diameter.

e. the lymph nodes of the hepatic hilum and the right pulmonary hilum, measuring up to 2 x 1 x 1 cm in dimension.

f. the adrenals, forming several nodules, measuring up to 1.0 cm in greatest diameter.

g. the mucosa of the posterior wall of the gastric fundus, forming a few aggregates of small cell carcinoma cells, measuring up to 2 mm in diameter.

h. the upper lobes of both the lungs, presenting lymphangial carcinomatosis microscopically.

3. Dilatation of the urinary bladder, marked, measuring 15 x 12 cm in external dimension, accompanying mucosal petechia. Hemorrhagic content with coagulation mass in the lumen (70 ml).

4. Hydroureteronephrosis, bilateral, moderate.

B. DIC-related findings:

1. Parenchymal and capsular hemorrhage of the pancreas head and body, marked, with spotty fat necrosis.

2. Petechia of the skin of bilateral arms, slight.

C. Other findings:

1. Subcapsular serous cysts of both the kidneys (150; 165 g), measuring up to 7.5 x 5.5 x 4.0 cm in dimension, with a focal hemorrhagic infarct in the upper 1/3 of the right kidney, measuring 1.5 x 1.3 cm in dimension. Pressure atrophy of the renal parenchyma due to dilatation of the pelvis (see A-4).

2. Patent lumen of bilateral ureters down to the orifice of the urinary bladder (see A-4).

3. Ulcers of the stomach at the lesser curvature of the body, a few, measuring up to 1.5 x 1.0 cm in dimension. Histologically, ulcer, Ul-II, covered with inflammatory exudate including candidiasis (see A-2-G).

4. Atherosclerosis of the aorta, moderate, with atheromas accompanying calcium deposition and ulceration.

5. Brown atrophy of myocardium of the heart (350 g), with mild coronary arteriosclerosis.

6. Anthracosis of the lungs (240; 340 g), moderate, with an old tuberculous scar of the right upper lobe (S-2) and fibrous adhesion of the right upper pleura. .

7. Unremarkable thyroid gland (12 g).

8. Atrophy of the ovaries with corpora albicantia.

9. Fatty aged female cadaver (155 cm/ 53 kg).

Clinical Summary; A 69-year-old female was admitted to out hospital on May 10 1996 because of gross hematuria. Her past medical history was positive for gastric ulcer at the age of 66. She was not a habitual alcohol drinker nor cigarette smoker. She noticed gross hematuria on May 5 1996, and was admitted to the regional hospital because of coagulation mass pointed out in the cavity of the urinary bladder and bilateral hydronephrosis. Then, after a short period, she was referred to our hospital. On admission, she was diagnosed with neurogenic bladder, chronic cystitis and bilateral hydronephrosis in association with bleeding in the bladder, and transurethral hemostatic procedure was undergone, which showed inflammatory lesion with edema, redness, and telangiectasia on the right wall and neck of the bladder. Laboratory tests revealed total protein 5.1 g/dl, total bilirubin 0.3 mg/dl, AST 64 IU/l, ALT 40 IU/l, Al-P 172, LDH 475 IU/l, glucose 258 mg/dl, urea nitrogen 31 mg/dl, creatinine 1.6 mg/dl, Na 108 mEq/dl, K 5.4 mEq/dl, Cl 80 mEq/dl, Ca 9.1 mEq/dl, amylase 192 IU/dl, CPK 498, RBC 2.14 x 106/mm3, Ht 18.0%, Hb 6.4 g/dl, MCV 84, MCH 31, MCHC 37, WBC 12,890, Plt 12.9 x 104/mm3, FDP 59.8. Bleeding in the bladder persisted, and platelet count was decreasing to 5.7 x 104/mm3 on May 11 while FDP was concomitantly increasing. Treatment with FOY, FFP, and AT-III was ineffective and DIC score was 8 points on May 20. CT-scan revealed multiple low density areas in the liver on May 21, with the increased level of CA 19-9 (456 ng/ml) and amylase. The cytology of the urine was diagnosed as class III on May 24 and June 2, respectively. The level of CA 19-9 was further increased in June (1127.6 ng/ml) and she passed away on June 14.

Comments; This is an uncommon case of small cell undifferentiated carcinoma (SCUC) of the urinary bladder, accompanying squamous cell carcinoma component focally at the luminal surface, resulting in extensive metastasis to multiple organs with SCUC element and DIC. Although SCUC of the urinary bladder is rare with about 100 cases in the literature (Holmang, 1995), the urinary bladder is reported to be the most common site of extrapulmonary SCUC in the genitourinary tract. It is unclear whether SCUC of the urinary blader is related to smoking, and this patient had no smoking history. Mills reported that eight of their 12 SCUC cases were associated with other forms of carcinoma, including transitional cell carcinoma (seven cases), adenocarcinoma (three cases), squamous cell carcinoma (three cases), spindle cell carcinoma (one case), and atypical carcinoid tumor (one case), as is the current case which accompanied squamous cell carcinoma.

Immunohistochemistry usually reveals a wide spectrum of activity; NSE was positive in 6/6 in Lopez's series, 10/10 in Grignon's series and 8-10/12 in Mills' series, and cytokeratin was positive in 7/10 in Grignon's series and 8/12 in Mills' series. The tumor cells of the present subject were positively reacted with anti-cytokeratin and anti-NSE antibodies as well, but negative with other (neuro)endocrine-related markers.

Characteristic urinary cytologic features of 23 patients with SCUC of the urinary bladder at Memorial Sloan-Kettering Cancer Center for a 30-year period are reported by Ali et all, which are summarized as (a) isolated single cells/lack of nesting or grouping, (b) mostly naked nuclei, rarely with scant cytoplasm, (c) minimal pleomorphism or anisonucleosis, (d) hypercellularity, (f) nuclear molding, etc. Retrospective review of the cytologic specimens in the current patient, taking these pathological features into account, indicates that some diagnostic features of SCUC were present.

The most common presenting symptom of SCUC is gross hematuria, as is the present patient. SCUC of the urinary bladder is a highly aggressive and usually lethal neoplasm, and the survivals of 5 cases with unresectable tumor were 4 months in median in Mills' series, and of 13 cases 7.3 months in Holmang's series. It is likely that the DIC of the present subject might have been caused by diffuse hemorrhage and fat necrosis of the pancres in association with the metastasis of the bladder cancer.

References;

1. Holmang S, Borghede G, Johansson SL. Primary small cell carcinoma of the urinary bladder: a report of 25 cases [review]. J Urol 1995; 153:1820-1822.
2. Grignon DJ, Ro JY, et al. Small cell carcinoma of the urinary bladder. Cancer 1992; 69:527-536.
3. Lopez JI, Angulo JC, et al. Small cell carcinoma of the urinary bladder. A clinicopathological study of six cases. Br J Urol 1994; 73:43-49.
4. Mills SE, Wolfe JT, et al. Small cell undifferentiated carcinoma of the urinary bladder. A light-microscopic, and ultrastructural study of 12 cases. Am J Surg Pathol 1987; 11:606-617.
5. Ali SZ, Reuter VE, Zakowski MF. Small cell neuroendocrine carcinoma of the urinary bladder. A clinicopathological study with emphasis on cytologic features. Cancer 1997; 79:356-361.

Akio Hasegawa,MD,PhD

Pathologist
December 9 1996



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