ANATOMIC PATHOLOGY Original Article
Primary Signet-Ring Cell Carcinoma of the Urinary Bladder DAVID J. GRIGNON, M.D., JAE Y. RO, M.D., ALBERTO G. AYALA, M.D., AND DOUGLAS E. JOHNSON, M.D.
related cause. From a literature review, the authors accepted 35 cases that met their criteria and combined them with their 12 cases for statistical analysis. Prognosis was worse with a pure diffuse versus a mixed tumor (P = 0.004) and for nonurachal versus urachal origin (P = 0.005). The difference in five-year survival rates between stages B and D disease (P < 0.05) was also statistically significant. (Key words: Signet-ring carcinoma; Adenocarcinoma; Urinary bladder) Am J Clin Pathol 1991;95: 13-20
In 1955 Saphir1 first described signet-ring cell carcinoma of the urinary bladder as a distinct entity. Since then, at least 39 additional cases have been reported under that term, and 17 more have been described within larger series of primary bladder2"8 and urachal9 adenocarcinomas. It is generally acknowledged that this tumor carries a poor prognosis; however, most reports have been of single cases, with the largest series being the six cases studied by Blute and associates.10 In this article we review the clinicopathologic features of 12 cases of signet-ring cell carcinoma of the urinary bladder; 11 of the tumors were primary in the bladder proper and 1 was primary in the urachus. In addition, we have culled 35 cases from the literature, combined them with our 12, and analyzed the data statistically to evaluate possible prognostic factors; this is the first time such an analysis has been performed.
or unclassified carcinoma of the urinary bladder seen at the University of Texas M. D. Anderson Cancer Center between 1948 and 1987 were identified from a search of the database maintained by the Department of Patient Studies; they totaled 317. All cases for which pathologic slides were unavailable for review were eliminated, irrespective of diagnosis, as were cases in which a papillary or invasive transitional cell carcinoma component was present, leaving 76 pure primary adenocarcinomas available for review. Twelve of these met our criteria for signetring carcinoma (see below). Clinical Data Clinical data were obtained by chart review and comprised patient age, sex, race, presenting symptoms, presence or absence of hematuria, cystoscopic findings, clinical stage (Marshall modification of Jewett staging protocol)," tumor location, initial treatment, length of follow-up, and status at follow-up. Stage included pathologic evaluation as available. Special attention was paid to exclude tumors of other primary sites.
MATERIALS AND METHODS Patients All patients with a diagnosis of primary adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma,
Pathologic Findings From the Departments of Pathology and Urology. The University of Texas M. D. Anderson Cancer Center, Houston, Texas. All slides were reviewed by three of the authors (D.J.G., Received February 2, 1990; accepted for publication August 14, 1990. J.Y.R., A.G.A.). Cases were included only when a diffuse Address reprint requests to Jae Y. Ro, M.D., Department of Pathology, Box 85, M. D. Anderson Hospital, 1515 Holcombe Boulevard, Houston, signet-ring cell component was present. This was defined by the presence of individual signet-ring cells permeating Texas 77030.
13
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
Primary signet-ring cell carcinoma is an uncommon malignancy arising in the urinary bladder. The authors report 12 cases collected at their institution. Median age for the ten men and two women was 58 years; the most frequent presentation was hematuria. In two of nine cases no mucosal lesion was cystoscopically visible. Eleven tumors were of nonurachal origin and one of urachal. At diagnosis, one tumor was stage B, two stage C, seven stage D, and two stages unknown. Nine of 12 patients were dead of disease (range, 1-16 months; median, 9 months), 1 alive with metastatic disease, 1 alive and well, and 1 dead of an un-
14
ANATOMIC PATHOLOGY Article
Literature Review For the purpose of this discussion, we have excluded those cases in which a transitional cell component was associated with the signet-ring carcinoma1012-17 because we believe that the presence of a transitional component clouds a usable definition of signet-ring cell tumors. If mucin staining is performed routinely in otherwise typical transitional cell carcinomas, signet-ring cells are frequently identified. We have also excluded those cases for which the clinical details are inadequate for additional analys j s 2,5-7,18-21 Q n e Qf t n e c a s e s re p 0r ted by Rosas-Uribe and Luna has been included in the current series.22 This leaves a total of 35 cases available for review.1'7"101314'22"39 These 35 cases were combined with our 12 cases, making a total group of 47 patients on which statistical analysis was based. A.J.C.P. •
Statistical Analysis Statistical significance was tested from the KaplanMeier survival curves. RESULTS Clinical Results Ofthe 76 pure primary adenocarcinomas reviewed, 12 (15.8%) met the criteria outlined for inclusion as signetring cell carcinoma. Clinical features of these cases are detailed in Table 1. Ten of the patients were men and two were women; ages ranged from 37 to 78 years (mean, 55.6 years; median, 58 years). The most frequent presentation was hematuria (8 of 11 patients, 72.7%); two patients presented with irritative symptoms, one with an abdominal mass and one with a supraclavicular mass. Cystoscopyfindingswere available for nine cases. In seven of these a mass lesion was identified; it was described as pedunculated in two cases, as ill-defined and sessile or flat in three cases, and as fungating in one case. In one case the bladder was observed to be "contracted" with no mucosal or mass lesions identified and in another case an elevated area with normal mucosa was described. In six of eight nonurachal tumors, the lesion involved the posterior wall, trigone, or both, and two tumors were located on the lateral aspect of the bladder. The single urachal case was located in the dome. Tumor stage at diagnosis was reported for ten cases: one stage B; two stage C; and seven stage D (four, Dl; three, D2). Initial treatment consisted of surgery alone for one case (transurethral resection), combined surgery plus radiation therapy for one case, surgery plus chemotherapy for two cases, radiation therapy alone for two cases, chemotherapy alone for four cases (two systemic and two intraarterial), and combined radiation therapy and chemotherapy for one case. In one case no therapy was given. Nine of the 12 patients (75%) died of their disease between 1 and 16 months after diagnosis (mean, 8.9 months; median, 9 months). Among the three who have not died of disease, one was alive but had extensive progressive disease at 18 months; one was alive and well at 32 months; and one died of an unrelated cause (pancreatic adenocarcinoma) at 90 months. Pathologic Results Slides available for review in these 12 cases ranged from 1 to 11 per case (mean, 7 slides). Eleven of the tumors were considered to be of nonurachal origin and one of urachal type. In ten ofthe cases the tumor showed a pure, diffuse, signet-ring cell structure. Two tumors showed a nuary 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
the bladder wall in a linitis plastica fashion. Histologic features evaluated were the architectural patterns of the tumor (diffuse signet-ring, colloid, enteric, or gland formation not otherwise specified); the presence or absence of carcinoma in situ, pagetoid spread of signet-ring cells, cystitis cystica, cystitis glandularis, and intestinal metaplasia; the depth of invasion; and the presence or absence of vascular or lymphatic invasion. Cystitis glandularis was defined by the presence of mucin-secreting epithelium within the nests of cystitis cystica and intestinal metaplasia by the presence of mucin-secreting epithelium on the mucosal surface. When paraffin blocks were available, a series of mucin stains (Alcian blue at pH 0.9 and pH 2.7, Mayer's mucicarmine, and periodic acid-Schiff [PAS], with and without digestion) was used to evaluate the type or types of mucin present. Tumors were classified as urachal or nonurachal in origin, as indicated by clinical and pathologic criteria. Features that have been suggested as necessary for a diagnosis of urachal carcinoma are as follows: (1) location in the dome of the bladder, (2) absence of cystitis cystica and cystitis glandularis, (3) involvement of muscle or deeper structures, (4) an intact or ulcerated epithelium, (5) presence of a suprapelvic mass, (6) sharp demarcation between tumor and normal surface epithelium, (7) presence of urachal remnants, and (8) tumor growth in the bladder wall branching into Retzius' space.2-7 Johnson and associates9 considered these criteria too restrictive and suggested that the critical features are the following: (1) location ofthe tumor in the bladder wall, (2) findings of a sharp demarcation between the tumor and the surface epithelium, and (3) exclusion of a primary adenocarcinoma elsewhere that has spread to the bladder. We have adopted these criteria; cases not meeting them were classified as nonurachal in origin.
47/F/W
42/M/W
65/M/W
57/M/W
63/M/W
63/M/W
59/M/W
37/M/W
49/M/W
78/M/W
49/M/W
60/F/W
Case Number
1
2
3
4
5
6
7
8
9
10
11
12
Hem, back pain
Abdominal mass
Hem
Hem, supraclavicular mass Hem
Frequency
Hem, dysuria
Hem
NA
Irritative symptoms
Hem
Hem
Signs and Symptoms
NA
Pedunculated mass Ill-defined sessile mass Ill-defined sessile mass NA
Contracted bladder Distortion by mass in lateral wall Diffuse mass
Fungating tumor Elevated area, normal mucosa NA
Solid tumor, 6 cm
Cystoscopy Findings
Dl
P
D
NA
T, N
NA
C
Dl
D2
Dl
L
T, P
D2
T,P, L
D2
NA
NA
P
XRT (46 Gy) + Chemo (Vin, MTX, 5FU, cyclo) None
Dl
N, L
DOD DOD DUC DOD DOD
13 12 90 9 1
None Developed pancreatic carcinoma 36 mo later, Chemo (CCNU, 5FU, Dox, mito-C) Metastases to scrotum and penis at 19 mo X R T ( 3 0 G y ) + Chemo (Dox, 5FU) None
DOD DOD DOD A + W DOD
16 8 3 27 5 18
None Repeat TUR at 5 mo, partial cystectomy at 12 mo
None
AWD: extensive local disease including abdominal wall, metastases to pelvic lymph nodes
DOD
Bone mets and extension to abdominal wall and scrotum Chemo (5FU, Dox, mito-C) Local recurrence-Chemo {cis-P, Dox, Cyclo) + XRT Mets to lungs, bones, and lymph nodes; interferon added None
13
None
Status
Treatment
Follow-up (mo)
Additional
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
droxyurea; MTX = methotrexate; Vin = vincristine; DUC = dead of an unrelated cause; DOD = dead of disease; A + W = alive and well (without evidence of disease); AWD = alive with disease; mo = months; NA = not available. • Chemotherapy not specified as intraarterial or intravesical was systemic.
Cystoprostatectomy + Chemo {cis-P, Cyclo, Dox) Partial cystectomy + postop XRT TUR
Intraarterial (5FU, mito-C, Dox) Chemo (5FU, Dox, Mito-C, cis-P) Chemo (5FU, Dox, mito-C, cis-P)
Chemo (cis-P) by arterial infusion
XRT (65 Gy)
B2
L
C
D,P
Initial Treatment TUR + Chemo (5FU hydroxy, MTX + thiotepa [1]) XRT (50 Gy)
Stage
Tumor Location
i
cs
Ring Carcir
M = male; F = rcmale; W = white; Hem = hematuria; D = dome; T = trigone; P = posterior, L = lateral; N = neck; TUR = transurethral resection; XRT * extemal-beam radiotherapy, Gy = Gray; chemo = chemotherapy; I = intravesical; Dox = doxorubicin; cyclo = cyclophosphamide; cis-P = cisplatin; mito-C = mitomycin C; 5 FU = 5 fluorouracil; hydroxy = hy-
Age (yr)i Sex/ Race
TABLE 1. SIGNET-RING CELL C A R C I N O M A , CLINICAL FEATURES
Urinary Bladder Sic,
16
ANATOMIC PATHOLOGY Original Article
Literature Review
'*
*- • • i
In the group as a whole, stage at the time of diagnosis was reported for 34 cases; 5 were stage B; 7, stage C; and 22, stage D. The five-year survival rates for patients in whom tumors were stage B, C, and D were 75%, 38%, and 12%, respectively. Overall, the differences in outcome related to stage did not achieve statistical significance when
^
*
i
*
V "1 t **• *
The total group (our series plus cases culled from the literature) comprised 36 men and 11 women, for a roughly 3:1 male-female ratio. Ages ranged from 34 to 81 years (mean, 55.8 years). Thirty-five of the tumors were of nonurachal origin, 10 were of apparent urachal origin, and in 2 the type were uncertain. Hematuria was a presenting symptom in 25 of 39 cases (64.1%) where indicated; irritative symptoms were reported in 24 of the 39 (61.5%). Cystoscopic or gross features were described for 34 of the cases. In 16 of these (47.1%) no mucosal or mass lesion was present. The most common description was that of an "edematous mucosa" (26.5%), often with the adjective "bullous" applied. In other cases the mucosal surface was erythematous or finely granular. Frequently the bladder wall was described as "thickened" or "fibrotic" on bimanual examination. In more than half the cases (52.9%) some sort of mass lesion was recognized. These ranged from polypoid or pedunculated to sessile to ulcero-infiltrative. In other cases masses were observed to be present within the bladder wall, encroaching on the lumen.
I
,t%
^ * »%\>.„"
&m
r(•
\ t
»
* ~
FIG. 1 (upper). Photomicrograph of primary signet-ring cell adenocarcinoma of the urinary bladder with cells having cytoplasm replaced by a single large mucin containing vacuole. Alcian blue (X250). FlG. 2 (center). Photomicrograph of primary signet-ring cell adenocarcinoma of the urinary bladder with cells having foamy, multivesicular cytoplasm. Hematoxylin and eosin (X300). FlG. 3 (lower). Photomicrograph of primary signet-ring cell adenocarcinoma of the urinary bladder with cells having pleomorphic nuclei and glassy, eosinophilic cytoplasm. Hematoxylin and eosin (X300).
A.J.C.P. • January 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
mixed pattern, one including solid areas and one a mixture of colloid and nonspecific types. Individual signet-ring cells contained nuclei pressed to one edge of the cell and distorted by cytoplasmic mucin that appeared as a single clear vacuole in some tumors (Fig. 1) and as a foamy, multivesicular cytoplasmic material in others (Fig. 2).In other instances the nuclei had a more ovoid appearance, were again pushed to one edge of the cell, and had cytoplasm that stained pink with hematoxylin and eosin (Fig. 3).In these cases the cytoplasm demonstrated strong, diffuse positivity with mucin stains. Uninvolved mucosa was present in material from nine of the cases. Three contained foci of cystitis cystica, but cystitis glandularis and intestinal metaplasia were never found. In one case individual signet-ring cells extensively involved the transitional epithelium, producing a pagetoid appearance (Fig. 4).This was seen both adjacent to and distant from the tumor. Mucin stains used on nine of the tumors showed cytoplasmic positivity in all instances with Alcian blue at pH 2.7, Mayer's mucicarmine, and PAS with digestion. Three of the nine tumors also stained positively with Alcian blue at pH 0.9.
17
GRIGNON ET AL. Urinary Bladder Signet-Ring Carcinoma
FIG. 4. Photomicrograph of transitional epithelium overlying a primary signet-ring cell adenocarcinoma of the urinary bladder illustrating involvement of the epithelium by individual neoplastic cells. Hematoxylin and eosin (X250).
nuclei localized to one edge of a cell that had homogeneous eosinophilic cytoplasm. The latter type of cell typically demonstrated cytoplasmic mucin positivity. Saphir, in his
I
100
150
TIME (MONTHS)
FIG. 5. Kaplan-Meier survival curves of primary signet-ring cell adenocarcinoma of the urinary bladder by stage; differences were statistically significant only for stage B versus stage D (P < 0.05).
Vol. 95 • No. I
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
compared by Kaplan-Meier survival curves (Fig. 5). The difference in five-year survival rates between stage B and stage D disease was statistically significant (P < 0.05); differences between stages B and C and between stages C and D did not reach statistical significance (P > 0.05). Pathologically the lesions encompassed a wide range of descriptions. All cases included in this discussion had at least some component with a diffuse signet-ring pattern. In 27 of the 47 cases (57.4%), the tumors were described as being diffuse, pure signet-ring, or "linitis plastica-like." In the remainder the signet-ring cell component was mixed with some other pattern: colloid in 12, enteric in 1, colloid and enteric in 3, nonspecific adenocarcinoma in 3, and nonspecific adenocarcinoma plus small cell carcinoma in 1. The stage at presentation differed significantly between the two groups: in the pure group only 1 case was stage B (4%), with 4 stage C (17%) and 19 stage D (79%). In contrast, within the mixed group there was a more uniform stage distribution, with four stage B (40%), three stage C (30%), and three stage D (30%). The difference in survival rate between those cases described as "diffuse" and those considered "mixed" was statistically significant (P = 0.004) (Fig. 6). The five-year survival rates for the diffuse and mixed types were 13% and 33%, respectively. The structural appearance of the so-called signet-ring cells has also varied, ranging from the usual signetring cell with a thin distorted nucleus compressed by a large cytoplasmic mucin vacuole to cells with pleomorphic
18
ANATOMIC PATHOLOGY Original Article 2 1H|
FlG. 6. Kaplan-Meier survival curves of primary signet-ring cell adenocarcinoma comparing those tumors having a pure, diffuse pattern (d) with those of mixed pattern (m); the difference was statistically significant (P = 0.004).
original description, referred to these cells as "monocytelike."1 Thirty-five of the cases (74.5%) were considered to be nonurachal and 10 (21.3%) urachal. In two cases (4.3%) the type was uncertain. Within the nonurachal group were 29 men and 6 women, whose mean age was 56.9 years. The urachal group consisted of six men and four women whose mean age was 52.3 years. The difference in survival rates between these groups was statistically significant (P = 0.005): thefive-yearsurvival rate was 44% for patients with urachal tumors and 15% for those with nonurachal tumors (Fig. 7). DISCUSSION Primary adenocarcinoma of the urinary bladder is uncommon, accounting for 0.5-2.0% of all bladder malignancies.7 The signet-ring variant, first reported in 19551 and since described in itself (at least 39 additional cases in the English literature1012"39) and within vesical adenocarcinoma series (17 cases2"9), is reported to account for between 2%7 and 24%6 of primary vesical adenocarcinomas. A review of seven series in which signet-ring cell carcinoma is discussed yields a mean frequency of 8.6% (20 of 233).2"8 We reviewed a total of 76 primary ade-
TIME (MONTHS)
FlG. 7. Kaplan-Meier survival curves of primary signet-ring cell adenocarcinoma of the urinary bladder comparing those of nonurachal type (nu) with the urachal type (u); the difference was statistically significant (P = 0.005).
A.J.C.P. • January 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
TIME (MONTHS)
nocarcinomas and found, using our criteria, 12 cases of the signet-ring cell variant (15.8%). Despite these reports, this entity has not been adequately defined. Saphir's original report described signet-ring cells as present "in a substantial number."1 Other authors refer to signet-ring cells being the "predominant"35 or "primary"15 cell type. For our study, we included only those cases having at least in part a diffuse, linitis plastica-like pattern of growth. We did not include tumors with a papillary or invasive transitional carcinoma component, although seven of the previously reported signet-ring cell cases included a transitional cell component.51012'"16 To date, no studies have evaluated signet-ring cell carcinomas statistically, because reports have been limited to single cases or series of two or three cases only. In this study we have reported the features seen in 12 cases from M. D. Anderson Cancer Center. Furthermore, to evaluate the significance of a range of factors, we have culled 35 additional cases from the literature and combined them with our own. The clinical and pathologic features described for the literature cases we selected are similar to those of our cases. Patients tend to present in a similar fashion with invasive transitional cell carcinoma of the bladder, with hematuria and irritative symptoms. The tumors most fre-
GRIGNON ET AL. Urinary Bladder Si> •t-Ring Carcinoma
designation "signet-ring cell carcinoma" to those tumors having this pattern. The histogenesis of nonurachal signet-ring cell carcinoma of the bladder is indefinite; however, several possibilities exist. The metaplastic potential of the urothelium has been well described, and it is presumed that most adenocarcinomas arise by this route.7 These changes may be present along the surface (intestinal metaplasia) or in areas of cystitis cystica (cystitis glandularis). In series of primary vesical adenocarcinomas, intestinal metaplasia or cystitis glandularis or both are found in between 14%8 and 66%2 of cases. Despite this, fairly few cases demonstrating transition from one of these lesions to adenocarcinoma have been described.42 In the current series, none of the nine diffuse signet-ring cell tumors evaluable had either of these alterations. This experience is similar to that reported in the literature: among 14 cases with a pure diffuse signet-ring structure, none showed either cystitis glandularis or intestinal metaplasia. 1,14,2U24,26,32~34,36 Isolated signet-ring cells in otherwise normal transitional epithelium have been described occasionally. In the case reported by Braun and associates,24 isolated signet-ring cells were found overlying the tumor. This feature was also present in one of the three cases reported by Choi and associates13; the tumor was composed predominantly of signet-ring cells with foci of squamous cell carcinoma. In our series we found one case in which the overlying transitional epithelium was extensively infiltrated by signet-ring cells. Because individual mucin-secreting cells may be found scattered in nonneoplastic transitional epithelium, it is hypothetically possible that diffuse signetring cell adenocarcinoma arises from these cells. However, it seems more likely, given the rarity of the finding, that these cases represent examples of pagetoid spread by the tumor. A third possible origin for signet-ring cell carcinoma would be a metaplastic change in transitional cell carcinoma. In six reported cases,12"17 areas of transitional cell carcinoma were admixed with the signet-ring cell variant. In the case reported by Austin and Safford,12 the original tumor was a papillary transitional cell carcinoma with prominent glandular metaplasia, and over time it developed into a predominantly signet-ring cell tumor. In our series we excluded cases that had a papillary or invasive transitional cell carcinoma component, and so this phenomenon was not seen. In summary, we have presented 12 cases of primary signet-ring cell adenocarcinoma of the urinary bladder and combined these with 35 additional cases from the literature. Statistical analysis had demonstrated a statistically significant worse prognosis for those cases having a pure, diffuse signet-ring pattern; those of nonurachal
Vol. 95 •No. 1
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
quently arise in the sixth decade of life, and there is a male preponderance. Patients tend to present with advanced disease—65% of all cases are stage D—and with metastases, prompting a search for a primary site. It is therefore important to realize that cystoscopically the bladder mucosa may be quite unremarkable, showing only edematous, erythematous, or elevated "normal" mucosa. In these instances random biopsies may reveal the characteristic signet-ring cells in the lamina propria. Stage has been reported to correlate with outcome for bladder adenocarcinomas in general.3,8'40,41 In only one study have data been analyzed statistically, confirming this impression.3 In the series of cases collected in this study, stage at diagnosis was a statistically significant predictor of outcome only when stage B disease was compared with stage D. Traditionally, adenocarcinomas of the urinary bladder have been separated into those arising from the urachus and those within the bladder proper. This division has both treatment and prognostic implications that can be analyzed statistically. In the current review, patients with signet-ring cell carcinoma of urachal origin were younger than those with the nonurachal type and were more equally distributed by sex. These tendencies have been previously described for bladder adenocarcinomas in general.3 The difference in survival rate proved to be highly significant between these two groups (P = 0.005), with those with urachal tumors doing much better. The survival curves also are significantly different; the tendency for early death in the nonurachal group contrasts with the rapid decline in survival seen between three and six years for the urachal cases. This difference in survival between patients with the urachal and nonurachal types was previously reported by Kondo and associates.31 Pathologically, we separated these tumors into two subgroups, those that had a diffuse or linitis plastica-like structure and those in which the signet-ring cells were mixed with other adenocarcinoma patterns. This separation proved to be valid not only histologically, but also with respect to outcome. The difference in survival rates between these groups was statistically significant (P = 0.004): the pure diffuse form had a much worse outcome. In reviewing our experience with primary adenocarcinomas as a whole, the five-year survival for the nonsignet-ring cell adenocarcinomas was 47% (unpublished data). This is similar to the experience of Thomas and associates8 (overall five-year survival, all adenocarcinomas, 42%). In contrast, Anderstrom and associates3 reported an overall five-year survival rate of only 18% in the 64 cases (all types) they studied. Because of the extremely poor survival rate associated with the pure, diffuse signet-ring histologic characteristics, we would restrict the
19
20
ANATOMIC PATHOLOGY
Original Article origin; and those presenting at late stage. The histogenesis of these rare tumors remains obscure. Acknowledgments. The authors thank Mona Poitras for excellent secretarial assistance and Penny Brasher, Department of Epidemiology and Biostatistics, The University of Western Ontario, London, for statistical analysis. They thank the following physicians for providing pathologic materials: A. L. Guarda, M.D., Orlando, Florida; R. A. Roe, M.D., Little Rock, Arkansas; J. F. Nickerson, M.D., Atlanta, Georgia; J. B. White, M.D., Fort Worth, Texas; R. P. Smith, M.D., Spokane, Washington; and H. C. Moore, M.D., Topeka, Kansas.
REFERENCES
A.J.C.P. • January 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
1. Saphir O. Signet-ring cell carcinoma of the urinary bladder. Am J Pathol 1955;31:223-231. 2. Abenoza P, Manivel C, Fraley EE. Primary adenocarcinoma of urinary bladder clinicopathologic study of 16 cases. Urology 1987;29: 9-14. 3. Anderstrom C, Johansson SL, von Schultz L. Primary adenocarcinoma of the urinary bladder: a clinicopathologic and prognostic study. Cancer 1983;52:1273-1280. 4. Fuselier HA Jr, Bran nan W, Ochsner MG, Matos LH. Adenocarcinoma of the bladder as seen at Ochsner medical institutions. South Med J 1978;71:804-806. 5. Johnson DE, Hogan JM, Ayala AG. Primary adenocarcinoma of the urinary bladder. South Med J 1972;65:527-530. 6. Melicow MM. Tumors of the urinary bladder: a clinicopathological analysis of over 2500 specimens and biopsies. J Urol 1955;74: 498-521. 7. Mostofi FK, Thomson RV, Dean AL Jr. Mucous adenocarcinoma of the urinary bladder. Cancer 1955;8:741-758. 8. Thomas DG, Ward AM, Williams JL. A study of 52 cases of adenocarcinoma of the bladder. Br J Urol 1971;43:4-15. 9. Johnson DE, Hodge GB, Abdul-Karim FW, Ayala AG. Urachal carcinoma. Urology 1985;26:218-221. 10. Blute ML, Engen DE, Travis WD, Kvols LK. Primary signet ring cell adenocarcinoma of the bladder. J Urol 1989;141:17-21. 11. Marshall VF. The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J Urol 1952;68:714-723. 12. Austin GE, Safford J. Signet ring cell carcinoma of bladder. Urology 1978;12:458-460. 13. Choi H, Lamb S, Pintar K, Jacobs SC. Primary signet-ring cell carcinoma of the urinary bladder. Cancer 1984;53:1985-1990. 14. DeFillipo N, Blute R, Klein LA. Signet-ring cell carcinoma of bladder: evaluation of three cases with review of literature. Urology 1987;29:479-483. 15. Gonzalez E, Fowler MR, Venable DD. Primary signet ring cell adenocarcinoma of the bladder (linitis plastica of the bladder): report of a case and review of the literature. J Urol 1982; 128:10271030. 16. Naeim F, Schlezinger RM, de la Maza LM. Primary signet ring cell carcinoma of the bladder: report of a case and review of the literature. J Urol 1972;108:274-276. 17. Payan HM, Mendoza C Jr, Cabinum D, Gerwig WH Jr. Primary signet ring cell carcinoma of the urinary bladder. Arch Surg 1966;92:958-959. 18. Bernath AS, Addonizio JC, Thelmo W, Davidian MD, Herman B. Clinicopathological conference: unusual cause of bilateral ureteral obstruction. J Urol 1982; 127:1169-1171. 19. Bernstein SA, Reuter VE, Carroll PR, Whitmore WF Jr. Primary signet-ring cell carcinoma of urinary bladder. Urology 1988;31: 432-436.
20. Dreffke F, Linde JVD, Babiel H. Signet ring cell carcinoma of the urinary bladder. Z Urol Nephrol 1987;80:75-80. 21. Reading LC, D'Onofrio GMD, Tulloch AGS, Knight DE, Walters MNI, Ojeda VJ. Primary linitis plastica carcinoma of urinary bladder. Urology 1983;22:310-313. 22. Rosas-Uribe A, Luna MA. Primary signet ring cell carcinoma of the urinary bladder: report of two cases. Arch Pathol 1969;88:294297. 23. Bowlby LS, Smith ML. Signet-ring cell carcinoma of the urinary bladder: primary presentation as a Krukenberg tumor. Gynecol Oncol 1986;25:376-381. 24. Braun EV, Ali M, Fayemi AO, Beaugard E. Primary signet ring cell carcinoma of the urinary bladder: review of the literature and report of a case. Cancer 1981;47:1430-1435. 25. Corwin SH, Tassy F, Malament M, Grady HG. Rare signet ring cell variant of mucinous adenocarcinoma of the bladder. J Urol 1971;106:697-700. 26. DeMay RM, Grathwohl MA. Signet-ring-cell (colloid) carcinoma of the urinary bladder: cytologic, histologic and ultrastructural findings in one case. Acta Cytol (Baltimore) 1985;29:132-136. 27. DeTure FA, Dein R, Hackett RL, Drylie DM. Primary signet ring cell carcinoma of bladder exemplifying vesical epithelium multipotentiality. Urology 1975;6:240-244. 28. Hirasawa S, Oki M, Abe H, et al. A case of signet ring cell carcinoma of the urinary bladder. Hinyokika Kiyo 1985;31:2049-2053. 29. Jakse G, Schneider HM, Jacobi GH. Urachal signet-ring cell carcinoma, a rare variant of vesical adenocarcinoma: incidence and pathological criteria. J Urol 1978;120:764-766. 30. Kitamura H, Sumikawa T, Fukuoka H, Kanisawa M. Primary signetring cell carcinoma of the urinary bladder: report of two cases with histochemical studies. Acta Pathol Jpn 1985;35:675-686. 31. Kondo A, Ogisu B, Mitsuya H. Signet-ring cell carcinoma involving the urinary bladder: report of a case and review of 21 cases. Urol Int 1981;36:373-379. 32. Kums JJM, van Helsdingen PJRO. Signet-ring cell carcinoma of the bladder and the prostate: report of 4 cases. Urol Int 1985;40: 116-119. 33. Ponz M, Luzuriaga J, Robles JE, et al. Primary signet-ring cell carcinoma of the urinary bladder (linitis plastica). Eur Urol 1985; 11: 212-214. 34. Poore E, Egbert B, Jahnke R, Kraft JK. Signet ring cell adenocarcinoma of the bladder: linitis plastica variant. Arch Pathol Lab Med 1981;105:203-204. 35. Sagalowsky A, Donohue JP. Sixteen-year survival with metastatic signet ring cell bladder carcinoma. Urology 1980;15:501-504. 36. Tanaka T, Kanai N, Sugie S, et al. Primary signet-ring cell carcinoma of the urinary bladder. Pathol Res Pract 1987;182:130-132. 37. Townsend GH, Sarma DP. Signet-ring cell carcinoma of the urinary bladder. J La State Med Soc 1987;139:47-48. 38. Yoshida H, Iwata H, Ochi K, Yoshida A, Fukunishi R. Primary signet-ring cell carcinoma of urinary bladder. Urology 1981;17: 481-483. 39. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: problems in interpretation. A report of three cases and review of the literature. Int J Gynecol Pathol 1988;7:197211. 40. Jacobo E, Loening S, Schmidt JD, Culp DA. Primary adenocarcinoma of the bladder: a retrospective study of 20 patients. J Urol 1977;117:54-56. 41. Kramer SA, Bredael J, Croker BP, Paulson DF, Glenn JF. Primary non-urachal adenocarcinoma of the bladder. J Urol 1979; 121: 278-281. 42. Lin JI, Yong HS, Tseng CH, Marsidi PS, Choy C, Pilloff B. Diffuse cystitis glandularis associated with adenocarcinomatous change. Urology 1980;15:411-415.
Primary Signet-Ring Cell Carcinoma of the Urinary Bladder DAVID J. GRIGNON, M.D., JAE Y. RO, M.D., ALBERTO G. AYALA, M.D., AND DOUGLAS E. JOHNSON, M.D.
related cause. From a literature review, the authors accepted 35 cases that met their criteria and combined them with their 12 cases for statistical analysis. Prognosis was worse with a pure diffuse versus a mixed tumor (P = 0.004) and for nonurachal versus urachal origin (P = 0.005). The difference in five-year survival rates between stages B and D disease (P < 0.05) was also statistically significant. (Key words: Signet-ring carcinoma; Adenocarcinoma; Urinary bladder) Am J Clin Pathol 1991;95: 13-20
In 1955 Saphir1 first described signet-ring cell carcinoma of the urinary bladder as a distinct entity. Since then, at least 39 additional cases have been reported under that term, and 17 more have been described within larger series of primary bladder2"8 and urachal9 adenocarcinomas. It is generally acknowledged that this tumor carries a poor prognosis; however, most reports have been of single cases, with the largest series being the six cases studied by Blute and associates.10 In this article we review the clinicopathologic features of 12 cases of signet-ring cell carcinoma of the urinary bladder; 11 of the tumors were primary in the bladder proper and 1 was primary in the urachus. In addition, we have culled 35 cases from the literature, combined them with our 12, and analyzed the data statistically to evaluate possible prognostic factors; this is the first time such an analysis has been performed.
or unclassified carcinoma of the urinary bladder seen at the University of Texas M. D. Anderson Cancer Center between 1948 and 1987 were identified from a search of the database maintained by the Department of Patient Studies; they totaled 317. All cases for which pathologic slides were unavailable for review were eliminated, irrespective of diagnosis, as were cases in which a papillary or invasive transitional cell carcinoma component was present, leaving 76 pure primary adenocarcinomas available for review. Twelve of these met our criteria for signetring carcinoma (see below). Clinical Data Clinical data were obtained by chart review and comprised patient age, sex, race, presenting symptoms, presence or absence of hematuria, cystoscopic findings, clinical stage (Marshall modification of Jewett staging protocol)," tumor location, initial treatment, length of follow-up, and status at follow-up. Stage included pathologic evaluation as available. Special attention was paid to exclude tumors of other primary sites.
MATERIALS AND METHODS Patients All patients with a diagnosis of primary adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma,
Pathologic Findings From the Departments of Pathology and Urology. The University of Texas M. D. Anderson Cancer Center, Houston, Texas. All slides were reviewed by three of the authors (D.J.G., Received February 2, 1990; accepted for publication August 14, 1990. J.Y.R., A.G.A.). Cases were included only when a diffuse Address reprint requests to Jae Y. Ro, M.D., Department of Pathology, Box 85, M. D. Anderson Hospital, 1515 Holcombe Boulevard, Houston, signet-ring cell component was present. This was defined by the presence of individual signet-ring cells permeating Texas 77030.
13
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
Primary signet-ring cell carcinoma is an uncommon malignancy arising in the urinary bladder. The authors report 12 cases collected at their institution. Median age for the ten men and two women was 58 years; the most frequent presentation was hematuria. In two of nine cases no mucosal lesion was cystoscopically visible. Eleven tumors were of nonurachal origin and one of urachal. At diagnosis, one tumor was stage B, two stage C, seven stage D, and two stages unknown. Nine of 12 patients were dead of disease (range, 1-16 months; median, 9 months), 1 alive with metastatic disease, 1 alive and well, and 1 dead of an un-
14
ANATOMIC PATHOLOGY Article
Literature Review For the purpose of this discussion, we have excluded those cases in which a transitional cell component was associated with the signet-ring carcinoma1012-17 because we believe that the presence of a transitional component clouds a usable definition of signet-ring cell tumors. If mucin staining is performed routinely in otherwise typical transitional cell carcinomas, signet-ring cells are frequently identified. We have also excluded those cases for which the clinical details are inadequate for additional analys j s 2,5-7,18-21 Q n e Qf t n e c a s e s re p 0r ted by Rosas-Uribe and Luna has been included in the current series.22 This leaves a total of 35 cases available for review.1'7"101314'22"39 These 35 cases were combined with our 12 cases, making a total group of 47 patients on which statistical analysis was based. A.J.C.P. •
Statistical Analysis Statistical significance was tested from the KaplanMeier survival curves. RESULTS Clinical Results Ofthe 76 pure primary adenocarcinomas reviewed, 12 (15.8%) met the criteria outlined for inclusion as signetring cell carcinoma. Clinical features of these cases are detailed in Table 1. Ten of the patients were men and two were women; ages ranged from 37 to 78 years (mean, 55.6 years; median, 58 years). The most frequent presentation was hematuria (8 of 11 patients, 72.7%); two patients presented with irritative symptoms, one with an abdominal mass and one with a supraclavicular mass. Cystoscopyfindingswere available for nine cases. In seven of these a mass lesion was identified; it was described as pedunculated in two cases, as ill-defined and sessile or flat in three cases, and as fungating in one case. In one case the bladder was observed to be "contracted" with no mucosal or mass lesions identified and in another case an elevated area with normal mucosa was described. In six of eight nonurachal tumors, the lesion involved the posterior wall, trigone, or both, and two tumors were located on the lateral aspect of the bladder. The single urachal case was located in the dome. Tumor stage at diagnosis was reported for ten cases: one stage B; two stage C; and seven stage D (four, Dl; three, D2). Initial treatment consisted of surgery alone for one case (transurethral resection), combined surgery plus radiation therapy for one case, surgery plus chemotherapy for two cases, radiation therapy alone for two cases, chemotherapy alone for four cases (two systemic and two intraarterial), and combined radiation therapy and chemotherapy for one case. In one case no therapy was given. Nine of the 12 patients (75%) died of their disease between 1 and 16 months after diagnosis (mean, 8.9 months; median, 9 months). Among the three who have not died of disease, one was alive but had extensive progressive disease at 18 months; one was alive and well at 32 months; and one died of an unrelated cause (pancreatic adenocarcinoma) at 90 months. Pathologic Results Slides available for review in these 12 cases ranged from 1 to 11 per case (mean, 7 slides). Eleven of the tumors were considered to be of nonurachal origin and one of urachal type. In ten ofthe cases the tumor showed a pure, diffuse, signet-ring cell structure. Two tumors showed a nuary 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
the bladder wall in a linitis plastica fashion. Histologic features evaluated were the architectural patterns of the tumor (diffuse signet-ring, colloid, enteric, or gland formation not otherwise specified); the presence or absence of carcinoma in situ, pagetoid spread of signet-ring cells, cystitis cystica, cystitis glandularis, and intestinal metaplasia; the depth of invasion; and the presence or absence of vascular or lymphatic invasion. Cystitis glandularis was defined by the presence of mucin-secreting epithelium within the nests of cystitis cystica and intestinal metaplasia by the presence of mucin-secreting epithelium on the mucosal surface. When paraffin blocks were available, a series of mucin stains (Alcian blue at pH 0.9 and pH 2.7, Mayer's mucicarmine, and periodic acid-Schiff [PAS], with and without digestion) was used to evaluate the type or types of mucin present. Tumors were classified as urachal or nonurachal in origin, as indicated by clinical and pathologic criteria. Features that have been suggested as necessary for a diagnosis of urachal carcinoma are as follows: (1) location in the dome of the bladder, (2) absence of cystitis cystica and cystitis glandularis, (3) involvement of muscle or deeper structures, (4) an intact or ulcerated epithelium, (5) presence of a suprapelvic mass, (6) sharp demarcation between tumor and normal surface epithelium, (7) presence of urachal remnants, and (8) tumor growth in the bladder wall branching into Retzius' space.2-7 Johnson and associates9 considered these criteria too restrictive and suggested that the critical features are the following: (1) location ofthe tumor in the bladder wall, (2) findings of a sharp demarcation between the tumor and the surface epithelium, and (3) exclusion of a primary adenocarcinoma elsewhere that has spread to the bladder. We have adopted these criteria; cases not meeting them were classified as nonurachal in origin.
47/F/W
42/M/W
65/M/W
57/M/W
63/M/W
63/M/W
59/M/W
37/M/W
49/M/W
78/M/W
49/M/W
60/F/W
Case Number
1
2
3
4
5
6
7
8
9
10
11
12
Hem, back pain
Abdominal mass
Hem
Hem, supraclavicular mass Hem
Frequency
Hem, dysuria
Hem
NA
Irritative symptoms
Hem
Hem
Signs and Symptoms
NA
Pedunculated mass Ill-defined sessile mass Ill-defined sessile mass NA
Contracted bladder Distortion by mass in lateral wall Diffuse mass
Fungating tumor Elevated area, normal mucosa NA
Solid tumor, 6 cm
Cystoscopy Findings
Dl
P
D
NA
T, N
NA
C
Dl
D2
Dl
L
T, P
D2
T,P, L
D2
NA
NA
P
XRT (46 Gy) + Chemo (Vin, MTX, 5FU, cyclo) None
Dl
N, L
DOD DOD DUC DOD DOD
13 12 90 9 1
None Developed pancreatic carcinoma 36 mo later, Chemo (CCNU, 5FU, Dox, mito-C) Metastases to scrotum and penis at 19 mo X R T ( 3 0 G y ) + Chemo (Dox, 5FU) None
DOD DOD DOD A + W DOD
16 8 3 27 5 18
None Repeat TUR at 5 mo, partial cystectomy at 12 mo
None
AWD: extensive local disease including abdominal wall, metastases to pelvic lymph nodes
DOD
Bone mets and extension to abdominal wall and scrotum Chemo (5FU, Dox, mito-C) Local recurrence-Chemo {cis-P, Dox, Cyclo) + XRT Mets to lungs, bones, and lymph nodes; interferon added None
13
None
Status
Treatment
Follow-up (mo)
Additional
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
droxyurea; MTX = methotrexate; Vin = vincristine; DUC = dead of an unrelated cause; DOD = dead of disease; A + W = alive and well (without evidence of disease); AWD = alive with disease; mo = months; NA = not available. • Chemotherapy not specified as intraarterial or intravesical was systemic.
Cystoprostatectomy + Chemo {cis-P, Cyclo, Dox) Partial cystectomy + postop XRT TUR
Intraarterial (5FU, mito-C, Dox) Chemo (5FU, Dox, Mito-C, cis-P) Chemo (5FU, Dox, mito-C, cis-P)
Chemo (cis-P) by arterial infusion
XRT (65 Gy)
B2
L
C
D,P
Initial Treatment TUR + Chemo (5FU hydroxy, MTX + thiotepa [1]) XRT (50 Gy)
Stage
Tumor Location
i
cs
Ring Carcir
M = male; F = rcmale; W = white; Hem = hematuria; D = dome; T = trigone; P = posterior, L = lateral; N = neck; TUR = transurethral resection; XRT * extemal-beam radiotherapy, Gy = Gray; chemo = chemotherapy; I = intravesical; Dox = doxorubicin; cyclo = cyclophosphamide; cis-P = cisplatin; mito-C = mitomycin C; 5 FU = 5 fluorouracil; hydroxy = hy-
Age (yr)i Sex/ Race
TABLE 1. SIGNET-RING CELL C A R C I N O M A , CLINICAL FEATURES
Urinary Bladder Sic,
16
ANATOMIC PATHOLOGY Original Article
Literature Review
'*
*- • • i
In the group as a whole, stage at the time of diagnosis was reported for 34 cases; 5 were stage B; 7, stage C; and 22, stage D. The five-year survival rates for patients in whom tumors were stage B, C, and D were 75%, 38%, and 12%, respectively. Overall, the differences in outcome related to stage did not achieve statistical significance when
^
*
i
*
V "1 t **• *
The total group (our series plus cases culled from the literature) comprised 36 men and 11 women, for a roughly 3:1 male-female ratio. Ages ranged from 34 to 81 years (mean, 55.8 years). Thirty-five of the tumors were of nonurachal origin, 10 were of apparent urachal origin, and in 2 the type were uncertain. Hematuria was a presenting symptom in 25 of 39 cases (64.1%) where indicated; irritative symptoms were reported in 24 of the 39 (61.5%). Cystoscopic or gross features were described for 34 of the cases. In 16 of these (47.1%) no mucosal or mass lesion was present. The most common description was that of an "edematous mucosa" (26.5%), often with the adjective "bullous" applied. In other cases the mucosal surface was erythematous or finely granular. Frequently the bladder wall was described as "thickened" or "fibrotic" on bimanual examination. In more than half the cases (52.9%) some sort of mass lesion was recognized. These ranged from polypoid or pedunculated to sessile to ulcero-infiltrative. In other cases masses were observed to be present within the bladder wall, encroaching on the lumen.
I
,t%
^ * »%\>.„"
&m
r(•
\ t
»
* ~
FIG. 1 (upper). Photomicrograph of primary signet-ring cell adenocarcinoma of the urinary bladder with cells having cytoplasm replaced by a single large mucin containing vacuole. Alcian blue (X250). FlG. 2 (center). Photomicrograph of primary signet-ring cell adenocarcinoma of the urinary bladder with cells having foamy, multivesicular cytoplasm. Hematoxylin and eosin (X300). FlG. 3 (lower). Photomicrograph of primary signet-ring cell adenocarcinoma of the urinary bladder with cells having pleomorphic nuclei and glassy, eosinophilic cytoplasm. Hematoxylin and eosin (X300).
A.J.C.P. • January 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
mixed pattern, one including solid areas and one a mixture of colloid and nonspecific types. Individual signet-ring cells contained nuclei pressed to one edge of the cell and distorted by cytoplasmic mucin that appeared as a single clear vacuole in some tumors (Fig. 1) and as a foamy, multivesicular cytoplasmic material in others (Fig. 2).In other instances the nuclei had a more ovoid appearance, were again pushed to one edge of the cell, and had cytoplasm that stained pink with hematoxylin and eosin (Fig. 3).In these cases the cytoplasm demonstrated strong, diffuse positivity with mucin stains. Uninvolved mucosa was present in material from nine of the cases. Three contained foci of cystitis cystica, but cystitis glandularis and intestinal metaplasia were never found. In one case individual signet-ring cells extensively involved the transitional epithelium, producing a pagetoid appearance (Fig. 4).This was seen both adjacent to and distant from the tumor. Mucin stains used on nine of the tumors showed cytoplasmic positivity in all instances with Alcian blue at pH 2.7, Mayer's mucicarmine, and PAS with digestion. Three of the nine tumors also stained positively with Alcian blue at pH 0.9.
17
GRIGNON ET AL. Urinary Bladder Signet-Ring Carcinoma
FIG. 4. Photomicrograph of transitional epithelium overlying a primary signet-ring cell adenocarcinoma of the urinary bladder illustrating involvement of the epithelium by individual neoplastic cells. Hematoxylin and eosin (X250).
nuclei localized to one edge of a cell that had homogeneous eosinophilic cytoplasm. The latter type of cell typically demonstrated cytoplasmic mucin positivity. Saphir, in his
I
100
150
TIME (MONTHS)
FIG. 5. Kaplan-Meier survival curves of primary signet-ring cell adenocarcinoma of the urinary bladder by stage; differences were statistically significant only for stage B versus stage D (P < 0.05).
Vol. 95 • No. I
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
compared by Kaplan-Meier survival curves (Fig. 5). The difference in five-year survival rates between stage B and stage D disease was statistically significant (P < 0.05); differences between stages B and C and between stages C and D did not reach statistical significance (P > 0.05). Pathologically the lesions encompassed a wide range of descriptions. All cases included in this discussion had at least some component with a diffuse signet-ring pattern. In 27 of the 47 cases (57.4%), the tumors were described as being diffuse, pure signet-ring, or "linitis plastica-like." In the remainder the signet-ring cell component was mixed with some other pattern: colloid in 12, enteric in 1, colloid and enteric in 3, nonspecific adenocarcinoma in 3, and nonspecific adenocarcinoma plus small cell carcinoma in 1. The stage at presentation differed significantly between the two groups: in the pure group only 1 case was stage B (4%), with 4 stage C (17%) and 19 stage D (79%). In contrast, within the mixed group there was a more uniform stage distribution, with four stage B (40%), three stage C (30%), and three stage D (30%). The difference in survival rate between those cases described as "diffuse" and those considered "mixed" was statistically significant (P = 0.004) (Fig. 6). The five-year survival rates for the diffuse and mixed types were 13% and 33%, respectively. The structural appearance of the so-called signet-ring cells has also varied, ranging from the usual signetring cell with a thin distorted nucleus compressed by a large cytoplasmic mucin vacuole to cells with pleomorphic
18
ANATOMIC PATHOLOGY Original Article 2 1H|
FlG. 6. Kaplan-Meier survival curves of primary signet-ring cell adenocarcinoma comparing those tumors having a pure, diffuse pattern (d) with those of mixed pattern (m); the difference was statistically significant (P = 0.004).
original description, referred to these cells as "monocytelike."1 Thirty-five of the cases (74.5%) were considered to be nonurachal and 10 (21.3%) urachal. In two cases (4.3%) the type was uncertain. Within the nonurachal group were 29 men and 6 women, whose mean age was 56.9 years. The urachal group consisted of six men and four women whose mean age was 52.3 years. The difference in survival rates between these groups was statistically significant (P = 0.005): thefive-yearsurvival rate was 44% for patients with urachal tumors and 15% for those with nonurachal tumors (Fig. 7). DISCUSSION Primary adenocarcinoma of the urinary bladder is uncommon, accounting for 0.5-2.0% of all bladder malignancies.7 The signet-ring variant, first reported in 19551 and since described in itself (at least 39 additional cases in the English literature1012"39) and within vesical adenocarcinoma series (17 cases2"9), is reported to account for between 2%7 and 24%6 of primary vesical adenocarcinomas. A review of seven series in which signet-ring cell carcinoma is discussed yields a mean frequency of 8.6% (20 of 233).2"8 We reviewed a total of 76 primary ade-
TIME (MONTHS)
FlG. 7. Kaplan-Meier survival curves of primary signet-ring cell adenocarcinoma of the urinary bladder comparing those of nonurachal type (nu) with the urachal type (u); the difference was statistically significant (P = 0.005).
A.J.C.P. • January 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
TIME (MONTHS)
nocarcinomas and found, using our criteria, 12 cases of the signet-ring cell variant (15.8%). Despite these reports, this entity has not been adequately defined. Saphir's original report described signet-ring cells as present "in a substantial number."1 Other authors refer to signet-ring cells being the "predominant"35 or "primary"15 cell type. For our study, we included only those cases having at least in part a diffuse, linitis plastica-like pattern of growth. We did not include tumors with a papillary or invasive transitional carcinoma component, although seven of the previously reported signet-ring cell cases included a transitional cell component.51012'"16 To date, no studies have evaluated signet-ring cell carcinomas statistically, because reports have been limited to single cases or series of two or three cases only. In this study we have reported the features seen in 12 cases from M. D. Anderson Cancer Center. Furthermore, to evaluate the significance of a range of factors, we have culled 35 additional cases from the literature and combined them with our own. The clinical and pathologic features described for the literature cases we selected are similar to those of our cases. Patients tend to present in a similar fashion with invasive transitional cell carcinoma of the bladder, with hematuria and irritative symptoms. The tumors most fre-
GRIGNON ET AL. Urinary Bladder Si> •t-Ring Carcinoma
designation "signet-ring cell carcinoma" to those tumors having this pattern. The histogenesis of nonurachal signet-ring cell carcinoma of the bladder is indefinite; however, several possibilities exist. The metaplastic potential of the urothelium has been well described, and it is presumed that most adenocarcinomas arise by this route.7 These changes may be present along the surface (intestinal metaplasia) or in areas of cystitis cystica (cystitis glandularis). In series of primary vesical adenocarcinomas, intestinal metaplasia or cystitis glandularis or both are found in between 14%8 and 66%2 of cases. Despite this, fairly few cases demonstrating transition from one of these lesions to adenocarcinoma have been described.42 In the current series, none of the nine diffuse signet-ring cell tumors evaluable had either of these alterations. This experience is similar to that reported in the literature: among 14 cases with a pure diffuse signet-ring structure, none showed either cystitis glandularis or intestinal metaplasia. 1,14,2U24,26,32~34,36 Isolated signet-ring cells in otherwise normal transitional epithelium have been described occasionally. In the case reported by Braun and associates,24 isolated signet-ring cells were found overlying the tumor. This feature was also present in one of the three cases reported by Choi and associates13; the tumor was composed predominantly of signet-ring cells with foci of squamous cell carcinoma. In our series we found one case in which the overlying transitional epithelium was extensively infiltrated by signet-ring cells. Because individual mucin-secreting cells may be found scattered in nonneoplastic transitional epithelium, it is hypothetically possible that diffuse signetring cell adenocarcinoma arises from these cells. However, it seems more likely, given the rarity of the finding, that these cases represent examples of pagetoid spread by the tumor. A third possible origin for signet-ring cell carcinoma would be a metaplastic change in transitional cell carcinoma. In six reported cases,12"17 areas of transitional cell carcinoma were admixed with the signet-ring cell variant. In the case reported by Austin and Safford,12 the original tumor was a papillary transitional cell carcinoma with prominent glandular metaplasia, and over time it developed into a predominantly signet-ring cell tumor. In our series we excluded cases that had a papillary or invasive transitional cell carcinoma component, and so this phenomenon was not seen. In summary, we have presented 12 cases of primary signet-ring cell adenocarcinoma of the urinary bladder and combined these with 35 additional cases from the literature. Statistical analysis had demonstrated a statistically significant worse prognosis for those cases having a pure, diffuse signet-ring pattern; those of nonurachal
Vol. 95 •No. 1
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
quently arise in the sixth decade of life, and there is a male preponderance. Patients tend to present with advanced disease—65% of all cases are stage D—and with metastases, prompting a search for a primary site. It is therefore important to realize that cystoscopically the bladder mucosa may be quite unremarkable, showing only edematous, erythematous, or elevated "normal" mucosa. In these instances random biopsies may reveal the characteristic signet-ring cells in the lamina propria. Stage has been reported to correlate with outcome for bladder adenocarcinomas in general.3,8'40,41 In only one study have data been analyzed statistically, confirming this impression.3 In the series of cases collected in this study, stage at diagnosis was a statistically significant predictor of outcome only when stage B disease was compared with stage D. Traditionally, adenocarcinomas of the urinary bladder have been separated into those arising from the urachus and those within the bladder proper. This division has both treatment and prognostic implications that can be analyzed statistically. In the current review, patients with signet-ring cell carcinoma of urachal origin were younger than those with the nonurachal type and were more equally distributed by sex. These tendencies have been previously described for bladder adenocarcinomas in general.3 The difference in survival rate proved to be highly significant between these two groups (P = 0.005), with those with urachal tumors doing much better. The survival curves also are significantly different; the tendency for early death in the nonurachal group contrasts with the rapid decline in survival seen between three and six years for the urachal cases. This difference in survival between patients with the urachal and nonurachal types was previously reported by Kondo and associates.31 Pathologically, we separated these tumors into two subgroups, those that had a diffuse or linitis plastica-like structure and those in which the signet-ring cells were mixed with other adenocarcinoma patterns. This separation proved to be valid not only histologically, but also with respect to outcome. The difference in survival rates between these groups was statistically significant (P = 0.004): the pure diffuse form had a much worse outcome. In reviewing our experience with primary adenocarcinomas as a whole, the five-year survival for the nonsignet-ring cell adenocarcinomas was 47% (unpublished data). This is similar to the experience of Thomas and associates8 (overall five-year survival, all adenocarcinomas, 42%). In contrast, Anderstrom and associates3 reported an overall five-year survival rate of only 18% in the 64 cases (all types) they studied. Because of the extremely poor survival rate associated with the pure, diffuse signet-ring histologic characteristics, we would restrict the
19
20
ANATOMIC PATHOLOGY
Original Article origin; and those presenting at late stage. The histogenesis of these rare tumors remains obscure. Acknowledgments. The authors thank Mona Poitras for excellent secretarial assistance and Penny Brasher, Department of Epidemiology and Biostatistics, The University of Western Ontario, London, for statistical analysis. They thank the following physicians for providing pathologic materials: A. L. Guarda, M.D., Orlando, Florida; R. A. Roe, M.D., Little Rock, Arkansas; J. F. Nickerson, M.D., Atlanta, Georgia; J. B. White, M.D., Fort Worth, Texas; R. P. Smith, M.D., Spokane, Washington; and H. C. Moore, M.D., Topeka, Kansas.
REFERENCES
A.J.C.P. • January 1991
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
1. Saphir O. Signet-ring cell carcinoma of the urinary bladder. Am J Pathol 1955;31:223-231. 2. Abenoza P, Manivel C, Fraley EE. Primary adenocarcinoma of urinary bladder clinicopathologic study of 16 cases. Urology 1987;29: 9-14. 3. Anderstrom C, Johansson SL, von Schultz L. Primary adenocarcinoma of the urinary bladder: a clinicopathologic and prognostic study. Cancer 1983;52:1273-1280. 4. Fuselier HA Jr, Bran nan W, Ochsner MG, Matos LH. Adenocarcinoma of the bladder as seen at Ochsner medical institutions. South Med J 1978;71:804-806. 5. Johnson DE, Hogan JM, Ayala AG. Primary adenocarcinoma of the urinary bladder. South Med J 1972;65:527-530. 6. Melicow MM. Tumors of the urinary bladder: a clinicopathological analysis of over 2500 specimens and biopsies. J Urol 1955;74: 498-521. 7. Mostofi FK, Thomson RV, Dean AL Jr. Mucous adenocarcinoma of the urinary bladder. Cancer 1955;8:741-758. 8. Thomas DG, Ward AM, Williams JL. A study of 52 cases of adenocarcinoma of the bladder. Br J Urol 1971;43:4-15. 9. Johnson DE, Hodge GB, Abdul-Karim FW, Ayala AG. Urachal carcinoma. Urology 1985;26:218-221. 10. Blute ML, Engen DE, Travis WD, Kvols LK. Primary signet ring cell adenocarcinoma of the bladder. J Urol 1989;141:17-21. 11. Marshall VF. The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J Urol 1952;68:714-723. 12. Austin GE, Safford J. Signet ring cell carcinoma of bladder. Urology 1978;12:458-460. 13. Choi H, Lamb S, Pintar K, Jacobs SC. Primary signet-ring cell carcinoma of the urinary bladder. Cancer 1984;53:1985-1990. 14. DeFillipo N, Blute R, Klein LA. Signet-ring cell carcinoma of bladder: evaluation of three cases with review of literature. Urology 1987;29:479-483. 15. Gonzalez E, Fowler MR, Venable DD. Primary signet ring cell adenocarcinoma of the bladder (linitis plastica of the bladder): report of a case and review of the literature. J Urol 1982; 128:10271030. 16. Naeim F, Schlezinger RM, de la Maza LM. Primary signet ring cell carcinoma of the bladder: report of a case and review of the literature. J Urol 1972;108:274-276. 17. Payan HM, Mendoza C Jr, Cabinum D, Gerwig WH Jr. Primary signet ring cell carcinoma of the urinary bladder. Arch Surg 1966;92:958-959. 18. Bernath AS, Addonizio JC, Thelmo W, Davidian MD, Herman B. Clinicopathological conference: unusual cause of bilateral ureteral obstruction. J Urol 1982; 127:1169-1171. 19. Bernstein SA, Reuter VE, Carroll PR, Whitmore WF Jr. Primary signet-ring cell carcinoma of urinary bladder. Urology 1988;31: 432-436.
20. Dreffke F, Linde JVD, Babiel H. Signet ring cell carcinoma of the urinary bladder. Z Urol Nephrol 1987;80:75-80. 21. Reading LC, D'Onofrio GMD, Tulloch AGS, Knight DE, Walters MNI, Ojeda VJ. Primary linitis plastica carcinoma of urinary bladder. Urology 1983;22:310-313. 22. Rosas-Uribe A, Luna MA. Primary signet ring cell carcinoma of the urinary bladder: report of two cases. Arch Pathol 1969;88:294297. 23. Bowlby LS, Smith ML. Signet-ring cell carcinoma of the urinary bladder: primary presentation as a Krukenberg tumor. Gynecol Oncol 1986;25:376-381. 24. Braun EV, Ali M, Fayemi AO, Beaugard E. Primary signet ring cell carcinoma of the urinary bladder: review of the literature and report of a case. Cancer 1981;47:1430-1435. 25. Corwin SH, Tassy F, Malament M, Grady HG. Rare signet ring cell variant of mucinous adenocarcinoma of the bladder. J Urol 1971;106:697-700. 26. DeMay RM, Grathwohl MA. Signet-ring-cell (colloid) carcinoma of the urinary bladder: cytologic, histologic and ultrastructural findings in one case. Acta Cytol (Baltimore) 1985;29:132-136. 27. DeTure FA, Dein R, Hackett RL, Drylie DM. Primary signet ring cell carcinoma of bladder exemplifying vesical epithelium multipotentiality. Urology 1975;6:240-244. 28. Hirasawa S, Oki M, Abe H, et al. A case of signet ring cell carcinoma of the urinary bladder. Hinyokika Kiyo 1985;31:2049-2053. 29. Jakse G, Schneider HM, Jacobi GH. Urachal signet-ring cell carcinoma, a rare variant of vesical adenocarcinoma: incidence and pathological criteria. J Urol 1978;120:764-766. 30. Kitamura H, Sumikawa T, Fukuoka H, Kanisawa M. Primary signetring cell carcinoma of the urinary bladder: report of two cases with histochemical studies. Acta Pathol Jpn 1985;35:675-686. 31. Kondo A, Ogisu B, Mitsuya H. Signet-ring cell carcinoma involving the urinary bladder: report of a case and review of 21 cases. Urol Int 1981;36:373-379. 32. Kums JJM, van Helsdingen PJRO. Signet-ring cell carcinoma of the bladder and the prostate: report of 4 cases. Urol Int 1985;40: 116-119. 33. Ponz M, Luzuriaga J, Robles JE, et al. Primary signet-ring cell carcinoma of the urinary bladder (linitis plastica). Eur Urol 1985; 11: 212-214. 34. Poore E, Egbert B, Jahnke R, Kraft JK. Signet ring cell adenocarcinoma of the bladder: linitis plastica variant. Arch Pathol Lab Med 1981;105:203-204. 35. Sagalowsky A, Donohue JP. Sixteen-year survival with metastatic signet ring cell bladder carcinoma. Urology 1980;15:501-504. 36. Tanaka T, Kanai N, Sugie S, et al. Primary signet-ring cell carcinoma of the urinary bladder. Pathol Res Pract 1987;182:130-132. 37. Townsend GH, Sarma DP. Signet-ring cell carcinoma of the urinary bladder. J La State Med Soc 1987;139:47-48. 38. Yoshida H, Iwata H, Ochi K, Yoshida A, Fukunishi R. Primary signet-ring cell carcinoma of urinary bladder. Urology 1981;17: 481-483. 39. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: problems in interpretation. A report of three cases and review of the literature. Int J Gynecol Pathol 1988;7:197211. 40. Jacobo E, Loening S, Schmidt JD, Culp DA. Primary adenocarcinoma of the bladder: a retrospective study of 20 patients. J Urol 1977;117:54-56. 41. Kramer SA, Bredael J, Croker BP, Paulson DF, Glenn JF. Primary non-urachal adenocarcinoma of the bladder. J Urol 1979; 121: 278-281. 42. Lin JI, Yong HS, Tseng CH, Marsidi PS, Choy C, Pilloff B. Diffuse cystitis glandularis associated with adenocarcinomatous change. Urology 1980;15:411-415.
