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Mayo Clin Proc. 2010 December; 85(12): 1130–1136.
PMCID: PMC2996149

Primary Signet Ring Cell Carcinoma of the Prostate

Abstract

Nine patients treated with primary signet ring cell carcinoma of the prostate were identified among 29,783 cases of prostate cancer evaluated at Mayo Clinic from January 15, 1970, until January 2, 2009. A PubMed search of the English-language literature published from January 1, 1980, to January 1, 2010, was then performed using the key words signet ring cell and prostate, identifying 42 cases. This study reviews those cases, along with the additional 9 reported herein, and evaluates clinical characteristics, histologic diagnoses, treatment modalities, and outcomes. Mean age at diagnosis was 68 years (range, 50-85 years), and mean prostate-specific antigen level was 95.3 ng/mL (range, 1.9-536.0 ng/mL; to convert to μg/L, multiply by 1). Most patients (66%) had non–stage IV carcinoma, the most common Gleason sum was 8 (33%), and mean survival was 29 months. The presence of a primary signet ring cell carcinoma of the prostate was best confirmed by negative findings on gastrointestinal work-up, a positive stain for prostate-specific acid phosphatase, and negative carcinoembryonic antigen test results.

GI = gastrointestinal; PSA = prostate-specific antigen; PSAP = prostate-specific acid phosphatase; RARP = robot-assisted radical prostatectomy; SRCC = signet ring cell carcinoma; TURP = transurethral resection of the prostate

Signet ring cell carcinoma (SRCC) of the prostate is a rare tumor characterized by an intracytoplasmic vacuole compressing the nucleus into a crescent shape at the cellular level. Although SRCC is primarily found in the stomach and colon, it can also be found in the pancreas, breast, thyroid, bladder, and prostate. Our review of the English-language literature identified only 42 cases of SRCC of the prostate through case reports and case series. Several studies list up to 17 patients; however, they are not independently reported and therefore could not be included in this analysis. Establishing a diagnosis of SRCC of the prostate requires histopathologic examination of the tissue, a negative gastrointestinal (GI) work-up (including computed tomography of the abdomen, a colonoscopy, and an esophagogastroduodenoscopy), and various stains that help localize the primary site of cancer to the prostate. The prognosis of patients with SRCC of the prostate is grim, and recommendations for treatment are sparse because so few cases are reported. This study reviews the established pathologic criteria, treatment, and outcomes of prostatic SRCC and contributes 9 additional patients to the available literature.

PATIENTS AND METHODS

With the approval of the Mayo Clinic Institutional Review Board, tumor registries from Mayo Clinic campuses in Arizona, Florida, and Rochester, MN, were queried to identify patients with documented SRCC of the prostate. The medical records of the 9 identified patients were reviewed thoroughly. Tumor registry data were cross-referenced with Social Security death records to determine survival.

A PubMed search was then performed of the English-language literature published from January 1, 1980, to January 1, 2010, using the key words signet ring cell and prostate. Only cases from the English-language literature describing SRCC with a primary prostate tumor were included; studies examining mucinous adenocarcinoma of the prostate, thought to be a variant of mucinous neoplasm rather than a primary SRCC, were excluded. Individual cases were outlined, and the articles were summarized regarding patient age, survival, and treatment. When available, the stage, grade, prostate-specific antigen (PSA) level, Gleason sum, histologic characteristics (special staining), and GI work-up were evaluated.

RESULTS

According to the tumor registries, 29,783 cases of prostate cancer were evaluated at Mayo Clinic from January 15, 1970, until January 2, 2009. Among these, only 9 cases of SRCC of the prostate were identified (Table 1), for an incidence of 30 per 100,000 cases of prostate cancer. Details of these cases follow.

TABLE 1.
Characteristics of Patients With Signet Ring Featuresa,b

Case 1

A 58-year-old man presented with lower urinary tract symptoms. Fourteen years before presentation, he had had a perianal abscess and a rectocutaneous fistula that ultimately required an abdominoperineal resection and that proved benign on pathologic analysis. At the time of presentation, he was found to have left ureteral obstruction and underwent open left nephrostomy tube placement and transurethral resection of the prostate (TURP). Pathology demonstrated a grade 4 adenocarcinoma with signet ring cell features. The patient underwent radiation therapy, the exact dosage of which could not be determined from a review of the record, followed by multiple resections of the prostate. He never underwent a formal GI work-up. He died 2 years later of peritoneal carcinomatosis of a primary tumor of unknown origin. The patient was treated at an outside facility immediately before his death. Thus, the pathology and events surrounding his death are unclear.

Case 2

Three years after undergoing TURP (with findings of benign tissue), an 82-year-old man presented to an outside facility with back pain, hip pain, and abnormal findings on a digital rectal examination. He underwent a biopsy of the prostate, which revealed grade 4 adenocarcinoma of the prostate with signet ring cell features. The patient subsequently underwent bilateral orchiectomy. He died 5 months later of hypotensive shock as a result of pneumonia.

Case 3

A 68-year-old man from Mexico presented with abrupt onset of serious bone pain that aroused suspicion for metastatic prostate cancer. The patient underwent a biopsy and was found to have a grade 3 to 4, stage VI adenocarcinoma of the prostate with signet ring cell features. The patient was initially treated with a dose of intramuscular luprolide and, after presenting to our institution, underwent a bilateral orchiectomy. One year later, the patient underwent palliative radiation therapy for osseous metastasis causing substantial pain. The patient died soon after radiation, within 11 months of diagnosis.

Case 4

Eleven months after undergoing TURP (with findings of benign tissue), a 65-year-old man presented with recurrent obstructive symptoms. The patient underwent a second TURP and was found to have a grade 3 adenocarcinoma of the prostate with signet ring cell features. A bone scan demonstrated bony metastasis. The patient underwent bilateral orchiectomy and began taking stilbestrol. The patient died at an outside institution 2 years later from complications arising from metastatic SRCC of the prostate.

Case 5

A 67-year-old man underwent a retropubic radical prostatectomy in 1988 at an outside institution. Pathology demonstrated a grade 3 of 4, a Gleason 3+5=8, N0, M0, stage C adenocarcinoma of the prostate with signet ring cell features. The patient developed a PSA recurrence and was treated initially with leuprolide. Two years later, he had a PSA failure on androgen blockade and was referred to our institution. The patient underwent contrast-enhanced computed tomography, the results of which were normal. There was no record of a colonoscopy, and a bone scan at the time of consultation (4 years after prostatectomy) was positive for distant metastases. The patient continued taking leuprolide and remained asymptomatic at his last follow-up in 1993. The patient died 9 years after his initial diagnosis of unknown causes.

Case 6

A 67-year-old man who was being evaluated for a recurrent polyp in the hepatic flexure had abnormal findings on digital rectal examination. Biopsy of the prostate was performed, and pathology showed a Gleason 4+5=9 adenocarcinoma of the prostate with signet ring cell features involving 25% of the cores. The patient's pretreatment PSA level was 1.9 ng/mL (to convert to μg/L, multiply by 1). Other than the colonic polyp, no other evidence of malignancy was found on computed tomography, bone scans, and multiple colonoscopies. The patient elected to undergo hormone therapy while he underwent a right hemicolectomy for the polyp, which was found to be a tubular adenoma with high-grade dysplasia. The patient underwent external-beam radiation for a total dose of 7600 Gy in 38 fractions. After completing his radiation, he stopped his hormonal therapy. To date, he has no detectable PSA level.

Case 7

A 79-year-old man presented with a 3-year history of intermittent gross hematuria. Cystoscopy revealed a 1.5-cm mass in his prostatic urethra. On biopsy, a grade 4/4 invasive adenocarcinoma of the prostate with signet ring cell features was discovered near the bladder neck. The patient's PSA level at the time of diagnosis was 5.9 ng/mL. The patient underwent a full work-up, including a colonoscopy with biopsy specimens negative for neoplasia. He then underwent cystoprostatectomy with ileal conduit secondary to the lesion location. Final pathologic diagnosis was T3bN1M0. The tumor was positive for cytokeratin 7 and 20 and for homeobox protein CDX2 but negative for PSA, making a prostatic origin less likely. However, because of the negative GI work-up and the presence of prostate cancer cells of normal appearance in addition to the signet ring cells, we elected to evaluate this patient in our series. The patient died within 4 months of complications from urosepsis.

Case 8

A 51-year-old man presented with a history of a robotassisted radical prostatectomy (RARP) performed at an outside facility. He was found to have a Gleason 3+5=8, T3bN0MX adenocarcinoma with signet ring cell features and positive margins. The patient underwent a complete evaluation at the outside facility, including imaging and colonoscopy. However, only computed tomographic and bone scan findings were reviewed at our institution, which were negative for evidence of metastasis or for a primary tumor of a different origin. The patient underwent external-beam radiation therapy at an outside institution (dose unspecified) and is currently alive with no evidence of malignancy.

Case 9

A 59-year-old man presented with an elevated PSA level of 4.8 ng/mL. He underwent a transrectal needle biopsy demonstrating a Gleason 4+4=8 adenocarcinoma with signet ring cell features (Figure). A thorough GI work-up was performed; cystoscopy ruled out metastasis or a primary tumor of a different origin. Physical examination demonstrated an enlarged gland, with minimal induration on the left. The patient underwent a RARP with bilateral pelvic lymphadenectomy. Final pathologic stage was Gleason 4+4=8, T2bN0M0 with signet ring cell features. The patient began receiving adjuvant hormonal therapy and will continue this therapy for 2 years.

FIGURE.
Signet ring cells seen on biopsy specimen (patient 9).

Literature Review

Twenty articles were identified in the English-language literature and are summarized in Table 2. In total, 42 patients with SRCC of the prostate were included in the review. Our experience added an additional 9 patients. A summary of the characteristics of all 51 patients is presented in Table 3. The PSA level varied widely, from 1.9 to 536 ng/mL. More patients (33%) presented with stage 4 cancer than with any other stage of cancer. The most common Gleason sum was 8 (33%), and a combination of surgery, radiation, and hormonal therapy was most often used (41%), followed closely by hormonal therapy alone (31%).

TABLE 2.
Summary of Cases from 20 Referencesa
TABLE 3.
Characteristics of 51 Patients With Primary Signet Ring Cell Carcinoma of the Prostatea,b

The minority of patients 31% (16/51) had a documented GI work-up to determine the primary SRCC source. For pathologic diagnosis, the most common stains performed were the periodic acid–Schiff stain, performed in 70% of patients; the prostate-specific acid phosphatase (PSAP) stain, performed in 70% of patients; and the Alcian blue stain, performed in 62% of patients. These were positive in 50% (18/36), 87% (34/39), and 44% (14/32) of cases, respectively. Carcinoembryonic antigen (39%) and mucicarmine (39%) were less commonly used and were positive in 20% (4/20) and 40% (8/20) of patients, respectively. The extent of signet ring cell involvement of the specimen was reported in 76% (39/51) of cases. Of these, 84% (33/39) documented more than 20% of the tumor-containing signet ring cells.

The mean overall survival was 28 months in the compiled group. Evaluating treatment-specific survival, the highest survival (mean, 45 months) was seen in the group receiving a combination of surgical and hormonal therapy, followed by the radiation and hormonal therapy group (mean, 37 months). The shortest survival was seen after surgical therapy alone, which reflected one patient who died of sepsis unrelated to his cancer 4 months after surgery.

DISCUSSION

Signet ring is a term used to describe the histologic appearance of a tumor cell characterized by compression of the nucleus into the form of a crescent by a large cytoplasmic vacuole.14 Signet ring cell changes were first described in 19811 and are estimated to occur in 2.5% of cases of adenocarcinoma of the prostate.21 Guerin et al14 proposed that SRCC should be classified as a variant of high-grade adenocarcinoma rather than a separate histologic diagnosis. In support of this proposition, SRCC is often found in the presence of other high-grade prostatic adenocarcinoma patterns. Regardless of histologic classification, the grim prognosis and rarity of SRCC of the prostate warrant closer investigation.

On the basis of the combined data from this study and the literature review, the average age at diagnosis was 68 years (range, 50-85 years), which is comparable to the previously reported 68.2 years.13 The mean survival was 29 months. Reports indicate that up to 75% of cases present with locally advanced or metastatic disease at the time of diagnosis.16 However, many of these patients were evaluated before the PSA era, which may account for their late presentations. During the early years of the study period, patients at Mayo Clinic were analyzed using a grading system unique to this institution. In this evaluation, a Gleason sum of 8 is equal to a grade of 3 or 4, whereas a Gleason sum of 7 approximates a grade of 2 or 3. We found that more patients presented with non–stage IV than with stage IV disease (66% vs 33%). Fujita et al16 presented a case series of 42 patients with SRCC, which demonstrated that stage IV is a poor predictor of survival. Interestingly, neither PSA levels nor treatment modalities were predictive of survival in that group of patients. Although currently available survival data are varied, 5-year survival is dismal by all reports. For instance, Fujita et al16 reported overall survival rates of 82.0% at 1 year and 11.7% at 5 years, whereas Saito and Iwaki22 reported a 5-year survival rate of 0% for their 17 reported cases. Saito and Iwaki further found that all patients had advanced stage disease at presentation and poor response to hormones. Importantly, neither of these studies presented these patients independently and, for this reason, could not be included in our analysis.

Diagnosis

Multiple tests have been established to assist in the diagnosis of SRCC of the prostate. Because the GI tract is a more common location for signet ring cells, many of these tests focus on differentiating a primary tumor of the prostate from one located in the GI tract. In our review of the literature, only 31% of patients had a reported GI work-up. Most of the 9 cases at our own institution did not undergo formal GI evaluation, and one patient with negative findings on work-up had histologic criteria supporting a GI primary tumor on final pathology. Clearly, it is important to differentiate between tumors of GI and prostate origin because the treatment of a metastatic GI primary tumor would require additional and alternative therapies. When analyzing the patients from our series who did not undergo a formal GI work-up, we can only assume that the prostate was the primary source using the pattern of spread and response to hormonal therapy as support.

Histologic criteria for SRCC of the prostate are highly variable in the available literature. Some publications have reported that the cells should stain negative for leukocyte common antigen and alpha–smooth muscle actin.13 Signet ring carcinoma cells also usually stain negative for carcinoembryonic antigen; however, about 20% of cases in the literature report positive stains.23 Reports concerning whether cells should stain positive for PSA and PSAP have been inconsistent, although it appears most do.3 In this investigation, 87% of those actually tested for PSA and PSAP had positive stains. Other immunohistochemical stains that can be used to ensure a primary prostate tumor include α-methylacyl coenzyme A racemase (P504S)24,25 and cytokeratin 5/6.26 The cytoplasmic vacuoles can contain lipids or mucin12 and stain positive with mucicarmine in about 50% of cases, PAS in about 60%, and alcian blue in 60%.12 Some authors suggest that malignant signet cells should constitute more than 20% to 50% of the tumor21,23; however, previous case reports have not followed this strict criterion, and cases with 5% to 50% have been accepted as SRCC of the prostate.3,6 In our review of the literature, 84% of patients had reports of signet ring cells constituting more than 20% of the specimen. Perhaps the clearest indication of a primary tumor of prostate origin is the presence of prostatic adenocarcinoma cells of more typical appearance in the specimen.23

Treatment Decisions

Historically, the treatment approach for SRCC has been similar to that for traditional adenocarcinoma of the prostate, involving variable combinations of hormonal therapy, radiation, and surgery. However, on the basis of the available cases, the response to hormonal therapy is unpredictable. No definitive explanation for this variability has been given; however, Lilleby et al18 reported a case of SRCC treated with neoadjuvant hormonal therapy and radiotherapy with a favorable response still noted at 12 months of follow-up. Moreover, Kanematsu and Hiura11 reported a case of primary SRCC with an undetectable PSA level 3 years after a radical prostatectomy and preoperative androgen blockade. Akagashi et al15 further reported a case of an undetectable PSA level 20 months after being treated with complete androgen blockade. They also reviewed 5 other cases treated with androgen blockade, noting variable survival rates, with all 5 reported patients dying within 25 months of treatment.15 In the current series, case 6 was treated with hormonal therapy and external-beam radiation, with no evidence of disease at 4 years of follow-up. Twelve months after RARP, case 9 is alive and free of disease and is currently undergoing hormone ablative treatments. Although the numbers are small in our literature review, the highest survival (mean, 45 months) was found in the 4 patients treated with a combination of surgery and hormone ablation. No single treatment modality is ideal for treating SRCC, but we think that an aggressive multimodal treatment paradigm should be considered. This will likely rely on early hormonal intervention and aggressive surgical resection (including node dissection for staging), potentially followed by adjuvant radiation therapy.

Other variants of prostate adenocarcinoma are often confused with SRCC. Reyes et al27 described 3 cases in which high-grade prostatic intraepithelial neoplasia had adjacent SRCC. Mucinous carcinoma with signet ring cells is diagnosed when at least 25% of the tumor is constituted of extracellular mucin and less than 25% of tumor cells feature signet rings. Survival rates have been reported to be 16.7% at 3 years for this particular subtype.22 However, caution must be used when making this diagnosis because smooth muscle and lymphocytes can take on a signet ring appearance after transurethral resection and needle biopsy. This is an artifact secondary to changes that the cells undergo during TURP and should not be mistaken for carcinoma.28 When tumor cells are numerous and infiltrate or destroy the prostatic glands, invasion by signet ring cell carcinoma is suggested. Positive stains for leukocyte common antigen, PSA, and cytokeratins (AE1/AE3 or CAM) may help differentiate true malignancy from artifact in these cases.12 Signet ring cells have also been identified in benign prostate nodules.29

Our review has clear limitations. First, it is retrospective and considers only a small number of patients. Furthermore, because of the rarity of the disease, the review spans more than 30 years. Thus, many of the patients described were diagnosed as having the disease before the PSA era and likely presented at an advanced stage. Early cases did not use the same stains available today to rule out a primary tumor of GI origin. Furthermore, some of the 9 patients we presented were treated at an outside institution, and pathologic specimens were not available for full analysis. The exact treatment doses of radiation and hormonal therapies were not reported, which confounds evaluation of survival by modality. By evaluating cases presented in the literature in addition to the cases presented herein, we hope to add to the available data in treating this difficult condition.

CONCLUSION

Signet ring cell carcinoma, a rare and aggressive subtype of adenocarcinoma of the prostate, requires careful diagnosis via thorough evaluation and specialized staining processes. Although the rarity of this disease does not allow for the establishment of absolute recommendations, treatment is often similar to traditional radical management of cancer of the prostate, with emphasis on an aggressive multimodal approach. Patients with SRCC of the prostate have an ominous prognosis and should be treated aggressively and followed up closely.

REFERENCES

1. Giltman LI. Signet ring adenocarcinoma of the prostate. J Urol. 1981;126(1):134-135. [PubMed]
2. Kums JJ, van Helsdingen PJ. Signet-ring cell carcinoma of the bladder and the prostate: report of 4 cases. Urol Int. 1985;40(2):116-119. [PubMed]
3. Ro JY, el-Naggar A, Ayala AG, Mody DR, Ordóñez NG. Signet-ring-cell carcinoma of the prostate: electron-microscopic and immunohistochemical studies of eight cases. Am J Surg Pathol. 1988;12(6):453-460. [PubMed]
4. Remmele W, Weber A, Harding P. Primary signet-ring cell carcinoma of the prostate. Hum Pathol. 1988;19(4):478-480. [PubMed]
5. Hejka AG, England DM. Signet ring cell carcinoma of prostate: immunohistochemical and ultrastructural study of a case. Urology. 1989;34(3):155-158. [PubMed]
6. Alline KM, Cohen MB. Signet-ring cell carcinoma of the prostate. Arch Pathol Lab Med. 1992;116(1):99-102. [PubMed]
7. Catton PA, Hartwick RW, Srigley JR. Prostate cancer presenting with malignant ascites: signet-ring cell variant of prostatic adenocarcinoma. Urology. 1992;39(5):495-497. [PubMed]
8. Ben-Izhak O, Lichtig C. Signet-ring cell carcinoma of the prostate mimicking primary gastric carcinoma. J Clin Pathol. 1992;45(5):452-454. [PMC free article] [PubMed]
9. Skodras G, Wang J, Kragel PJ. Primary prostatic signet-ring cell carcinoma. Urology. 1993;42(3):338-342. [PubMed]
10. Leong FJ, Leong AS, Swift J. Signet-ring carcinoma of the prostate. Pathol Res Pract. 1996;192(12):1232-1238. [PubMed]
11. Kanematsu A, Hiura M. Primary signet ring cell adenocarcinoma of the prostate treated by radical prostatectomy after preoperative androgen deprivation. Int J Urol. 1997;4(5):522-523. [PubMed]
12. Torbenson M, Dhir R, Nangia A, Becich MJ, Kapadia SB. Prostatic carcinoma with signet ring cells: a clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature. Mod Pathol. 1998;11(6):552-559. [PubMed]
13. Kuroda N, Yamasaki I, Nakayama H, et al. Prostatic signet-ring cell carcinoma: case report and literature review. Pathol Int. 1999;49(5):457-461. [PubMed]
14. Guerin D, Hasan N, Keen CE. Signet ring cell differentiation in adenocarcinoma of the prostate: a study of five cases. Histopathology. 1993;22(4):367-371. [PubMed]
15. Akagashi K, Tanda H, Kato S, et al. Signet-ring cell carcinoma of the prostate effectively treated with maximal androgen blockade. Int J Urol. 2003;10(8):456-458. [PubMed]
16. Fujita K, Sugao H, Gotoh T, Yokomizo S, Itoh Y. Primary signet ring cell carcinoma of the prostate: report and review of 42 cases. Int J Urol. 2004;11(3):178-181. [PubMed]
17. Yoshimura K, Fukui I, Ishikawa Y, Maeda H, Yamauchi T, Kawai T. Locally-confined signet-ring cell carcinoma of the prostate: a case report of a long-term survivor. Int J Urol. 1996;3(5):406-407. [PubMed]
18. Lilleby W, Axcrona K, Alfsen GC, Urnes T, Hole KH. Diagnosis and treatment of primary signet-ring cell carcinoma of the prostate. Acta Oncol. 2007;46(8):1195-1197. [PubMed]
19. Derouiche A, Ouni A, Kourda N, Belhadj K, Ben Jilani S, Chebil M. A new case of signet ring cell carcinoma of the prostate. Clin Genitourin Cancer. 2007;5(7):455-456. [PubMed]
20. Matsuoka Y, Arai G, Ishimaru H, Takagi K, Ito Y. Primary signet-ring cell carcinoma of the prostate. Can J Urol. 2007;14(6):3764-3766. [PubMed]
21. Torbenson M, Dhir R, Nangia A, Becich MJ, Kapadia SB. Prostatic carcinoma with signet ring cells: a clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature. Mod Pathol. 1998;11(6):552-559. [PubMed]
22. Saito S, Iwaki H. Mucin-producing carcinoma of the prostate: review of 88 cases. Urology. 1999;54(1):141-144. [PubMed]
23. Randolph TL, Amin MB, Ro JY, Ayala AG. Histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. Mod Pathol. 1997;10(6):612-629. [PubMed]
24. Jiang Z, Woda BA, Rock KL, et al. P504S: a new molecular marker for the detection of prostate carcinoma. Am J Surg Pathol. 2001;25(11):1397-1404. [PubMed]
25. Zhou M, Jiang Z, Epstein JI. Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer. Am J Surg Pathol. 2003;27(6):772-778. [PubMed]
26. Trpkov K, Bartczak-McKay J, Yilmaz A. Usefulness of cytokeratin 5/6 and AMACR applied as double sequential immunostains for diagnostic assessment of problematic prostate specimens. Am J Clin Pathol. 2009;132(2):211-220. [PubMed]
27. Reyes AO, Swanson PE, Carbone JM, Humphrey PA. Unusual histologic types of high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol. 1997;21(10):1215-1222. [PubMed]
28. Alguacil-Garcia A. Artifactual changes mimicking signet ring cell carcinoma in transurethral prostatectomy specimens. Am J Surg Pathol. 1986;10(11):795-800. [PubMed]
29. Wang HL, Humphrey PA. Exaggerated signet-ring cell change in stromal nodule of prostate: a pseudoneoplastic proliferation. Am J Surg Pathol. 2002;26(8):1066-1070. [PubMed]

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