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Glassy Cell Carcinoma of the Endometrium: A Case Report and Review of the Literature.

Glassy cell carcinoma (GCC) was originally described in the cervix by Glucksmann and Cherry[1] in 1956, and it was considered to be an aggressive tumor and highly resistant to radiation therapy. Since its first description in the endometrium by Christopherson et al[2-6] in 1982, only 11 cases have been reported in the literature. Cases of GCC arising in the fallopian tubes and colon have also been described.[7,8] Microscopically, the tumor cells are arranged in diffuse solid sheets. They have a ground-glassy cytoplasm, distinct cell wall, and large nuclei with prominent nucleoli. The exact percentage of glassy cells needed to make the diagnosis of GCC is not well established, but it may range from 30% to 100%[1,9] Ultrastructurally, glassy cells may show intermediate filaments, polyribosomes, tonofibrils, and desmosomes. The positivity of tumor cells for cytokeratin (CK), epithelial membrane antigen, and carcinoembryonic antigen (CEA) immunohistochemical stains has been inconsistent. Despite the wide consideration of GCC as being a poorly differentiated variant of adenosquamous carcinoma, its nature is still the subject of doubt and debate. We report an additional case of GCC of the endometrium in a 60-year-old woman with 5 years of follow-up and review the literature.

REPORT OF A CASE

A 60-year-old woman, gravida 2, para 1, presented to her physician for heavy vaginal bleeding of 4 months' duration. Her menarche started at the age of 12 years, and her last cycle occurred at the age of 55 years. Pelvic examination revealed no uterine enlargement or adnexal masses. A computed tomographic scan of the pelvis showed an enlarged uterus and a 3.0-cm pedunculated mass in the fundus. An endometrial biopsy was performed, followed by a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node dissection.

PATHOLOGIC FINDINGS

Hysterectomy specimen consisted of a uterus, cervix, and the attached left and right ovaries and fallopian tubes. The uterus measured 9.3 x 5.0 x 4.7 cm and weighed 127 g. The serosa was smooth and shiny. The cross section revealed a 3.7 x 2.0 x 2.0-cm polypoid friable mass in the uterine fundus, which appeared to infiltrate the myometrium. The cervix, ovaries, and fallopian tubes were unremarkable. Thirty-eight lymph nodes were detected in the "lymph node dissection" specimen. The tissue was formalin fixed and paraffin embedded. Sections for hematoxylin-eosin and immunohistochemistry stains were taken. Fresh tissues were submitted for electron microscopy (EM) and flow cytometry studies. Mucin and periodic acid-Schiff stains were done. Immunohistochemistry stains for neuron-specific enolase, protein gene product 9.5, chromogranin A, chromogranin B, vimentin, CEA, smooth muscle actin, muscle-specific actin, CAM 5.2, CK5+8, CK7, 34[Beta]E12, Leu-5, CK18, CK19, CK20, CK22, desmoplakin, desmin, myoglobin, estrogen and progesterone receptors, p53, Ki-67, and HER-2 protein were performed using the avidin-biotin complex technique.

Microscopic examination of the endometrial biopsy specimen and the endometrial tumor showed replacement of the normal endometrium by neoplastic cells, which had 2 different growth patterns: a glandular pattern with areas of squamous differentiation (adenoacanthoma) and a diffuse solid pattern (GCC) (Figure 1). In the first pattern, the glands showed a villoglandular configuration (Figure 2). The epithelial cells lining the glands had an abundant mucin-secreting cytoplasm and a round-to-oval, hyperchromatic, basally oriented nuclei with small nucleoli (Figure 3). Large areas of benign squamous metaplasia were also present. The second pattern, approximately 60% to 70% of the specimen, consisted of neoplastic cells that had abundant, eosinophilic cytoplasm with a ground-glass appearance, a well-demarcated cell membrane, and large nuclei with prominent nucleoli (Figure 4). No keratin pearls were seen. Heavy inflammatory cells mainly composed of lymphocytes and neutrophils were seen throughout the tumor. Mitosis of 2 to 3 of 10 high-power field were found. Tumor cells were seen invading less than one third of the myometrium thickness. No tumor involvement was seen in all 38 lymph nodes examined. The cervix, fallopian tubes, and ovaries were free of tumor The glassy cells were positive for vimentin (Figure 5), neuron-specific enolase, protein gene product 9.5, p53 (80% with nuclear pattern), and Ki-67 (70%-80%) and negative for chromogranin A and B, CEA, smooth muscle actin, muscle-specific actin, CAM 5.2, 34[Beta]E12, Leu-5, CK7, CK19, CK20, CK22, desmoplakin, desmin, myoglobin, HER-2 protein, and estrogen and progesterone receptors. Very rare tumor cells were positive for CK5+8 and CK18. Mucicarmine stain was negative and periodic acid-Schiff stain was positive and seen decorating the cell membrane. The EM findings were significant for numerous cytoplasmic intermediate filaments, compatible with vimentin filaments (Figure 6) and polyribosomes. Few primitive desmosomes and sparse tonofibrils were rarely observed. The flow cytometry revealed a diploid cell population with S-phase of 8.3% to 15.8%. The patient had a clinical stage IB endometrial cancer as defined by the International Federation of Gynecology and Obstetrics (FIGO), and she received an additional 26 Gy of pelvic irradiation. She was still alive and disease free 5 years after the initial diagnosis.

[ILLUSTRATIONS OMITTED]

COMMENT

Glassy cell carcinoma is a rare neoplasm that occurs in various sites, such as the cervix, endometrium, fallopian tubes, and colon, with the uterine cervix being the most frequent location. The incidence of GCC in the endometrium is extremely rare, and according to Christopherson et al,[2] it can account for 0.5% of all endometrial carcinomas. Including the case described herein, a total of 12 cases have been reported to date (Table). The patients ranged in age from 52 to 96 years (mean, 66.5 years), which is the same age range as women who present with classic endometrial adenocarcinoma. The usual clinical presentation is vaginal bleeding. Nine of 12 patients had low clinical stage disease (FIGO stage I), 2 had stage III disease, and 1 patient had stage IV disease. The treatment consisted of total hysterectomy with bilateral salpingo-oophorectomy in 6 cases and hysterectomy (not otherwise specified) in 3 cases. Six patients who were treated by total hysterectomy with bilateral salpingo-oophorectomy or hysterectomy alone received a subsequent radiation therapy. Two patients had only radiation therapy, and 1 patient received hormonal therapy only. The follow-up ranged from 5 months to 66 months (mean, 35.5 months). Three of 9 patients with stage I disease were alive, 2 were free of disease, and 1 was alive with disease. In the series of patients with stage I disease studied by Christopherson et al, one patient survived for 72 months and died from pneumonia with no evidence of disease, and another committed suicide and no data of her disease status were described. In conclusion, if we exclude the 1 patient who committed suicide due to the lack of information on her disease status, 3 of 8 patients would be considered disease free (37.5%). In patients with higher stage, 2 of 3 patients were still alive, one with no evidence of disease and the other with disease, at 24 and 16 months, respectively. Although GCC of the cervix is well known to have poor prognosis and to be resistant to radiotherapy, the prognosis of its endometrial counterpart is unknown. Because of the small number of cases reported in the literature, we were still not able to draw a conclusion about the prognosis of GCC of the endometrium. To define the clinical outcome of endometrial GCC by comparing it stage by stage and grade by grade with classic endometrial adenocarcinoma, we will have to wait for more data to become available.
 Reported Cases of Glassy Cell Carcinoma of the Endometrium(*)

 Source, y Age, y Symptoms Stage

Arends et al, [4] 1984 59 Vaginal bleeding IIIA
De Rosa et al,[6] 1987 58 Metrorrhagia IA
 52 Metrorrhagia IA
 58 Metrorrhagia IA
Hachisuga et al,[3] 1990 62 Vaginal bleeding IC
Dawson et al,[5] 1989 96 Vaginal bleeding IVB
Christopherson et al,[2] 56 Vaginal bleeding I
 1982 70 Vaginal bleeding I
 71 Vaginal bleeding I
 78 Vaginal bleeding I
 78 Vaginal bleeding III
Current case 60 Vaginal bleeding IB

 Source, y Age, y Symptoms Treatment

Arends et al, [4] 1984 59 Vaginal bleeding TAH, BSO, RT
De Rosa et al,[6] 1987 58 Metrorrhagia TAH, BSO
 52 Metrorrhagia TAH, BSO
 58 Metrorrhagia TAH, BSO
Hachisuga et al,[3] 1990 62 Vaginal bleeding TAH, BSO, RT
Dawson et al,[5] 1989 96 Vaginal bleeding Megestrol

Christopherson et al,[2] 56 Vaginal bleeding RT, hysterectomy
 1982 70 Vaginal bleeding RT, hysterectomy
 71 Vaginal bleeding RT, hysterectomy
 78 Vaginal bleeding RT
 78 Vaginal bleeding RT
Current case 60 Vaginal bleeding TAH, BSO, RT

 Source, y Age, y Symptoms Follow-up

Arends et al, [4] 1984 59 Vaginal bleeding Alive at 2 years,
 NED
De Rosa et al,[6] 1987 58 Metrorrhagia Dead at 1 year of
 disease
 52 Metrorrhagia Dead at 1 year of
 disease
 58 Metrorrhagia Alive at 3 years
 AWD
Hachisuga et al,[3] 1990 62 Vaginal bleeding Alive at 5.5
 years, NED
Dawson et al,[5] 1989 96 Vaginal bleeding Alive at 16
 months, AWD (no
 progression
 disease)
Christopherson et al,[2] 56 Vaginal bleeding Dead at 5 months
 1982 70 Vaginal bleeding Dead at 32 months
 71 Vaginal bleeding Dead at 72 months,
 WED
 78 Vaginal bleeding Dead at 7 months
 from suicide
 78 Vaginal bleeding Dead at 5 months
 of disease
Current case 60 Vaginal bleeding Alive at 5 years,
 NED

(*) TAH indicates total abdominal hysterectomy; BSO, bilateral
salpingo-oophorectomy; RT, radiation therapy; NED, no evidence of
disease; AWD, alive with disease; and WED, with evidence of disease.


Despite the presence of poor prognostic factors in the present case, such as negativity for hormonal receptors and strong positivity for p53, Ki-67, and HER-2, the patient was still alive and disease free 5 years after the initial diagnosis.[10-14] Most probably the clinical stage is still the most important prognostic factor. However, the significance of those prognostic factors in endometrial GCC must be explored and confirmed by analyzing more cases.

Histologically, the classic GCC showed neoplastic cells that are often arranged in sheets and disorganized nests. They have eosinophilic, sometimes amphophilic, cytoplasm with a ground-glass appearance. The nuclei are large and hyperchromatic with prominent nucleoli. Mitosis are frequent. This neoplasm is usually infiltrated by heavy inflammatory cells, mostly eosinophils and lymphocytes. In reviewing the literature, all cases (aside from the case studied by Dawson et al, which was hampered by the lack of morphologic description) had some glandular component and various amount of mucin staining. Our case had 2 components, the first was a moderately differentiated adenocarcinoma with extensive areas of benign squamous metaplasia and the second was a GCC that constituted 60% to 70% of the tumor volume.

Although GCC is widely considered a poorly differentiated variant of adenosquamous carcinoma, the absence of keratin staining by tumor cells has led Arends et al[4] to doubt its nature. Other investigators, such as Costa et al,[15] suggested that GCC should not be regarded as a distinct entity but as part of a spectrum of differentiation in adenosquamous carcinoma. We believe that the positive expression of tumor cells for CK and other epithelial markers and the presence of tonofibrils and desmosomes are proportional to the degree of differentiation of squamous cell component existing in this neoplasm.

The histology (presence of glandular components in most cases), immunohistochemistry (variable expression for CK, endomysial antibody, and CEA), and EM data (rare tonofibrils, poorly formed desmosomes) as seen in our case and being reported in the literature confirmed the original belief that GCC is a poorly differentiated adenosquamous carcinoma. The question being raised by Costa et al[15] as to whether GCC should be considered as a distinct entity has to taken into consideration, and more rigid diagnostic criteria have to be established when making the diagnosis.

The differential diagnosis is similar to other large cell tumors, such as melanoma, large cell sarcoma, and lymphoma. Immunohistochemistry and EM studies are helpful in making the final diagnosis. Melanoma is positive for HMB-45 and S100 and shows melanosomes and premelanosomes on EM. Alveolar soft part sarcoma is periodic acid-Schiff positive, is diastase-resistant crystallin material positive, and has a characteristic rod-shaped crystal on EM. Large cell lymphoma is positive for leukocyte common antigen, can have a B- or T-cell lineage, and shows absence of cell junction on EM.

In summary, we presented a case of GCC of the endometrium in a 60-year-old woman treated with hysterectomy, bilateral salpingo-oophorectomy, and radiation therapy. The patient was alive and free of disease at 5 years of follow-up. We also summarized the clinical and histological findings in 11 previously reported cases. A well-defined prognosis of GCC of the endometrium is still premature because of the small number of reported cases. It is of no doubt that more reports of GCC in the endometrium will appear in the future, and understanding the clinical significance and the nature of GCC will be possible when more data become available.

References

[1.] Glucksman A, Cherry C. Incidence, histology, and response to radiation of mixed carcinomas (adenoacanthomas) of the uterine cervix. Cancer. 1956;9:971.

[2.] Christopherson WM, Alberhasky RC, Connelly PJ. Glassy cell carcinoma of the endometrium. Hum Pathol. 1982;13:418-421.

[3.] Hachisuga T, Sugimori H, Kaku T, Matsukuma K, Tsukamoto N, Nakano H. Glassy cell carcinoma of the endometrium. Gynecol Oncol. 1990;36:134-138.

[4.] Arends JW, Willebrand D, DeKoning Gangs HJ, Swaen GJV, Bosman FT. Adenocarcinoma of the endometrium with glassy-cell features--immunohistochemical observations. Histopathology. 1984;8:873-879.

[5.] Dawson EC, Belisnson JL, Lee K. Glassy cell carcinoma of the endometrium responsive to megestrol acetate. Gynecol Oncol. 1989;33:121-124.

[6.] De Rosa G, Barra E, Palombini L, Nappi C. Glassy cell carcinoma dell'endometrio. Pathologica. 1987;79:339-345.

[7.] Aru A, Rasmussen LA, Federspiel B, Horn T. Glassy cell carcinoma of the colon with human chorionic gonadotropin-production. Am J Surg Pathol. 1996; 20:187-192.

[8.] Herbold DR, Axelrod JH, Bodowski SJ, Freel JH. Glassy cell carcinoma of the fallopian tube: a case report. Int J Gynecol Pathol. 1988;7:384-390.

[9.] Nordstrom B, Strang P, Bergstrom R, Nilsson S, Tribukait B. A comparison of proliferation markers and their prognostic value for women with endometrial carcinoma, Ki-67, proliferating cell nuclear antigen, and flow cytometric S-phase fraction. Cancer. 1996;78:1942-1951.

[10.] Maier CRC, Norris HJ. Glassy cell carcinoma of the cervix. Obstet Gynecol. 1982;60:219-224.

[11.] Salvesen HB, Iversen OE, Akslen LA. Identification of high-risk patients by assessment of nuclear Ki-67 expression in a prospective study of endometrial carcinomas. Clin Cancer Res. 1998;11:2779-2785.

[12.] Taskin M, Lallas TA, Barber HR, Shevchuk MM. Bcl-2 and p53 in endometrial adenocarcinoma. Mod Pathol. 1997;10:728-734.

[13.] Heffner HM, Freedman AN, Asirwatham JE, Lele SB. Prognostic significance of p53, PCNA, and c-erbB-2 in endometrial carcinoma. Eur J Gynecol Oncol. 1999;20:8-12.

[14.] Creasman WT. Prognostic significance of hormone receptors in endometrial cancer. Cancer. 1993;71:1467-1470.

[15.] Costa MJ, Kenny MB, Hewan-Lowe K, Judd R. Glassy cell carcinoma features in adenosquamous carcinoma of the uterine cervix: histologic, ultrastructural, immunohistochemical, and clinical findings. Am J Clin Pathol. 1991;96: 520-528.

Accepted for publication December 14, 2000.

From the Departments of Pathology (Drs Mhawech and Terracciano) and Obstetrics Gynecology (Dr Dellas), Basel University Hospital, Basel, Switzerland.

Reprints: Luigi M. Terracciano, MD, Institute of Pathology, Schonbeinstrasse 40, Basel University Hospital, 4003 Basel, Switzerland (e-mail: Iterracciano@uhbs.ch).
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No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001 Gale, Cengage Learning. All rights reserved.

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Author:Mhawech, Paulette; Dellas, Athanassios; Terracciano, Luigi M.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2001
Words:2545
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