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Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Glassy cell carcinoma of the cervix: a literature review A. Zolciak-Siwinska a,*, J. Jonska-Gmyrek b a b
Department of Brachytherapy, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland Department of Radiotherapy, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 October 2013 Received in revised form 4 February 2014 Accepted 31 March 2014
Glassy cell carcinoma (GCC) is a histologically aggressive subtype of cervical cancer with rapid growth and early metastases. The prognosis for patients with GCC is poor. This article reviews the literature pertinent to the epidemiology, cytology, pathology, immunohistochemistry, treatment and prognosis of GCC. MEDLINE (PubMed) was searched for all articles or abstracts on patients diagnosed with GCC published (in English) since the original definition by Glucksmann and Cherry, Cancer 1956;9:971. Accurate diagnosis of GCC enables implementation of the correct treatment strategy. Early-stage GCC should be treated with hysterectomy and pelvic lymph node dissection, with adjuvant radiochemotherapy if at least one intermediate or high risk factor for cervical cancer is present. Advanced GCC should be treated with neoadjuvant radiochemotherapy or chemotherapy with the aim of making the disease operable. There is a need for retrospective evaluation of GCC treatment from several centres to explore knowledge about this rare entity. Future studies should explore the role of targeted therapies and the most efficient chemotherapy regimen for the management of GCC. ß 2014 Published by Elsevier Ireland Ltd.
Keywords: Glassy cell carcinoma Epidemiology Treatment Outcomes
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology and clinical data . . . . . . . . . . . Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histopathology and immunohistochemistry. Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future direction . . . . . . . . . . . . . . . . . . . . . . . Condensation . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction A comprehensive search of PubMed revealed that approximately 300 cases of glassy cell carcinoma (GCC) have been reported in the literature since it was first defined by Glucksmann and Cherry [1]. A brief review of the existing English literature was
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undertaken to improve understanding of this rare entity. All publications with the keywords ‘glassy cell carcinoma’ and ‘uterine cervix’ were analysed, along with articles cited in the reference lists of these publications. No trials or large studies were identified because of the rarity of GCC. Epidemiology and clinical data
* Corresponding author at: Maria Sklodowska-Curie Memorial Cancer Center, Radiotherapy, Roentgen Street 5, 02-781 Warsaw, Poland. E-mail address: [email protected] (A. Zolciak-Siwinska).
The World Health Organization classification considers GCC to be a subtype of other epithelial tumours. GCC of the cervix is a rare pathological form, occurring in 1–5% of all cases of cervical cancer [1–3].
http://dx.doi.org/10.1016/j.ejogrb.2014.03.035 0301-2115/ß 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Zolciak-Siwinska A, Jonska-Gmyrek J. Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.03.035
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The mean age of patients with GCC is approximately 10 years younger than the mean age of all patients with cervical cancer [2,4]. An association was observed between GCC and either recent or current pregnancy [5–9], possibly due to the generally younger age of women affected by GCC. A strong association has been found between GCC and high-risk human papillomavirus (HPV) infection; HPV 18, 16 and 32 were detected in 67% (n = 28) of examined cases [10–13]. The most common presenting symptom is vaginal bleeding for 3–4 months [2,14]. GCC grows around the squamocolumnar junction or into the endocervical canal with extension into the vagina and parametrium [2,4]. GCC has a rapid progression rate and a high rate of metastases outside the pelvis, in contrast to squamous cell carcinoma [2]. Local recurrence usually occurs at the apex of the vagina, parametrium and para-aortic lymph nodes [3,15]. Distant extrapelvic metastases to the lung, liver, spleen and bones have been observed [2]. Most recurrences were identified within 24 months of primary therapy [4,8], with one observation of distant metastasis 31 months after treatment [3]. Cytology The aggressive natural history of GCC encourages the use of early detection methods. Unfortunately, there are problems with the interpretation of cytological smears. Some appear positive for malignant cells, and others suggest invasive squamous cell carcinoma or undifferentiated carcinoma. GCC does not have a distinctive cytological appearance [2,16]. In Papanicolaou tests, tumour cells are arranged in sheets and clusters with large abundant granular cytoplasm and large pleomorphic nuclei. The nuclei have coarse irregular chromatin and prominent nucleoli. The presence of large nucleoli may be mistaken for inclusions of herpes virus or Reed-Stenberg cells. Cytoplasmic vacuolization and bizarre cells with multinucleation and an inflammatory cell infiltrate can be seen [9,15,17–20]. Histopathology and immunohistochemistry GCC is a poorly differentiated adenosquamous carcinoma. The pathological diagnosis of cervical GCC is based on criteria established by Gluksmann and Cherry [1] and amplified by Littman et al. [2]. There are three main criteria for microscopic diagnosis of GCC: (1) cells with a moderate amount of cytoplasm and a ground-glass or finely granular appearance; (2) a distinct cell wall that stains with eosin and periodic acid–Schiff (PAS); and (3) large nuclei with prominent nucleoli. In addition, failure of the tumour cells to stain with mucicarmine or PAS after diastase digestion, absent or rare squamous or glandular differentiation, large cell size (three to five times the size of lymphocytes or neutrophils), a high mitotic rate with frequent abnormal forms and a dense inflammatory infiltrate of plasma cells, and eosinophils are observed. The composition of large cells with abundant chromatin gives GCC its characteristic glassy appearance. Glassy cell features are described as predominant (>85% of histology) or focal (33–85% of histology). It is possible that GCC is part of the spectrum of histological findings in adenosquamous carcinoma, rather than a distinct histological subtype of cervical cancer [19]. Immunohistochemically, GCC expresses markers for both squamous cell carcinoma (p63, cytokeratin 34 beta E12) and adenocarcinoma (CAM5.2, MUC1, MUC2, CEA). The proliferation index of monoclonal antibody Ki-67 was high (70%) in five analysed cases [7]. This estimates the growth fraction of tumour accurately and provides valuable prognostic information. Among 11 patients with GCC, oestrogen, progesterone receptor and Her2/neu protein were found to be positive in two (18%), one (9%) and five (45.4%) cases, respectively [9]. Her2/neu
overexpression may correlate with more aggressive behaviour and a worse clinical outcome. The analysis of histological material from 13 patients revealed no immunohistochemically detectable receptor protein in tumour cells [14]. GCC is not believed to be hormone dependent and it is considered that these patients could be treated with hormone replacement therapy. Other findings confirming GCC are positivity for cytokeratin (MNF116), vimentin and carcino-embryonic antigen, and negativity for HMB-45 (marker for melanoma) [15].
Treatment Radical hysterectomy with bilateral pelvic lymph node dissection – consisting of the removal of all lymphatic tissue around the common, external and internal iliac vessels and anterior to the obturator nerve – is the treatment of choice for early-stage GCC [21] (FIGO Stage I and operable Stage II). When the case is high risk for para-aortic lymph node metastasis due to the presence of pelvic lymph node involvement, para-aortic lymphadenectomy below the origin of the inferior mesenteric artery is worth considering [22]. Identification of patients with cervical cancer requiring adjuvant therapy after surgery is important; therefore, risk factors for local recurrence or dissemination have been extracted. High risk factors include: large lesion; metastases to lymph nodes; involvement of parametrium; and insufficient surgical margins [23–27]. Intermediate risk factors include: lymphovascular space invasion; deep stromal invasion; and tumour size >3 cm [3]. Patients with GCC of the uterine cervix and at least one high or intermediate risk factor should receive adjuvant treatment [3]. Radical radiotherapy (RT) as adjuvant treatment reduces the recurrence rate in patients with GCC [28] and improves survival [3,4]. Lotocki et al. [4] reported RT with 50 Gy to the whole pelvis and 20 Gy 137Cs to the upper part of the vagina following radical hysterectomy in patients with FIGO Stage I disease, or 40 Gy to the whole pelvis and 35 Gy 137Cs as intracavital brachytherapy (BT) followed by surgery in patients with FIGO Stage II disease. Piura et al. reported the delivery of 45–70.2 Gy to the pelvis in daily fractions of 1.8 Gy and BT, with two vaginal intracavital 137Cs applications (each 20–30 Gy) [21]. There is a lack of detailed information on techniques, RT doses and high-dose-rate BT used in GCC patients in the literature. Although GCC is not within the scope of the National Comprehensive Cancer Network Version 2.2013 [29], the principles of radiation therapy for cervical cancer should be used in patients with GCC. Computed tomography (CT)-based treatment planning is the standard of care for external beam radiotherapy (EBRT). Magnetic resonance imaging (MRI) is the best imaging modality for determining soft tissue and parametrial involvement in patients with advanced tumours. Positron emission tomography (PET) imaging is useful for defining the nodal status. The volume of EBRT should cover the gross disease, parametria, uterosacral ligaments, vaginal margin, presacral, external iliac, internal iliac and obturator nodes. For patients at higher risk of lymph node involvement, the radiation volume should cover the common iliac and para-aortic nodes. Coverage of microscopic nodal disease requires an EBRT dose of 45–50 Gy in conventional fractionation of 1.8–2 Gy daily, with a boost of 10–15 Gy for limited volumes of gross disease (unresected adenopathy). Either cisplatin or cisplatin + 5-fluorouracil should be given during EBRT. BT may be used in posthysterectomy patients with a vaginal cylinder. Although the prognosis is worse in patients with adenocarcinoma or adenosquamous carcinoma, this difference does not exist in high-risk postsurgical patients who receive cisplatin-based radiochemotherapy compared with RT alone [28].
Please cite this article in press as: Zolciak-Siwinska A, Jonska-Gmyrek J. Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.03.035
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Table 1 Treatment schedule and survival rates in patients with glassy cell carcinoma published in recent series. Year
Author
FIGO stage (n)
Survival
Treatment
1992
Lotocki et al. [4]
1999
Piura et al. [21]
2000
Chung et al. [18]
2001
Gray et al. [3]
IB (11) IB (8) II (6) II (5) III (2) IB (3) IIIB–IVB (2) IB (2) II (6) IIIB (1) IB (14)
45% 5-year OS 87% 5-year OS 50% 5-year OS 85% 5-year OS 0% 5-year OS 100%, 4–18 months, NED 0%, died after 3–12 months One pt alive at 63 months, one pt lost to follow-up 50% DFS (8–42 months) 0% DFS 71%, DFS at median follow-up 28.5 months
IIB (5) IIIB (3) I (10) II (8) III (1) IV (2) IB (1) IIB (1) IIIB (1) IB (2) II (7)
60%, DFS at median 28.5 months 33%, DFS at median 28.5 months 50%, 5-year OS 36%, 5-year OS 0%, 5-year OS 0%, 5-year OS 0%, 5-year OS 0%, 5-year OS 0%, 5-year OS Alive 5, 10 months 57%, 2-year DFS, two lost to follow-up
IIIB (2)
50% 2-year OS
S S + RT RT RT + S RT S + RT RT/nothing S/nothing S/S + RT + CHTH RT + CHTH 7 pts: S 5 pts: S + RT 2 pts: S + RT + CHTH Not stated Not stated S (RT not stated) RT RT RT S + RT + CHTH S + RT + CHTH CHTH + RT S + RT 5 pts: S + RT + CHTH 2 pts: CHTH S + RT + CHTH/CHTH
2004
Hopkins and Morley [42]
2004
Deshpande et al. [8]
2006
Kuroda et al. [9]
S, surgery; RT, radiotherapy; CHTH, chemotherapy; pts, patients; OS, overall survival; DFS, disease-free survival; NED, no evidence of disease.
As GCC often affects young women, some authors have considered preservation of the patient’s ovaries during radical surgery for early-stage GCC. The successful treatment of a patient with FIGO Stage IB1 disease with conization and laparoscopic lymphadenectomy has been reported [30], but there are also two documented cases of ovarian metastases [31,32]. The aggressive nature of this tumour should be a contra-indication for ovarian conservation in patients with GCC of the uterine cervix. The treatment strategy in patients with advanced disease is downstaging to make the disease operable. Patients with FIGO Stage IIB bulky and Stage IIIB disease following neoadjuvant intraarterial chemotherapy, treated with carboplatin–etoposide–epirubicin or cisplatin–etoposide–mitomycin C, had surprisingly good responses [33,34]. Multimodal treatment with postsurgical radiochemotherapy based on paclitaxel–carboplatin has been shown to be effective [22]. Paclitaxel–carboplatin has also been shown to be effective in recurrent cancer or in primary neoadjuvant treatment of bulky tumours [35–37]. Cases that have not responded to chemotherapy have also been reported [38–40]. The question concerning the treatment of patients with advanced GCC remains unanswered. Patients with FIGO Stage IIB bulky and Stage III disease can be treated with radical radiochemotherapy or multidrug chemotherapy. Once remission is achieved, radical hysterectomy with lymphadenectomy should be considered. In cases with FIGO Stage IVB disease, palliative chemotherapy using paclitaxel–carboplatin does not prolong survival [38]. The issue of chemotherapy requires further study. Due to huge variation in the treatment methods used, it is difficult to draw conclusions regarding therapy and outcome. Prognosis GCC is considered to be refractory to both radiation and surgical therapy [2]. Glucksmann and Cherry [1] noted that, after irradiation, the glassy cells enlarged and occasionally showed some parakeratosis, but typically they exhibited no increased differentiation in the form of keratinization or mucin production. Littman et al. [2] only observed marked radiation changes in one of
eight operated cases. These observations suggest that irradiation alone leads to a poor response in bulky tumours. The reason for the poor surgical outcomes is that many patients were understaged, which played a role in poor prognosis rather than the tumour being less sensitive to treatment, as described previously [41], patients were not treated properly. Patients should be evaluated for the presence of disseminated disease before starting definitive treatment. The staging process should be completed as quickly as possible due to rapid growth of the tumour. GCC has a reputation for a particularly poor prognosis, but there has been significant improvement in diagnostic possibilities with the introduction of CT, MRI and PET. In older studies, the 5-year survival rate was reported to be between 13% and 30% [2,16,19,42–44]. In some studies, average survival was less than 1 year. Multimodal therapy changed this grim outlook for early-stage patients, and 5-year survival is now 80% in patients with FIGO Stage I disease [4,21]. A patient with FIGO Stage I or Stage II disease is curable, but outcomes for patients with FIGO Stage III or Stage IV disease remain dismal. Hopkins and Morley undertook an analysis of material published before 1991 [42]. Table 1 shows a summary of outcomes published recently, excluding case reports and histopathological examinations where clinical data were missing.
Future direction Unfortunately, publications concerning GCC are scarce. This review of the available literature still contains insufficient information, underscoring the need to conduct retrospective analyses from the last 20 years in several centres. This would enable a clinical review to be undertaken, summarizing treatment outcomes using modern diagnostic methods and adequate therapy. It appears that a 3-year follow-up period is sufficient for a reliable assessment of survival in patients with GCC. As noted above, GCC exhibits Her-2/neu overexpression in 45% of cases. Following detection of this protein, the use of the antiHER2 monoclonal antibody trastuzumab in the management
Please cite this article in press as: Zolciak-Siwinska A, Jonska-Gmyrek J. Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.03.035
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can be considered. Future studies should investigate the most efficient chemotherapy regimen. Condensation A multimodal approach increases the chance of cure for patients with FIGO Stage I and II glassy cell carcinoma. Conflict of interest None declared. References [1] Glucksmann A, Cherry C. Incidence, histology and response to radiation of mixed carcinomas (adenocanthomas) of the uterine cervix. Cancer 1956;9:971–9. [2] Littman P, Clement PB, Henriksen B, et al. Glassy cell carcinoma of the cervix. Cancer 1976;37:2238–46. [3] Gray HJ, Garcia R, Tamimi HK, et al. Glassy cell carcinoma of the cervix revisited. Gynecol Oncol 2002;85:274–7. [4] Lotocki RJ, Krepart GV, Paraskevas M, Vadas G, Heywood M, Fung FK. Glassy cell carcinoma of the uterine cervix: a bimodal treatment strategy. Gynecol Oncol 1992;44:254–9. [5] Johnston GA, Azizi F, Reale F, Jones HA. Glassy cell carcinoma of the cervix: report of three cases. J Nat Med Assoc 1982;74:361–3. [6] Cherry CP, Glucksmann A. A histology of carcinomas of the uterine cervix and survival rates in pregnant and non-pregnant patients. Surg Gynecol Obstet 1961;113:763–76. [7] Zhu HT, Li SX. Glassy cell carcinoma of cervix: a clinicopathologic analysis of 5 cases. Zhonghua Bing Li Xue Za Zhi 2011;40:523–7. [8] Deshpande A, Kotwal M, Bobhate S. Glassy cell carcinoma of the uterine cervix: a rare histology. Report of three cases with a review of the literature. Indian J Cancer 2004;41:92–5. [9] Kuroda H, Toyozumi Y, Masuda T, et al. Glassy cell carcinoma of the cervix: cytologic features and expression of estrogen receptor, progesterone receptor and Her2/neu protein. Acta Cytol 2006;50:418–22. [10] Kim SK, Shim HS, Lee KG, An HJ, Lee KR, Cho NH. Glassy cell carcinoma predominantly commits to a squamous lineage and is strongly associated with high-risk type human papillomavirus infection. Int J Gynecol Pathol 2009;28:389–95. [11] Kenny MB, Unger ER, Chenggis ML, Costa MJ. In situ hybridization for human papillomavirus DNA in uterine adenosquamous carcinoma with glassy cell features (‘glassy cell carcinoma’). Am J Clin Pathol 1992;98:180–7. [12] Kato N, Katayama Y, Kaimori M, Motoyama T. Glassy cell carcinoma of the uterine cervix: histochemical, immunohistochemical, and molecular genetic observations. Int J Gynecol Pathol 2002;21:134–40. [13] Hirai Y, Kawamata Y, Takeshima N, et al. Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. Int J Oncol 2004;24:977–86. [14] Atlas I, Gajewski W, Falkenberry S, Granai CO, Steinhoff MM. Absence of estrogen and progesterone receptors in glassy cell carcinoma of the cervix. Obstet Gynecol 1998;91:136–8. [15] Reis-Filho JS, Fillus Neto J, Schonemann E, Sanderson A, Schmitt FC. Glassy cell carcinoma of the uterine cervix. Report of a case with cytohistologic and immunohistochemical study. Acta Cytol 2001;45:407–10. [16] Pak HY, Yokota SB, Paladugu RR, Agliozzo CM. Glassy cell carcinoma of the cervix. Cytologic and clinicopathologic analysis. Cancer 1983;52:307–12. [17] Khalbuss WE, Pantanowitz L, Monaco S. Cytomorphology of unusual primary tumors in the Pap test. Cytojournal 2013;10:17. [18] Chung JH, Koh JS, Lee SS, Cho KJ. Glassy cell carcinoma of the uterine cervix. Cytologic features and expression of estrogen and progesterone receptors. Acta Cytol 2000;44:551–6.
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Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Glassy cell carcinoma of the cervix: a literature review A. Zolciak-Siwinska a,*, J. Jonska-Gmyrek b a b
Department of Brachytherapy, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland Department of Radiotherapy, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 October 2013 Received in revised form 4 February 2014 Accepted 31 March 2014
Glassy cell carcinoma (GCC) is a histologically aggressive subtype of cervical cancer with rapid growth and early metastases. The prognosis for patients with GCC is poor. This article reviews the literature pertinent to the epidemiology, cytology, pathology, immunohistochemistry, treatment and prognosis of GCC. MEDLINE (PubMed) was searched for all articles or abstracts on patients diagnosed with GCC published (in English) since the original definition by Glucksmann and Cherry, Cancer 1956;9:971. Accurate diagnosis of GCC enables implementation of the correct treatment strategy. Early-stage GCC should be treated with hysterectomy and pelvic lymph node dissection, with adjuvant radiochemotherapy if at least one intermediate or high risk factor for cervical cancer is present. Advanced GCC should be treated with neoadjuvant radiochemotherapy or chemotherapy with the aim of making the disease operable. There is a need for retrospective evaluation of GCC treatment from several centres to explore knowledge about this rare entity. Future studies should explore the role of targeted therapies and the most efficient chemotherapy regimen for the management of GCC. ß 2014 Published by Elsevier Ireland Ltd.
Keywords: Glassy cell carcinoma Epidemiology Treatment Outcomes
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology and clinical data . . . . . . . . . . . Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histopathology and immunohistochemistry. Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future direction . . . . . . . . . . . . . . . . . . . . . . . Condensation . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction A comprehensive search of PubMed revealed that approximately 300 cases of glassy cell carcinoma (GCC) have been reported in the literature since it was first defined by Glucksmann and Cherry [1]. A brief review of the existing English literature was
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undertaken to improve understanding of this rare entity. All publications with the keywords ‘glassy cell carcinoma’ and ‘uterine cervix’ were analysed, along with articles cited in the reference lists of these publications. No trials or large studies were identified because of the rarity of GCC. Epidemiology and clinical data
* Corresponding author at: Maria Sklodowska-Curie Memorial Cancer Center, Radiotherapy, Roentgen Street 5, 02-781 Warsaw, Poland. E-mail address: [email protected] (A. Zolciak-Siwinska).
The World Health Organization classification considers GCC to be a subtype of other epithelial tumours. GCC of the cervix is a rare pathological form, occurring in 1–5% of all cases of cervical cancer [1–3].
http://dx.doi.org/10.1016/j.ejogrb.2014.03.035 0301-2115/ß 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Zolciak-Siwinska A, Jonska-Gmyrek J. Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.03.035
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The mean age of patients with GCC is approximately 10 years younger than the mean age of all patients with cervical cancer [2,4]. An association was observed between GCC and either recent or current pregnancy [5–9], possibly due to the generally younger age of women affected by GCC. A strong association has been found between GCC and high-risk human papillomavirus (HPV) infection; HPV 18, 16 and 32 were detected in 67% (n = 28) of examined cases [10–13]. The most common presenting symptom is vaginal bleeding for 3–4 months [2,14]. GCC grows around the squamocolumnar junction or into the endocervical canal with extension into the vagina and parametrium [2,4]. GCC has a rapid progression rate and a high rate of metastases outside the pelvis, in contrast to squamous cell carcinoma [2]. Local recurrence usually occurs at the apex of the vagina, parametrium and para-aortic lymph nodes [3,15]. Distant extrapelvic metastases to the lung, liver, spleen and bones have been observed [2]. Most recurrences were identified within 24 months of primary therapy [4,8], with one observation of distant metastasis 31 months after treatment [3]. Cytology The aggressive natural history of GCC encourages the use of early detection methods. Unfortunately, there are problems with the interpretation of cytological smears. Some appear positive for malignant cells, and others suggest invasive squamous cell carcinoma or undifferentiated carcinoma. GCC does not have a distinctive cytological appearance [2,16]. In Papanicolaou tests, tumour cells are arranged in sheets and clusters with large abundant granular cytoplasm and large pleomorphic nuclei. The nuclei have coarse irregular chromatin and prominent nucleoli. The presence of large nucleoli may be mistaken for inclusions of herpes virus or Reed-Stenberg cells. Cytoplasmic vacuolization and bizarre cells with multinucleation and an inflammatory cell infiltrate can be seen [9,15,17–20]. Histopathology and immunohistochemistry GCC is a poorly differentiated adenosquamous carcinoma. The pathological diagnosis of cervical GCC is based on criteria established by Gluksmann and Cherry [1] and amplified by Littman et al. [2]. There are three main criteria for microscopic diagnosis of GCC: (1) cells with a moderate amount of cytoplasm and a ground-glass or finely granular appearance; (2) a distinct cell wall that stains with eosin and periodic acid–Schiff (PAS); and (3) large nuclei with prominent nucleoli. In addition, failure of the tumour cells to stain with mucicarmine or PAS after diastase digestion, absent or rare squamous or glandular differentiation, large cell size (three to five times the size of lymphocytes or neutrophils), a high mitotic rate with frequent abnormal forms and a dense inflammatory infiltrate of plasma cells, and eosinophils are observed. The composition of large cells with abundant chromatin gives GCC its characteristic glassy appearance. Glassy cell features are described as predominant (>85% of histology) or focal (33–85% of histology). It is possible that GCC is part of the spectrum of histological findings in adenosquamous carcinoma, rather than a distinct histological subtype of cervical cancer [19]. Immunohistochemically, GCC expresses markers for both squamous cell carcinoma (p63, cytokeratin 34 beta E12) and adenocarcinoma (CAM5.2, MUC1, MUC2, CEA). The proliferation index of monoclonal antibody Ki-67 was high (70%) in five analysed cases [7]. This estimates the growth fraction of tumour accurately and provides valuable prognostic information. Among 11 patients with GCC, oestrogen, progesterone receptor and Her2/neu protein were found to be positive in two (18%), one (9%) and five (45.4%) cases, respectively [9]. Her2/neu
overexpression may correlate with more aggressive behaviour and a worse clinical outcome. The analysis of histological material from 13 patients revealed no immunohistochemically detectable receptor protein in tumour cells [14]. GCC is not believed to be hormone dependent and it is considered that these patients could be treated with hormone replacement therapy. Other findings confirming GCC are positivity for cytokeratin (MNF116), vimentin and carcino-embryonic antigen, and negativity for HMB-45 (marker for melanoma) [15].
Treatment Radical hysterectomy with bilateral pelvic lymph node dissection – consisting of the removal of all lymphatic tissue around the common, external and internal iliac vessels and anterior to the obturator nerve – is the treatment of choice for early-stage GCC [21] (FIGO Stage I and operable Stage II). When the case is high risk for para-aortic lymph node metastasis due to the presence of pelvic lymph node involvement, para-aortic lymphadenectomy below the origin of the inferior mesenteric artery is worth considering [22]. Identification of patients with cervical cancer requiring adjuvant therapy after surgery is important; therefore, risk factors for local recurrence or dissemination have been extracted. High risk factors include: large lesion; metastases to lymph nodes; involvement of parametrium; and insufficient surgical margins [23–27]. Intermediate risk factors include: lymphovascular space invasion; deep stromal invasion; and tumour size >3 cm [3]. Patients with GCC of the uterine cervix and at least one high or intermediate risk factor should receive adjuvant treatment [3]. Radical radiotherapy (RT) as adjuvant treatment reduces the recurrence rate in patients with GCC [28] and improves survival [3,4]. Lotocki et al. [4] reported RT with 50 Gy to the whole pelvis and 20 Gy 137Cs to the upper part of the vagina following radical hysterectomy in patients with FIGO Stage I disease, or 40 Gy to the whole pelvis and 35 Gy 137Cs as intracavital brachytherapy (BT) followed by surgery in patients with FIGO Stage II disease. Piura et al. reported the delivery of 45–70.2 Gy to the pelvis in daily fractions of 1.8 Gy and BT, with two vaginal intracavital 137Cs applications (each 20–30 Gy) [21]. There is a lack of detailed information on techniques, RT doses and high-dose-rate BT used in GCC patients in the literature. Although GCC is not within the scope of the National Comprehensive Cancer Network Version 2.2013 [29], the principles of radiation therapy for cervical cancer should be used in patients with GCC. Computed tomography (CT)-based treatment planning is the standard of care for external beam radiotherapy (EBRT). Magnetic resonance imaging (MRI) is the best imaging modality for determining soft tissue and parametrial involvement in patients with advanced tumours. Positron emission tomography (PET) imaging is useful for defining the nodal status. The volume of EBRT should cover the gross disease, parametria, uterosacral ligaments, vaginal margin, presacral, external iliac, internal iliac and obturator nodes. For patients at higher risk of lymph node involvement, the radiation volume should cover the common iliac and para-aortic nodes. Coverage of microscopic nodal disease requires an EBRT dose of 45–50 Gy in conventional fractionation of 1.8–2 Gy daily, with a boost of 10–15 Gy for limited volumes of gross disease (unresected adenopathy). Either cisplatin or cisplatin + 5-fluorouracil should be given during EBRT. BT may be used in posthysterectomy patients with a vaginal cylinder. Although the prognosis is worse in patients with adenocarcinoma or adenosquamous carcinoma, this difference does not exist in high-risk postsurgical patients who receive cisplatin-based radiochemotherapy compared with RT alone [28].
Please cite this article in press as: Zolciak-Siwinska A, Jonska-Gmyrek J. Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.03.035
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Table 1 Treatment schedule and survival rates in patients with glassy cell carcinoma published in recent series. Year
Author
FIGO stage (n)
Survival
Treatment
1992
Lotocki et al. [4]
1999
Piura et al. [21]
2000
Chung et al. [18]
2001
Gray et al. [3]
IB (11) IB (8) II (6) II (5) III (2) IB (3) IIIB–IVB (2) IB (2) II (6) IIIB (1) IB (14)
45% 5-year OS 87% 5-year OS 50% 5-year OS 85% 5-year OS 0% 5-year OS 100%, 4–18 months, NED 0%, died after 3–12 months One pt alive at 63 months, one pt lost to follow-up 50% DFS (8–42 months) 0% DFS 71%, DFS at median follow-up 28.5 months
IIB (5) IIIB (3) I (10) II (8) III (1) IV (2) IB (1) IIB (1) IIIB (1) IB (2) II (7)
60%, DFS at median 28.5 months 33%, DFS at median 28.5 months 50%, 5-year OS 36%, 5-year OS 0%, 5-year OS 0%, 5-year OS 0%, 5-year OS 0%, 5-year OS 0%, 5-year OS Alive 5, 10 months 57%, 2-year DFS, two lost to follow-up
IIIB (2)
50% 2-year OS
S S + RT RT RT + S RT S + RT RT/nothing S/nothing S/S + RT + CHTH RT + CHTH 7 pts: S 5 pts: S + RT 2 pts: S + RT + CHTH Not stated Not stated S (RT not stated) RT RT RT S + RT + CHTH S + RT + CHTH CHTH + RT S + RT 5 pts: S + RT + CHTH 2 pts: CHTH S + RT + CHTH/CHTH
2004
Hopkins and Morley [42]
2004
Deshpande et al. [8]
2006
Kuroda et al. [9]
S, surgery; RT, radiotherapy; CHTH, chemotherapy; pts, patients; OS, overall survival; DFS, disease-free survival; NED, no evidence of disease.
As GCC often affects young women, some authors have considered preservation of the patient’s ovaries during radical surgery for early-stage GCC. The successful treatment of a patient with FIGO Stage IB1 disease with conization and laparoscopic lymphadenectomy has been reported [30], but there are also two documented cases of ovarian metastases [31,32]. The aggressive nature of this tumour should be a contra-indication for ovarian conservation in patients with GCC of the uterine cervix. The treatment strategy in patients with advanced disease is downstaging to make the disease operable. Patients with FIGO Stage IIB bulky and Stage IIIB disease following neoadjuvant intraarterial chemotherapy, treated with carboplatin–etoposide–epirubicin or cisplatin–etoposide–mitomycin C, had surprisingly good responses [33,34]. Multimodal treatment with postsurgical radiochemotherapy based on paclitaxel–carboplatin has been shown to be effective [22]. Paclitaxel–carboplatin has also been shown to be effective in recurrent cancer or in primary neoadjuvant treatment of bulky tumours [35–37]. Cases that have not responded to chemotherapy have also been reported [38–40]. The question concerning the treatment of patients with advanced GCC remains unanswered. Patients with FIGO Stage IIB bulky and Stage III disease can be treated with radical radiochemotherapy or multidrug chemotherapy. Once remission is achieved, radical hysterectomy with lymphadenectomy should be considered. In cases with FIGO Stage IVB disease, palliative chemotherapy using paclitaxel–carboplatin does not prolong survival [38]. The issue of chemotherapy requires further study. Due to huge variation in the treatment methods used, it is difficult to draw conclusions regarding therapy and outcome. Prognosis GCC is considered to be refractory to both radiation and surgical therapy [2]. Glucksmann and Cherry [1] noted that, after irradiation, the glassy cells enlarged and occasionally showed some parakeratosis, but typically they exhibited no increased differentiation in the form of keratinization or mucin production. Littman et al. [2] only observed marked radiation changes in one of
eight operated cases. These observations suggest that irradiation alone leads to a poor response in bulky tumours. The reason for the poor surgical outcomes is that many patients were understaged, which played a role in poor prognosis rather than the tumour being less sensitive to treatment, as described previously [41], patients were not treated properly. Patients should be evaluated for the presence of disseminated disease before starting definitive treatment. The staging process should be completed as quickly as possible due to rapid growth of the tumour. GCC has a reputation for a particularly poor prognosis, but there has been significant improvement in diagnostic possibilities with the introduction of CT, MRI and PET. In older studies, the 5-year survival rate was reported to be between 13% and 30% [2,16,19,42–44]. In some studies, average survival was less than 1 year. Multimodal therapy changed this grim outlook for early-stage patients, and 5-year survival is now 80% in patients with FIGO Stage I disease [4,21]. A patient with FIGO Stage I or Stage II disease is curable, but outcomes for patients with FIGO Stage III or Stage IV disease remain dismal. Hopkins and Morley undertook an analysis of material published before 1991 [42]. Table 1 shows a summary of outcomes published recently, excluding case reports and histopathological examinations where clinical data were missing.
Future direction Unfortunately, publications concerning GCC are scarce. This review of the available literature still contains insufficient information, underscoring the need to conduct retrospective analyses from the last 20 years in several centres. This would enable a clinical review to be undertaken, summarizing treatment outcomes using modern diagnostic methods and adequate therapy. It appears that a 3-year follow-up period is sufficient for a reliable assessment of survival in patients with GCC. As noted above, GCC exhibits Her-2/neu overexpression in 45% of cases. Following detection of this protein, the use of the antiHER2 monoclonal antibody trastuzumab in the management
Please cite this article in press as: Zolciak-Siwinska A, Jonska-Gmyrek J. Glassy cell carcinoma of the cervix: a literature review. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.03.035
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can be considered. Future studies should investigate the most efficient chemotherapy regimen. Condensation A multimodal approach increases the chance of cure for patients with FIGO Stage I and II glassy cell carcinoma. Conflict of interest None declared. References [1] Glucksmann A, Cherry C. Incidence, histology and response to radiation of mixed carcinomas (adenocanthomas) of the uterine cervix. Cancer 1956;9:971–9. [2] Littman P, Clement PB, Henriksen B, et al. Glassy cell carcinoma of the cervix. Cancer 1976;37:2238–46. [3] Gray HJ, Garcia R, Tamimi HK, et al. Glassy cell carcinoma of the cervix revisited. Gynecol Oncol 2002;85:274–7. [4] Lotocki RJ, Krepart GV, Paraskevas M, Vadas G, Heywood M, Fung FK. Glassy cell carcinoma of the uterine cervix: a bimodal treatment strategy. Gynecol Oncol 1992;44:254–9. [5] Johnston GA, Azizi F, Reale F, Jones HA. Glassy cell carcinoma of the cervix: report of three cases. J Nat Med Assoc 1982;74:361–3. [6] Cherry CP, Glucksmann A. A histology of carcinomas of the uterine cervix and survival rates in pregnant and non-pregnant patients. Surg Gynecol Obstet 1961;113:763–76. [7] Zhu HT, Li SX. Glassy cell carcinoma of cervix: a clinicopathologic analysis of 5 cases. Zhonghua Bing Li Xue Za Zhi 2011;40:523–7. [8] Deshpande A, Kotwal M, Bobhate S. Glassy cell carcinoma of the uterine cervix: a rare histology. Report of three cases with a review of the literature. Indian J Cancer 2004;41:92–5. [9] Kuroda H, Toyozumi Y, Masuda T, et al. Glassy cell carcinoma of the cervix: cytologic features and expression of estrogen receptor, progesterone receptor and Her2/neu protein. Acta Cytol 2006;50:418–22. [10] Kim SK, Shim HS, Lee KG, An HJ, Lee KR, Cho NH. Glassy cell carcinoma predominantly commits to a squamous lineage and is strongly associated with high-risk type human papillomavirus infection. Int J Gynecol Pathol 2009;28:389–95. [11] Kenny MB, Unger ER, Chenggis ML, Costa MJ. In situ hybridization for human papillomavirus DNA in uterine adenosquamous carcinoma with glassy cell features (‘glassy cell carcinoma’). Am J Clin Pathol 1992;98:180–7. [12] Kato N, Katayama Y, Kaimori M, Motoyama T. Glassy cell carcinoma of the uterine cervix: histochemical, immunohistochemical, and molecular genetic observations. Int J Gynecol Pathol 2002;21:134–40. [13] Hirai Y, Kawamata Y, Takeshima N, et al. Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. Int J Oncol 2004;24:977–86. [14] Atlas I, Gajewski W, Falkenberry S, Granai CO, Steinhoff MM. Absence of estrogen and progesterone receptors in glassy cell carcinoma of the cervix. Obstet Gynecol 1998;91:136–8. [15] Reis-Filho JS, Fillus Neto J, Schonemann E, Sanderson A, Schmitt FC. Glassy cell carcinoma of the uterine cervix. Report of a case with cytohistologic and immunohistochemical study. Acta Cytol 2001;45:407–10. [16] Pak HY, Yokota SB, Paladugu RR, Agliozzo CM. Glassy cell carcinoma of the cervix. Cytologic and clinicopathologic analysis. Cancer 1983;52:307–12. [17] Khalbuss WE, Pantanowitz L, Monaco S. Cytomorphology of unusual primary tumors in the Pap test. Cytojournal 2013;10:17. [18] Chung JH, Koh JS, Lee SS, Cho KJ. Glassy cell carcinoma of the uterine cervix. Cytologic features and expression of estrogen and progesterone receptors. Acta Cytol 2000;44:551–6.
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