Villoglandular papillary adenocarcinoma was first described by Young and Scully in 1989 as a distinct entity with the histological features of exophytic growth proliferation, villous and papillary architecture and mild to moderate nuclear atypia. We report one case of villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix with lymph node metastasis and reviewed the clinicopathological features of six other cases reported in the literature. Our patient is the seventh similar reported cases. They ranged in age from 29 to 54 (mean, 41) years. Five had lymphovascular invasion. All except our patient were treated with radical hysterectomy and radiotherapy. She was followed-up for 7 months and unfortunately died due to chest infectio

Geok, Chin Tan

Manickam Swaminathan,

Md Ali Siti Aishah,

Mohd Dali Ahmad Zailani Hatta,

Mohd Sidik Shiran,

Poo, Ling Ong

English

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Med & Health 2006; 1(1): 85-90 Villoglandular Papillary Adenocarcinoma of the Uterine Cervix with Lymph Node Metastasis - A Case Report and Review of the Literature  1Geok Chin Tan, 4Mohd Sidik Shiran, 1Manickam Swaminathan, 1Md Ali Siti Aishah, 2Poo Ling Ong, 3Mohd Dali Ahmad Zailani Hatta  Department of 1Pathology, 2Pharmacy, and 3Obstestrics & Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur. 4Department of Pathology, Faculty of Medicine, Universiti Putra Malaysia.    ABSTRAK  Adenokarsinoma papilari-viloglandular telah pertama kali dihuraikan oleh Young dan Scully pada tahun 1989 sebagai suatu entiti tersendiri dengan ciri-ciri histologi seperti pertumbuhan eksofitik, struktur vilus dan papilari serta atipia nukleus yang sedikit ke sederhana. Kami melaporkan satu kes adenokarsinoma papilari-viloglandular serviks dengan metastasis ke nodus limfa dan mengkajisemula ciri-ciri klinikopatologi enam kes yang telah dilaporkan. Pesakit ini merupakan kes ketujuh dengan ciri-ciri yang sama seperti kes-kes yang telah dilaporkan. Umur ketujuh-tujuh pesakit adalah diantara 29 hingga 54 tahun (min, 41). Diantara tujuh kes ini, lima mempunyai invasi limfovaskular. Semua kecuali pesakit ketujuh telah dirawat dengan histerektomi radikal dan radioterapi. Jagaan susulan pesakit ketujuh adalah 7 bulan, malangnya beliau  telah meninggal dunia akibat infeksi respiratori.  Kata kunci: adenokarsinoma papilari viloglandular, adenokarsinoma, serviks   ABSTRACT  Villoglandular papillary adenocarcinoma was first described by Young and Scully in 1989 as a distinct entity with the histological features of exophytic growth proliferation, villous and papillary architecture and mild to moderate nuclear atypia. We report one case of villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix with lymph node metastasis and reviewed the clinicopathological features of six other cases reported in the literature. Our patient is the seventh similar reported cases. They ranged in age from 29 to 54 (mean, 41) years. Five had lymphovascular invasion. All except our patient were treated with radical hysterectomy and radiotherapy. She was followed-up for 7 months and unfortunately died due to chest infection.  Key words: villoglandular papillary adenocarcinoma, adenocarcinoma, cervix    Address for correspondence and reprint requests: Dr Tan Geok Chin, Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur. Email: tan_geok_chin@yahoo.com 85 Tan GC et. al. Med & Health 2006; 1(1): 85-90INTRODUCTION  Adenocarcinomas account for 10–20% of invasive cervical carcinomas (Young RH et al 1990). Young and Scully (1989) first described a new subset of cervical adenocarcinoma that was designated as ‘‘villoglandular papillary adenocarcinoma (VGPA) of the uterine cervix’’ in 1989. The histological features of VGPA are exophytic growth, papillary architecture and mild to moderate cellular atypia. It has been reported as a distinctive histological subtype which developed in relatively young women (33-52 years old) and has a favourable prognosis (Young RH et al 1989, Hopson L et al 1990, Jones MW et al 1993, Reed W et al 1993, Costa MJ et al 1995). Approximately 80 cases of VGPA have been reported in the literature (Young RH et al 1989, Jones MW et al 1993, Kaku T et al 1997, Stanley-Christian H et al 1997, Khunamrnpong S et al 2001). Its incidence has been quoted as 3.7-4.8% of the adenocarcinoma of the cervix (Garcea A et al 2003). There are only six cases of VGPA with lymph node metastasis reported in the literature, of which five showed lymphatic space permeation in the main tumour (Kaku T et al 1997, Utsugi K et al 2002, Khunamornpong S et al 2001, Garcea A et al 2003). We report a case of VGPA with right obturator lymph node metastasis and a review of the six similar cases reported in literature.   CASE REPORT  A 45-year-old multigravid Malay housewife presented with a one week history of generalised abdominal pain, which was intermittent, sharp stabbing in nature and aggravated by inspiration. She had two full term spontaneous vaginal deliveries that were antenatally uneventful. She was a known diabetic and hypertensive on metformin and prazosin for the past eight years. She never had a pap smear done. There was no family history of gynecological malignancy, smoking or alcohol consumption. There was no history of oral contraceptive usage. She was pale, and weighed 67 kilograms. Systemic examinations were unremarkable. Cervical examination revealed a nodular exophytic, friable, hemorrhagic growth, arising from the posterior wall of the cervix, measuring 2.0 cm in diameter. A piece of the tissue detached during manipulation. A biopsy was obtained, with the clinical impression of cervical carcinoma stage IB.  Microscopically, the cervical biopsy specimen was composed of fragments of polypoidal tissues with villous and papillary fronds arranged in complex branching pattern. The papillae were lined by glandular epithelium displaying mild to moderate nuclear atypia (Figure 1). Mitotic figure count was brisk (90/10 high power field). Lymphovascular invasion was not present. She was planned for a Wertheim hysterectomy, however, during the operation, frozen section detected right obturator lymph node metastasis (Figure 2). Wertheim hysterectomy was abandoned due to the advanced disease, instead, a bilateral salphingoophrectomy, myomectomy for leiomyoma and right iliac and obturator lymphadenectomy were performed. She also received 30 doses of external radiotherapy with concurrent chemotherapy of five cycles of weekly cisplatin. Unfortunately she died seven months after the surgery due to chest infection.   A synopsis of the clinicopathological features of villoglandular papillary adeno-carcinoma of uterine cervix with lymph node metastasis in the literature  There are approximately 80 cases of VGPA ever reported in the literature. Of these, six cases presented with lymph node metastasis (7.5%). A synopsis of the clinicopathological features of the above six cases together with our present case is listed in table 1. The ages ranged from 29 86 Villoglandular Papillary Adenocarcinoma of the Uterine Cervix Med & Health 2006; 1(1): 85-90                      Figure 1: Exophytic tumour composed of villous and papillary architecture (H&E, 10x magnification)                        Figure 2.  Histological section of the right obturator lymph node showing infiltration by metastatic adenocarcinoma (H&E stain, 20x magnification).    87 Tan GC et. al. Med & Health 2006; 1(1): 85-90   Table 1: Clinicopathological features of reported cases of villoglandular papillary adenocarcinoma with lymph node metastasis  Case Author Age Clinical presentation Stage LVI Lynph node metastasis Mitotic figure count Treatment Follow up Outcome 1 Kaku T et al 1997 (2 cases) 54 Abnormal uterine bleeding IIB Positive Positive (Right obturator lymph Node) - RAH with ERT 46 months DOD 2  33 Abnormal uterine bleeding IB Positive Positive (Left external iliac and left obturator lymph node) - RAH with ERT 10 months NED 3 Utsugi K et al 2002 48 Genital bleeding and vaginal discharge IIB Positive Positive (Right external iliac lymph node, left external iliac lymph nodes, and obturator lymph nodes) 105/10 HPF  Wertheim hysterectomy with pelvic lymphadenectomy and bilateral adenexectomy  with whole pelvic irradiation 17 years NED 4-5 Khunamornpong S et al 2001 (2 cases) - - IB-IIA Positive Positive - RAH with ERT 21-144 months NED 6 Garcea A et al 2003 29 Postcoital bleed IIB Negative Positive (Right obturator lymph node) - RAH with ERT 34 months NED 7 Present case 45 Abdominal pain IB Negative Positive (Right obturator lymph node) 90/10 HPF Bilateral salphingoophrectomy and lymphadenectomy with ERT and chemotherapy 7 months Died of Chest Infection  DOD - Died of disease, NED - No evidence of disease, RAH - Radical hysterectomy,    ERT - External radiation therapy, LVI - Lymphovascular invasion, HPF - High power field        88 Villoglandular Papillary Adenocarcinoma of the Uterine Cervix Med & Health 2006; 1(1): 85-90 to 54 years (mean, 41 years). The clinical presentation includes abnormal uterine bleeding (43%), vaginal discharge (14%), postcoital bleeding (14%) and abdominal pain (14%). Five cases had lymphovascular invasion (71%). The obturator lymph node (100%) is the commonest site of metastasis, with greater propensity towards the right side, followed by the external iliac lymph node (40%). The mitotic figure count reported by Utsugi K et al (2002) and the present case were 105/10HPF and 90/10HPF, respectively. All cases were followed up between seven months to 17 years, of which two died (28.6%), one due to the disease and the other because of chest infection.  DISCUSSION  Villoglandular papillary adenocarcinoma is a distinct entity and rare histological variant of cervical adenocarcinoma, which is believed to have a favourable prognosis and predominantly develops in young women with oral contraceptive use (Young RH et al 1989, Jones MW et al 1993). Young and Scully (1989) described a case of oral contraceptive use in their 13 cases of VGPA. Later, Jones et al (1993) demonstrated a statistically significant difference in the incidence of oral contraceptive use in five of the 24 VGPA. Other published series showed no consistent association between oral contraceptive use and villoglandular papillary adenocarcinoma, hence it remains debatable (Garcea A et al 1988). The three important histopathological features of VGPA are 1) an exophytic growth pattern, 2) papillary architecture and 3) mild to moderate nuclear atypia. The epithelium can be a mixture of endometrial, endocervical and intestinal differentiation. The differential diagnosis of VGPA includes 1) serous papillary adenocarcinoma in which complex papillae lined by markedly atypical nuclei with high mitotic activity are present, 2) endocervical adenocarcinoma with a minor villoglandular component, and 3) minimal deviation adenocarcinoma, with a diffusely infiltrative growth pattern and absence of cytologic atypia. Young and Scully (1989) mentioned that VGPA should be reserved for those tumours composed exclusively or almost exclusively of villoglandular papillary pattern (Young RH et al 1989). Various authors have reported the association of other patterns, for example squamous cell carcinoma (Kaku T et al 1997), small cell carcinoma (Van Nagell JR et al 1988) and adenocarcinoma in situ (Jones MW et al 1993). Hence, a thorough search for coexistence of a different malignancy such as squamous cell carcinoma, small cell carcinoma, etc. is mandatory. In most malignancies, the tumour size, depth of invasion, lymphovascular invasion and lymph node metastasis are considered histological risk factors for recurrence. Utsugi K et al (2002) tried to determine the relationship between mitotic figure counts with incidence of lymph node metastasis. They found a significant difference in mitotic figure count of 105/10HPF in their patient with lymph node metastasis, as compared with 12 other patients without lymph node metastasis where the median mitotic figure count was 28/10 HPF (range between 4-70/10 HPF) (Utsugi K et al 2002). The mitotic figure count for our patient is 90/10 HPF, which supports this observation. Various reports recommend conservative management, i.e. a cone biopsy, after a careful review of the histopathological findings (Young RH et al 1989, Jones MW et al 1993). We emphasise that a careful search for any lymphovascular invasion, coexistence of a different tumour such as squamous cell carcinoma or small cell carcinoma and mitotic figure count be carried out, and when present, they should be included in the histopathological report. These should be considered as poor prognostic factors for VGPA.  All the seven VGPA cases with lymph 89 Tan GC et. al. Med & Health 2006; 1(1): 85-90node metastases received radiotherapy and after a range of follow up of seven months to 17 years, six of the seven cases (86%) showed no evidence of disease. Although the number of cases is too small to give any conclusive comments, VGPA with lymph node metastases seems to have a better outcome after radical hysterectomy followed by radiotherapy and chemotherapy. Van Nagell JR, Powell DE, Gallion HH, Elliott DG, Donaldson ES, Carpenter AE, Higgins RV, Kryscio R and Pavlik EJ. Small cell carcinoma of the uterine cervix. Cancer 1988; 62:1586-1593. Young RH, Scully RE. 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Villoglandular papillary adenocarcinoma of the uterine cervix with lymph node metastasis - A case report and review of the literature

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