Recurrence of Poorly Differenciated Cervical Cancer by Single Splenic Metastasis: Case Report and Literature Review ()
1. Introduction
Cervical cancer is the tenth most common cancer in the world of all ages and all sexes, according to the World Health Organization in 2018. In Europe, the incidence of cancer of the cervix is 13, 4 per 100,000, with a mortality rate of around 5%. In Belgium [1] , there was an incidence of 11.1 per 100,000 (634 cases) in 2015, with 200 deaths, making cervical cancer the 12th most common cancer in women, while remaining a rare cause of death (1.7% of total cancer mortality). Almost entirely attributable to the HPV virus (99%) and its persistence, the incidence has been reduced from 60% to 90% and the mortality rate by 90% since screening with the PAP smear test. Thanks to HPV vaccination in Belgium from 2005 to 2015, the incidence decreased from 12.3% to 11.1%. The impact is still minimal to date but should be more significant in the years to come. In fact, the natural history of precancerous lesions towards invasive cancer is 15 years on average. Nevertheless, efforts are still to be made in the vaccination campaign, especially in the Wallonia-Brussels Federation. Indeed, vaccination coverage is 29% compared to 83% for Flanders [2] . In Belgium, the current coverage of cervical cytology screening, performed every 3 years, is 59%. Despite the almost systematic screening, some patients escape the system and we still see cervical cancer in advanced stages. In the case of invasive cancer [3] , dissemination is preferably done by lymphatic route and hematogenous dissemination occurs often later. Typical preferred hematogenous metastatic sites are the lungs, liver and bone system.
Here we report the case of a recurrence by single splenic metastasis. These splenic metastases are rare and are more often found during autopsies. In the literature, 16 articles relate spleen metastases in the context of recurrent cervical cancer.
2. Case Report
A 41-year-old patient presents to the emergency room for smelly bleeding. The vaginal examination performed under narcosis objectifies a 5 cm cervical mass. The histological analysis of the mass pleads for a florid dedifferentiated epithelial neoplastic process, with a primitive glandular not excluded. The clinical stage according to FIGO is IB. The PET-scan shows a neoplasia of the cervix involving the cervix, the corpus uteri, the left parameter and associated with a bulky left external iliac adenopathy and right common iliac. Pelvic magnetic resonance imaging (MRI) confirms a large tumor lesion of the cervical region of 5cm with infiltration of the parameters and bilateral iliac adenopathies. The rest of the examination is strictly normal. The FIGO stage after imaging is IIB.
Initially, the patient receives 50.4 Gy radiation therapy combined with cisplatin-based chemotherapy on a weekly basis. A new vaginal examination under narcosis shows the persistence of a large friable tumor occupying the cervix and hanging in the vagina of 4 cm. The right parameter is dubious on the internal third. Following this, two brachytherapy sessions with a dose of 7 Gy per session are performed. After a new examination under narcosis, the tumor had shrunk in size and was 3 cm in diameter with a soft parameter. The initial treatment ended with an enlarged hysterectomy with bilateral iliac lymph node dissection for tumor residue. The anatomopathological result confirms a poorly differentiated adenocarcinoma of the cervix of grade 3 of 2 × 1.1 cm with invasion of the right parameter. The surgical margins are clean. 3 out of 19 lymph nodes are invaded. The FIGO stage is IIB, TNM stage ypT2b ypN1. In multidisciplinary oncological consultation, simple monitoring is recommended.
Three years later, the patient presents a recurrence at the splenic level and at the pre-sacral level treated with chemotherapy (paclitaxel and carboplatin 8 cures). 8 months later, the metabolic response to treatment is complete in locoregional and almost complete in splenic location. Three months later, the patient presents a completely asymptomatic and isolated metabolic reactivation at the splenic level measuring 42 mm at MRI with expectant attitude. MRI 6 months later shows an increase in the lesion to 54 × 38 mm (Figure 1). 5 months later, a significant increase in size to 69 × 46 mm (Figure 2) will indicate the performing of a splenectomy.
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Figure 1. T2 weighted hyperintense lesion.
The procedure is performed 18 months after the discovery of this unique lesion in the spleen (Figure 3).
On pathology analysis, it is indeed a recurrence of primary cervical neoplasia with a necrotized tumor metastasis of 5 cm corresponding to an adenocarcinoma of endocervical origin (Figure 4 and Figure 5).
The patient will remain without recurrence to the Pet-scanner performed at 4 and 8 months. But at 13 months, she will present an aggressive recurrence in the form of lung, peritoneal and left adrenal metastases. This recurrence will lead to the patient’s death 14 months after the splenectomy was performed.
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Figure 3. Metastasis in splenectomy specimen.
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Figure 4. Splenic parenchyma infiltrated by the tumor. Arrow: tumor; Star: Splenic parenchyma. (HE; obj 10x).
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Figure 5. Histological image of adenocarcinoma. Arrows: formation of glandular lumen. (HE coloring; 40x lens).
3. Discussion
The follow-up of cervical cancer recommended by the European Society for medical oncology (ESMO) [4] includes, at least a clinical examination (vaginal examination and rectal examination) and an anamnesis with a cervico-vaginal smear (+HPV typing) 1x/3 - 6 months for 2 years then 1x/6 - 12 months for 3 years. After the 5-year period without recurrence, follow-up is done once a year. When two cervico-vaginal smears have a negative HPV typing, normal monitoring is resumed (smear 1x/3 years). If a recurrence is suspected following a clinical sign, a CT scan or PET-CT is performed.
Some authors [5] suggest the use of SCC antigen (squamous cell carcinoma antigen) [5] for epidermoid cancers, and CEA as a tool for monitoring the disease after primary treatment. Indeed, SCC antigen is a glycoprotein whose rate is influenced by tumor transformation. This biomarker is high in 28% - 88% of patients with epidermoid cancer. In the early stages, a high level of SCC-Ag is associated with a risk for recurrence (lymph node metastasis, stromal invasion, invasion of vascular spaces and big tumor size). We did not use SCC antigen but it probably have had little interest in the follow-up of adenocarcinoma.
In the case of splenic metastasis, the most common complaints are weight loss, pain in the left hypochondrium and nausea, which should therefore lead to an X-ray examination. However, in most cases, splenic metastasis is discovered during a follow-up examination in an asymptomatic patient (as in the case of our patient) or during imaging performed for a completely different reason. The risk of splenic metastasis is painful splenomegaly, thrombosis of the splenic vein and splenic rupture [6] .
Splenic metastases are rare entities and are most often associated with lung, breast or melanoma cancers. Their incidence varies between 2.9% and 9% for solid tumors [7] . They are found in more or less 1% of autopsies [8] . Fewer than 100 cases of single spleen metastases have been reported, 50% of which originate from the female genital tract [9] .
To date, in the literature, 16 articles (Table 1 and Table 2) report cases of recurrence in the spleen after primary treatment for cervical cancer, 12 of which describe recurrence of cervical cancer by single splenic metastasis (Table 1). Most cases are published in the form of a case report with review of the literature. In the majority of the situations described, a splenectomy is performed, with anatomo-pathological examination of the nature of the lesion in order to confirm the recurrence [10] . The most frequent histological type is epidermoid cancer. The recurrence delay is between 8 months and 5 years.
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Table 1. Single splenic metastasis (RT = Radiotherapy, BT = Brachytherapy, CT = Chimiotherapy).
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Table 2. Splenic metastasis and other concomitant lesion.
The spread of cervical cancer occurs more often either by local extension or by lymphatic route. The hematogenous pathway is rare. Therefore, the preferred hematogenous metastatic sites are the lungs, the bones, the mediastinum, the supraclavicular nodes and the liver. Furthermore, the pathophysiology of the mode of dissemination of cervical cancer within the spleen has not been clearly studied, but it seems that it is hematogenous [11] . The spleen is an unfavorable environment for the development of metastases. Several reasons have been put forward to explain this rarity of splenic metastases [22] :
1) Rare hematogenous pathway in cervical cancer; 2) the extension is most of the time local; 3) role of the splenic capsule; 4) poor afferent lymphatic vessels in the spleen; 5) tortuosity of the spleen vessels; 6) constant splenic blood flow with contractions in the spleen which force the blood from the sinusoids to go into the splenic veins; 7) anti-tumor antibodies present in the spleen; 8) concentration of phagocytes in the spleen.
Regarding therapeutic management, no consensus was found. Given that splenic recurrence is associated with a poor prognosis, excision of it by splenectomy seems to several authors to be an acceptable therapeutic option, more or less followed by chemotherapy according to certain publications, in order to improve survival [16] . Our patient had a 9 months disease-free survival, but an aggressive recurrence at 13 months.
4. Conclusion
In cervical cancers, splenic metastases are rare entities. The data in the literature is poor. No consensus is therefore determined for the monitoring and therapeutic management of these lesions. Splenectomy nevertheless seems to be the appropriate treatment to provide pathological confirmation of the recurrence and to avoid complications such as splenic rupture or thrombosis of the splenic vein. Monitoring by biomarkers like SCC antigen may be an approach for epidermoid types but this still requires studies. However, the key to this kind of neoplastic pathology is found upstream of the development of the disease through prevention; on the one hand, primary prevention with HPV vaccination and, on the other hand, secondary prevention with screening for precancerous lesions.