Malignant mixed tumour of the parotid gland in a preterm neonate with cytomegalovirus infection

Background

Most salivary gland swellings in children are benign, with mucoepidermoid carcinoma and acinic cell carcinoma being the most common salivary gland cancers in children.1 Malignant mixed tumour of salivary glands is a rare malignancy of all age groups, with very few cases reported in children so far.2 Researchers suggested a possible association between cytomegalovirus (CMV) and the development of salivary gland malignancies.3 In this article, we present the first documented case of this tumour in a fetus that showed infection with CMV. We discuss this group of salivary gland tumours in children, and we explore their possible relationship with viral infections.

Case presentation

A 21-year-old woman presented to the emergency department with severe cramps in the lower abdomen. The complaint started a few hours before the presentation and gradually increased in intensity and frequency. The patient denied associated symptoms such as nausea, vomiting, diarrhoea or dysuria. She had no significant family or surgical history.

Further questioning revealed that the patient is currently in her first pregnancy with a gestational age of about 24 weeks. The last examination was performed before 10 weeks by her doctor, with a normal progression of the pregnancy so far. The patient neither smokes nor consumes alcohol. She denied recent trauma, unusual physical activity and exposure to medications.

In the clinical examination, the vital signs were in the normal range with no fever. The inspection revealed a fundal height that matches the estimated gestational age. The palpation of the abdomen elicited diffuse tenderness in the periumbilical and hypogastric areas with no muscular guarding or signs of peritoneal irritation. Careful palpation showed uterus contractions with suspicion of active labour. The vaginal examination showed cervix dilatation up to 4 cm with effacement of 75% and the membranes were intact.

Investigations

We initiated the diagnostic study with a tocography, which showed regular uterine contractions and confirmed active labour. An emergency ultrasound examination showed a fetus in breech presentation with normal cardiac activity. The abdominal organs were normal with no free fluid. Measurement of the biparietal diameter and the femur length of the fetus confirmed the gestational age of 24 weeks. Surprisingly, the examination identified a heteroechoic mass of about 7×7 cm involving parts of the face. The origin of the mass could not be identified. The fetal heart rate monitoring was normal at 140 bpm. The laboratory values of the mother were in the expected range, including white blood cells and C reactive protein. There were no abnormalities in the urinalysis.

Differential diagnosis

With the above-mentioned constellation of symptoms, examination findings and test results, we were able to exclude common non-obstetric pathologies that can cause lower abdominal pain. The complaints were not typical for gastroenteritis. The absence of leucocytosis, pyuria and tenderness on paravertebral percussion made acute appendicitis or urinary tract infection unlikely. Ovarian cysts could be ruled out using ultrasound.

The patient had regular uterine contractions on the tocogram, which indicates preterm labour at 24 weeks. The differential diagnosis here includes many obstetric pathologies. As the membranes were intact, a premature rupture of membranes could be ruled out. The absence of fever and vaginal discharge and the normal inflammatory markers excluded intra-amniotic infection. Systematic maternal diseases, such as preeclampsia and gestational diabetes, could be also ruled out. The ultrasound study excluded multiple pregnancy and placental abnormalities. Therefore, the most likely cause of the preterm labour in this patient was the detected fetal abnormalities.

Treatment

After an extensive discussion with the patient, we refrained from tocolytic therapy or caesarean delivery due to the potential neoplastic entity that involves the fetus. With further labour progression, the fetus developed deteriorating bradycardia. The vaginal delivery occurred 4 hours later and yielded a dead female with a big mass involving parts of the lower face and mandible (figure 1).

Outcome and follow-up

The mother recovered uneventfully and could be discharged home after a few days. The histological examination of the neonate in the context of the autopsy showed a moderately-differentiated malignant mixed tumour of the left parotid gland (figure 2). The placenta exhibited a liquefactive transformation and the liver showed an infection with CMV. All other organs were within normal limits.

Prenatal testing for CMV was not performed and the mother stated that she had no known history of CMV infection. Later testing in the outpatient setting revealed positive IgG and negative IgM, which indicates a previous asymptomatic CMV infection.

Literature review

The review of the literature confirms that there are no more than 14 reported cases of malignant mixed tumours in the paediatric group. This report presents the first case described in a neonate. Although many cases of pleomorphic adenomas, sialoblastomas and congenital salivary gland anlage tumours were reported in neonates,16 17 we could not identify any reported case of the mixed malignant tumour in this age group.

Table 1 shows the characteristics of the six documented cases that could be retrieved from the literature. Many authors investigated salivary neoplasms in children without finding any case of malignant mixed tumours. For example, no single case was found in the 587 neoplasms that were treated between 1938 and 1975 in the University of Iowa,18 nor in the 21 neoplasms that were managed between 1955 and 1985 at John Hopkins Hospital.19

As table 1 shows, the first two reported cases were described in patients aged 14 and 15 years and were reported by Kauffmann and Stout based on two older publications.20–22 Nonetheless, it is not clear from the provided description if the diagnosis of malignancy was made from the outset or if the tumours were carcinosarcomas ex pleomorphic adenomas.

The youngest reported patient was a 6-year-old boy from The Children Hospital of Los Angeles. After radical resection, the tumour recurred and showed extensive involvement of the face and oral cavity, and the patient died within less than 1 year.9 Four years later, Castro et al described the only reported case in the submaxillary gland in their series that included 2135 primary major salivary gland tumours in children. The patient died a few months later despite the radical treatment.1 The next well-documented case came from Japan in 1994. It described one case of the tumour in a series that included 20 children with salivary gland neoplasms. As with the other cases, the prognosis was poor and the patient died a few months later.5

Kiratli et al were the first authors who dedicated a whole paper to describe a case of this tumour. The patient was a 10-year-old boy who presented with orbital metastasis and intraocular invasion with a primary tumour in the parotid gland. After radical surgery with eye enucleation, there were no signs of recurrence after more than 4 years of follow-up.8 The local infiltration seen in this patient coincides with the extensive local involvement of the face in our case and characterises the aggressive behaviour of this tumour.

Association with CMV

The histologic examination of the neonate in our case showed a synchronous infection with CMV, which raises questions about a possible correlation with the neoplastic process. The postnatal testing of the mother indicated a previous asymptomatic CMV infection. Therefore, it is not known if the acute infection occurred early in the course of pregnancy or if the involvement of the fetus resulted from reactivation during pregnancy. In either case, CMV was transmitted to the fetus and liver involvement was detected on histological examination.

Viruses have always been culprit factors in carcinogenesis. About one century ago, Rous demonstrated that sarcomas can be caused by viruses and was the first to demonstrate this correlation.23 CMV belongs to the herpes group of viruses and is considered one of the many known oncoviruses.3 There is growing evidence that active CMV infection is associated with malignancies in a variety of organs such as the colon, breast and brain.24 It is also presumed that CMV may play a role in the pathogenesis of salivary gland malignancies, as it shows a frequent existence in their ductal epithelium.3

This was initially supported by the finding that ‘purified CMV induces malignant transformation in salivary gland cells in an in vitro mouse model’.24 Furthermore, previous studies hypothesised that CMV might play a role in the pathogenesis of mucoepidermoid carcinoma of salivary glands. The carcinogenesis is initiated by the activation of a signalling pathway that involves the epidermal growth factor receptor, which is also a cellular receptor of CMV.24

Nonetheless, it is difficult to establish a definite correlation between the CMV infection and the carcinogenesis in this case due to the lack of a latency period. Besides, we cannot identify if the preterm labour and premature delivery occurred because of the abnormal fetus or rather because of the consequences of the CMV infection itself. More experimental studies are needed to provide answers to these questions.