Malignant neuroendocrine tumour of the appendix in childhood with loco-regional lymph node invasion

Laparoscopic appendicectomy is a common procedure in the paediatric age group. Rarely
has an unexpected diagnosis of a malignant neuroendocrine tumour of the appendix been
noted. Interestingly benign neuroendocrine tumours are the most common tumour of the
gastrointestinal tract in children, however malignant neuroendocrine tumours are rare
1]. Table 1 highlights the key publications on malignant neuroendocrine tumours within the paediatric
population. Definitive incidence reporting across the literature is lacking, with
varying incidences being reported. However, Parkes et al. 2] has been referenced widely in the literature with an incidence of 1.14 per million
children. The other large study by Boxberger et al. concluded that the incidence was
1 per 100,000 children, a value that is widely referenced in the literature.

Table 1. Highlights the incidence of malignant neuroendocrine tumours in the literature

Up to 90% are diagnosed incidentally after laparoscopic appendicectomy 1]. Usually there is a large female predominance 3]. This is interesting, when one considers the recent trend in the literature looking
at the conservative management of acute appendicitis in children 4].

The presenting features of both benign and malignant neuroendocrine tumours usually
follow that of acute appendicitis as highlighted in our case. The well described carcinoid
syndrome of flushing, diarrhoea and cardiac disease is rarely reported within the
paediatric population as this is associated with liver or retroperitoneal metastases.
It is in such cases that the 5 hydroxyindoleacetic acid (5HIAA) testing is positive
1],3],5],6].

Boxberger et. al studied neuroendocrine tumours in children over a five year period. They noted that
mean age of presentation was 13 yrs (4.5-19.5), the majority of those presented with
signs of acute appendicitis and the diagnosis was made histologically. The location
of the tumour similar to our case primarily was at the apex of the appendix (70%)
with extension into the mesoappendix in 63%. Extension into the mesoappendix was more
likely if the size of the primary tumour was over 15 mm.

It has been confirmed across the literature that site, size and grade are significant
in predicting aggressive behaviour of tumours 1],7]. Prognosis has been found to be directly related to tumour size. Rossi et al. questioned
whether or not mesoappendiceal involvement was an indicator or poor prognosis, however
their study confirmed previous studies findings, that size is the main determinant
of prognosis 8],9],10].

Decision on further operative treatment after histological confirmation of malignant
neuroendocrine tumours is based on the size of the tumour. If the tumour is less than
2 cm appendicectomy alone is the operation of choice. A low proliferative index, an
apical location of the tumour, and lack of angiolymphatic or mesoappendiceal invasion
are other factors that influence surgery. A right hemicolectomy is the operation of
choice if the tumour is greater than 2 cm, or if there is histological evidence of
mesoappendiceal extension or location of the tumour at the base with caecal extension.
However it must be noted that only 20% of resected specimens will show any residual
disease.

The World Health Organisation revised the classification system for neuroendocrine
tumours in 2010 and places considerable emphasis on the Ki67 proliferative index.
The Ki67 index is used to subdivide the neuroendocrine tumours into G1 or G2 neoplasms.
If the Ki67 index is less than 3%, these are classified as G1. A Ki67 index between
3-20% classifies the tumours as G2. G3 is represented by a Ki67 greater than 20%.
Ki67% has been studied as a factor for predicting metastases or recurrence. In 2013
Yamaguchi et. al investigated Ki67 as a predictive index of tumour spread. This important study reported
that a Ki67 index of 2.8% or greater gave a specificity of 86.8% of having metastases
or recurrence 11]. When assessing Ki67 as a marker for the biologic behaviour of tumours, it must be
considered that Ki67 expression varies during the disease progression. This is not
fully understood at present, but literature available suggests that Ki67 expression
does vary and depending on the time of measurement, Ki67 can result in the WHO classification
being upgraded. This has significant implications for treatment and follow up of these
patients 12].

The presence of lymph node involvement as in our case, is rare and has been reported
sporadically in 4-5% of paediatric cases 13],6]. A review of 414 cases looking at neuroendocrine tumour and metastases found that
only 4.1% of the cases had metastases identified. MacGillivary et. al confirmed that tumours greater than 2 cm and mesoappendiceal invasion are associated
with metastatic disease 6],14]. D’Aleo et. al suggested that a right hemicolectomy for a child with a neuroendocrine tumour of
the appendix is a radical procedure as the prognosis is quite good. 5 year survival
is reported between 90-100%. There is a trend towards limited resection as an alternative
option to the classic right hemicolectomy, with perhaps an ileocaecal resection deemed
appropriate 1].

No definitive follow up has been quoted in the literature. Despite the incidence of
recurrent disease being low, follow up is recommended. In general terms clinical follow
up, including chromogranin A (CgA) and 5 HIAA testing is recommended. No studies have
assessed the sensitivity of these biologic markers to detect metastases or local recurrence
3],15],16]. The ENETS guidelines recommend that if the tumour is less than 1 cm then no specific
follow up is needed. However if there is involvement of lymph nodes, long term follow
up is recommended. MRI or CT is recommended in cases where the initial tumour is greater
than 2 cm, local invasion or metastatic disease are present at diagnosis. MRI should
be considered in the young and in females of childbearing age due to the lower radiation
doses when compared to serial CT scanning. It is recommended that these high risk
patients are followed up at 6 months and 12 months post operatively and annually thereafter.