Case 2 -
Ileal Neuroendocrine Tumor (WHO Grade 1, ENETS/AJCC pT3, pN1, M0) with Surrounding Active Schistosoma Mansoni Infection
Tomas Slavik, Ampath Pathology, Pretoria, South Africa
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Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
ileum obstructed by a firm white tumor with vague focal yellow discoloration and a mural kink.
Microscopy demonstrated nests, acini, cords and single cell strands of neoplastic cells embedded in a
densely fibrous stroma. Tumor cells appeared monotonous with a moderate amount of light eosinophilic
granular cytoplasm. Nuclei were round with focal mild pleomorphism and demonstrated inconspicuous
nucleoli. A maximum of 1 mitosis/10 high power fields and Ki67 index of 1% were noted. Immunoperoxidase
stains for pancytokeratin (CAM5.2), synaptophysin, chromogranin A, CD56 and NSE were strongly positive.
S-100 was negative. No PAS-d staining was found in the neoplastic acinar component, which revealed
luminal CEA positivity. The tumor extended into the subserosal fat without involving the serosal surface
and two of fifteen mesenteric lymph nodes demonstrated metastatic tumor. The patient had no evidence of
other metastatic disease. Surrounding the tumor was a prominent eosinophil-rich granulomatous
infiltrate. This was directed at partly preserved elongated parasitic ova (approximately 120 µm in
length and half as wide). An isolated preserved spine was identified. The ova and spine were positive
for PAS-d and Ziehl-Neelsen stains. Isolated adult worms were also noted (intravenous and displaced into
the bowel lumen).
Case 2 - Figure 5
HE x40 - Monomorphic tumor cells with round nuclei and inconspicuous nucleoli
Case 2 - Figure 6
HE x4 - Extension of tumor into subserosal fat
Case 2 - Figure 7
Ki-67 x10 - Ki67 immunoperoxidase stain showing low proliferative index (1%)
Case 2 - Figure 8
HE x4 - Pronounced granulomatous inflammation directly adjacent to tumor
1. Neuroendocrine tumor
2. Combined neuroendocrine and glandular epithelial tumor
3. Gangliocytic paraganglioma with surrounding active schistosomiasis.
Ileal Neuroendocrine Tumor (WHO Grade 1, ENETS/AJCC pT3, pN1, M0) with Surrounding Active Schistosoma Mansoni Infection.
Gastrointestinal (GI) neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms arising from
the diffuse neuroendocrine system of the gut. Although these tumors have an endocrine phenotype and
characteristics, they also express neural markers, hence the term "neuroendocrine". GI NETs are rare,
but their incidence has been increasing steadily and significantly over the last four decades, at least
partly due to an improvement in the sensitivity of screening techniques . Lower jejunal and ileal
tumors now make up 23–28% of GI NETs and have an age-adjusted incidence rate of 0.28–0.88/100 000
population per year
Lower jejunal and ileal NETs often reveal macroscopic clues which aid in their distinction from
adenocarcinoma and other malignant small bowel tumors. Even large jejuno-ileal NETs usually demonstrate
an intact overlying mucosa. Extensive mural fibrosis (due to fibroblast growth factor production) leads
to muscularis propria thickening and frequent characteristic mural kinking/buckling. Formalin fixation
typically elicits a yellow tumor discoloration and hypervascularity may impart a red hue to the directly
adjacent bowel wall. Approximately 30% of jejuno-ileal NETs are multiple (often present as sessile
polyps) and may be associated with malignant tumors elsewhere in the GI tract
Jejuno-ileal NETs demonstrate a characteristic architecture, as originally documented by Soga and
Most tumors are of enterochromaffin (EC) cell-type (serotonin-producing) and demonstrate
type A (nested or insular) growth, sometimes with admixed type C (acinar, tubular or rosette-like) areas
The much less common L-cell (glucagon-like peptide and PP/PYY-producing) NET of the lower jejunum and
ileum usually demonstrates type B (trabecular or ribbon-like) growth, with minimal fibrosis. This tumor
revealed a type E (mixed) pattern, comprising type A, C as well as focal type B growth. Pure type D
(undifferentiated or sheet-like) growth has not been reported in lower jejunal or ileal neoplasms
Jejuno-ileal NETs have a bland cytology and low mitotic activity/proliferation index.
Secondary features include pronounced stromal fibrosis, which often leads to tumor retraction
artifact. Characteristic vascular mural thickening and intimal elastic sclerosis, combined with stromal
fibrosis, may cause secondary bowel ischemia. Tumor cells are often intimately associated with nerves,
possibly reflecting a histogenetic relationship.
Immunoperoxidase staining reveals positivity for pancytokeratin markers (particularly CAM5.2); CK7 and
CK20 are expressed in <25% of cases . Neuroendocrine markers such as synaptophysin, chromogranin
A/B, CD56, PGP9.5 and the much-derided NSE are positive. Intestinal differentiation is usually
manifested by strong CDX-2 nuclear staining. CEA positivity is present in up to 70% of tumors, most
often as apical/luminal staining in type C areas . Interestingly, approximately 30% of jejuno-ileal
NETs express prostatic acid phosphatase (PAP)
Prominent type C growth in a jejuno-ileal NET may raise the possibility of a combined neuroendocrine
and glandular tumor/mixed adenoneuroendocrine carcinoma (MANEC). Both components of the latter (by
definition each comprising > 30% of the tumor), however, usually have a malignant or high grade
histology . The monotonous cellular morphology, scarcity of mitoses, low proliferation index, absence
of necrosis, as well as diffusely positive neuroendocrine markers and absence of intracellular mucin in
areas of acinar growth exclude MANEC/a non-neuroendocrine glandular component.
Another diagnostic consideration is gangliocytic paraganglioma (paraganglioneuroma), a rare but
distinctive triphasic GI neoplasm which demonstrates an endocrine component. Although uncommonly seen
outside the duodenum, it has been documented in the jejunum and ileum
Admixed ganglion cells
and a prominent S-100 protein positive spindle cell stroma distinguish this tumor from a typical NET.
Nomenclature, grading and staging of lower jejunal and ileal neuroendocrine neoplasms
This ileal neuroendocrine tumor highlights the paradox of GI NETs: innocuous histology associated
with a potential for aggressive biologic behavior. Although Oberndorfer initially considered these
proliferations benign when he first coined the term "karzinoide tumoren" (carcinoma-like tumors) in 1907
, it is now widely accepted that they represent low grade malignancies. In contrast to other GI
NETs, tumors of the lower jejunum and ileum of comparable size demonstrate a more aggressive behavior
Even small (<1 cm) jejuno-ileal NETs demonstrate metastatic spread in 30% of cases
non-localized disease present in 70% of patients at diagnosis .
Whereas the histopathologic diagnosis of a jejuno-ileal NET is seldom challenging, the application of
standardized nomenclature, grading and staging is. Terminology in the literature remains confusing, with
the words "endocrine" and "neuroendocrine", as well as "neoplasm", "tumor", "carcinoma" and "carcinoid"
often used interchangeably . Various grading schemes are in use, and until recently no dedicated
staging system existed.
The previous World Health Organization (WHO 2000) classification of GI neuroendocrine neoplasms
attempted to develop a coherent terminology and advance prognostic stratification . The inclusion of
clinical and stage-related information in a hybrid grading scheme, and the creation of an "uncertain
malignant potential" category were problematic, however. Based on recommendations by the European
Neuroendocrine Tumor Society (ENETS)
, the revised 2010 WHO classification has attempted to rectify
these problems (although it has again changed the nomenclature). The term "neuroendocrine tumor (NET)"
has now been adopted for low and intermediate grade neoplasms, whilst the term "neuroendocrine carcinoma
(NEC)" is used for high grade neoplasms. A laudable change has been the separation of histological
grading and staging parameters , which has led to a more rational terminology and enabled grading of
advanced tumors for therapeutic decision making. Additionally, the current scheme recognizes the role of
tumor heterogeneity (with respect to site and cell type), and the low grade malignant potential of
virtually all GI NETs.
The 2010 WHO classification delineates three grades of GI neuroendocrine neoplasms (table 1). Well-
and poorly-differentiated neuroendocrine neoplasms are separated on the grounds of morphology and
proliferative rate. A tumor with high grade morphology and/or grade 3 proliferative activity is
considered a neuroendocrine carcinoma (NEC): small or large cell type. Whilst evidence exists for the
prognostic significance of the new grading scheme in foregut NETs, it remains to be validated for
intestinal NETs. Furthermore, mitotic count on an adequate NET tissue specimen is generally accepted as
an accurate indicator of proliferative rate, but the role of Ki67 (particularly in the US) remains
contentious . This marker is not routinely utilized in all laboratories, can demonstrate
heterogeneous staining and disagreement exists on the optimal method to evaluate the Ki67 index.
Additionally, definitive clinical data to determine the optimal proliferative threshold for each tumor
grade are still lacking . Despite these limitations, the Ki67 index has been shown to have
prognostic significance in midgut NETs . Ki67 is also of great diagnostic value in distinguishing
between a well-differentiated (low and intermediate grade) NET and (poorly-differentiated, high grade)
neuroendocrine carcinoma on small biopsies, as well as evaluating proliferative rate in biopsy material
with insufficient neoplastic tissue for an accurate mitotic count .
Until recently, no dedicated staging system was available for GI NETs. There are now two widely-used
site-specific TNM staging systems – one devised by ENETS  and the other by the American Joint
Committee on Cancer (AJCC)
, which are broadly based on the staging of conventional adenocarcinomas
of the same site. For the jejuno-ileum, these two NET staging systems are virtually identical 
(table 2). Although representing a definite step forward, these schemes may need refining, including
stratification of the number of lymph nodes involved by metastasis, distinction between nodal micro- and
macrometastases, and substaging of distant metastatic disease .
Evidence-based revision of these staging systems will likely be of value in further refining
jejuno-ileal NET prognostication, as tumor stage at diagnosis remains the most important predictor of
survival. Whilst overall survival at 5 and 10 years for jejuno-ileal NETs is cited as 60% and 43%,
five-year survival for patients with localized tumors is 65–75%, and 50% for those
with non-localized disease . Metastatic involvement of the liver, which will eventually develop in
most patients with jejuno-ileal NETs , also significantly impacts on outcome. In the absence of
hepatic metastases, 5- and 10-year survival rates for patients with a jejuno-ileal NET are 72% and 60%,
respectively; this drops to 35% and 15% if liver metastases are present . Much of this data is
dated, however, and continuing advances in diagnosis and therapy seem to be leading to significant
improvement in the outcome of patients with these tumors, particularly in specialized centers
Although the utilization of uniform and universally accepted nomenclature, grading and staging of
jejuno-ileal (and other GI) NETs remains the ultimate goal, this is not likely to be attained in the
foreseeable future. Pathologists should therefore adhere to a minimum pathology data set when reporting
GI NET cases. This should include specific pathologic variables required for grading and staging (as
well as the specific scheme used), and any other histological features of known or potential prognostic
significance (including vascular/perineural invasion and non-ischemic tumor necrosis). One such
international consensus data set for both biopsy and resection specimens of primary and metastatic GI
NETs has recently been proposed by Klimstra et al . Utilization of such a minimum data set is
advised to ensure seamless and consistent translation of an individual patient's disease into any
existing or revised scheme/system, thus ultimately improving prognostication and enabling optimal
Schistosomiasis and GI NETs
Schistosomiasis (bilharzia) is a trematode parasitic infection affecting some 200 million people
worldwide . Most human infections are caused by three species (Schistosoma
haematobium, japonicum and mansoni); S.
intercalatum and mekongi are less common. Geographic distribution
aids in the distinction between species. Parasite ova are usually identified on urine (S. haematobium) or stool (other Schistosoma spp)
microscopy. Size, morphology and staining characteristics are all of value in typing bilharzia ova in
histologic sections (table 3).
The causal relationship between S. haematobium and squamous cell
carcinoma of the urinary tract is well documented . Some data also suggest a possible association
between S. japonicum and colorectal as well as hepatocellular carcinoma
, but are not uniformly accepted. Potential mechanisms for the role of schistosomiasis in
carcinogenesis include the presence of endogenously produced carcinogens, chronic immunomodulation with
impairment of immunological surveillance, symbiotic action of other infective agents and the presence of
schistosomal toxins. Currently, there is scant literature on an association between schistosomiasis and
GI NETs. Only isolated cases of intestinal schistosomiasis associated with a rectal NET , as well as
appendiceal mixed neuroendocrine and glandular tumors (goblet cell carcinoids)  have been documented.
Whilst underreporting of this association in endemic areas is likely, no data exist to support a causal
role for schistosomiasis in the pathogenesis of jejuno-ileal or other GI NETs. This finding, therefore,
should be considered fortuitous.
Histopathologic diagnosis of a jejuno-ileal NET is seldom challenging, but application of standardized
terminology, grading and staging is. The recent 2010 WHO classification and ENETS/AJCC TNM staging
systems, whilst not without their limitations, have attempted to address problematic issues and past
shortcomings. WHO grading of GI NETs is currently based on tumor morphology and proliferative rate. The
introduction of dedicated GI NET staging systems is a step forward, but these will likely need refining
as more data become available. In the interim, pathologists should adhere to a minimum pathology data
set when reporting on these tumors. At present, no evidence exists to support a causal role for
schistosomiasis in the pathogenesis of GI NETs.
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