A NEW LOOK ON INTESTINAL SMOOTH MUSCLE TUMOURS: CLINICAL, HISTOLOGIC AND
IMMUNOHISTOCHEMICAL ASPECTS FOR RECLASSIFICATION
C.P.H.J. Maas, E-mail: cerielmaas@yahoo.com
According to the histological classification of tumours of the intestines of domestic animals
published by the World Health Organization, primary tumours of the intestinal tract can be of
epithelial, neuroendocrine, haematopoietic or mesenchymal origin (1). Most gastrointestinal (GI)
mesenchymal tumours with smooth muscle appearance have been diagnosed as either leiomyoma
(LM) or leiomyosarcoma (LMS) based on light microscopic examination of haematoxylin and eosin
(HE) stained tissue sections (2). Histological differentiation between benign and malignant
tumours is carried out by scoring tissue differentiation, nuclear pleomorphism, cellularity, presence
of nucleoli, mitotic count, and amount of necrosis, bleeding and inflammation present in the tissue
section (3,4). However, if these tumours are evaluated using immunohistochemical (IH) analysis
they actually prove to be a heterogeneous group of mesenchymal tumours of which some fail to
express smooth muscle markers (1,5), which may suggest another origin than smooth muscle
tissue. IH and ultrastructural studies of these tumours in human and veterinary patients show
differentiation towards either smooth muscle (myogenic), or neural tissue (neurogenic), a
combination of both (mixed), or undifferentiated tissue (anaplastic) (1,2,6). IH stains enable
differentiation between tumours from smooth muscle origin and stromal tumours.
In the human and veterinary literature, various IH stains are reported: Smooth muscle actin (SMA)
and desmin are used as markers for myogenic differentiation; S-100 is applied as a marker of
neurogenic differentiation; vimentin is reported as an indicator of mesenchymal origin of tissue and
KIT (CD 117) is used as a marker of a receptor tyrosine kinase. This receptor tyrosine kinase can
be found in several tissues including hematopoietic progenitor cells, mast cells, melanocytes and
the interstitial cells of Cajal (ICC). These ICC form a network in the GI tract that coordinates GI
peristalsis (2,7,8).
In humans, many of these tumours were formerly diagnosed as smooth muscle tumours but have
been reclassified as gastrointestinal stromal tumours (GIST), which in human medicine are defined
as KIT expressing tumours. Uncontrolled activity of KIT is an important step in the development of
GIST (1,7). Apart from the primary surgical therapy in humans, an additional medical treatment
under investigation is selective receptor tyrosine kinase inhibitor (imatinib mesylate) therapy (8).
In veterinary medicine, a higher incidence of malignant tumours with smooth muscle appearance is
reported in the small intestine and caecum, in contrast to benign tumours which were located more
often in the stomach (2,5,7). A retrospective study (9) was performed in canine patients, which
had been diagnosed with either LM or LMS of the small intestine and caecum, by means of
histological evaluation of paraffin-embedded and HE-stained tissue sections. Clinical data (patient
signalment; medical history; clinical, diagnostic imaging and surgical findings; survival data) were
reviewed, from medical records and telephone interviews with the veterinarian or owner. All HE
slides were (re)evaluated and scored. The original tissue sections were all investigated for
expression of SMA, desmin, S-100, vimentin and KIT.
The following method for (re)classification of intestinal tumours with light microscopic appearance
of smooth muscle was used (also see the flow-chart):
- LM are histological benign, express either or both SMA and desmin, with or without expression of
vimentin, and do not express S-100 and KIT. If the tumour should express KIT and vimentin, or S100 and vimentin it is reclassified, respectively, as GIST or GIST-like, regardless of histological
appearance.
- LMS are comparable to LM, but these tumours show a malignant appearance on histology.
- GIST express KIT and vimentin, either with or without expression of SMA, desmin and S-100.
They can show both a benign or malignant histological appearance.
- GIST-like tumours are histologically and IH identical to GIST but lack expression of KIT.
In this study (9) of which only part of the data is reported here, 47 dogs were included with small
intestinal tumours. Of the 40 dogs with original diagnosis of LMS, one was reclassified as LM, 17
were reclassified as GIST and 13 as GIST-like; of the seven dogs originally diagnosed with LM,
two were reclassified as GIST and four as GIST-like. In 25 patients, the tumour was located in the
caecum. Of the 23 tumours originally diagnosed as LMS, 22 were reclassified as GIST and one as
GIST-like. The two tumours originally diagnosed as LM were reclassified as one GIST and one
GIST-like tumour.
Mean age for dogs with small intestinal tumours (9.1± 2.3 years) was lower than for dogs with
caecal tumours (10.7± 1.9 years). In contrast to dogs with intestinal tumours which all showed
clinical signs, four dogs with caecal tumours showed no clinical signs at all and the mass was an
incidental finding. In dogs with intestinal tumours, weight loss was observed more often, whereas
intestinal perforation and peritonitis were observed more commonly in dogs with caecal tumours.
In general the caecal tumours showed higher scores for necrosis and bleeding. Between the
different reclassified tumours, the small intestinal LMS showed most nuclear pleomorphism,
poorest differentiation, most mitosis and nucleoli. Of the investigated variables, an increased
tumour diameter was observed an important negative prognostic indicator and castrated or spayed
dogs were observed to have better survival statistics than intact dogs.
For the 42 dogs with small intestinal tumours that were surgically-treated, the overall 1- and 2-year
survival time was 63% and 52% whereas, for the 19 dogs with caecal tumours that were surgically
treated, this was 84% and 66% respectively. Of the surgically-treated dogs, nine with a small
intestinal tumour and one with a caecal tumour, died within 15 days because of surgery or tumourrelated complications. For the remaining dogs with small intestinal tumours, the 1- and 2-year
recurrence free period was 80% and 67% whereas, for the dogs with the caecal tumours, this was
83% and 62% respectively.
IH analysis showed that many GIST (1,2,7) and GIST-like tumours (9) can display differentiation in
mixed myogenic and neurogenic direction, which is most suggestive of a relationship with primitive
mesenchymal cells capable of pluripotential differentiation (1). The ICC are in close contact with
smooth muscle cells and nerve fibres and they, like GIST, express KIT. Differentiation only in
myogenic direction without expression of KIT is an indication of smooth muscle origin (e.g. LM or
LMS) and solitary differentiation in a neurogenic direction can be suggestive of a tumour of neural
origin (e.g. peripheral nerve sheath tumour)(1). Tumours otherwise resembling GIST, but showing
no KIT expression, were reported in veterinary (7) and human patients (10,11). These tumours
were classified as GIST-like tumours in this report (9) to distinguish them from ‘true’ GIST.
Staining intensity, for the IH analysis, were observed to range from very intense with strong
punctuated or fibrillar staining to a vaguely positive cytoplasmic background staining, sometimes
even within the same tumour. The IH results in this study show similarities with previous reports in
dogs (2,7) but also major differences. This may be explained by differences in antibody
manufacturers and production methods, antibody (in)compatibility with canine tissue, suboptimal
antigen preservation, suboptimal or abnormal antigen expression in tumours and population
differences (7).
In this study, no significant influence on prognosis after surgical removal could be identified based
on tumour type (LM, LMS, GIST or GIST-like), histological or IH characteristics. Even dogs with
tumours with very malignant histological appearance can expect long-term survival if complete
excision of the tumour is accomplished. Since results of trials with imatinib mesylate seem
promising in humans (12), determining KIT expression may prove to be of clinical importance in
case of unresectable masses, recurrences, and/or metastases in dogs for future treatment.
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