Rhabdoid Signet- Ring Mixed Cell Subtype Gastrointestinal Stromal Tumor from the Stomach - Pathohistological and Immunohistochemical Analysis, Differential Diagnosis, Prognosis and Complex Treatment

To Cite This Article: Lena Marinova, Bistra Yordanov, Ruslan Kulinski, Nikolay Evgeniev, Radoslav Georgiev. Rhabdoid SignetRing Mixed Cell Subtype Gastrointestinal Stromal Tumor from the Stomach Pathohistological and Immunohistochemical Analysis, Differential Diagnosis, Prognosis and Complex Treatment. Am J Biomed Sci & Res. 2021 13(3). AJBSR.MS.ID.001867. DOI: 10.34297/AJBSR.2021.13.001867.


Introduction
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of gastrointestinal tract [1,2], although GIST may arise from any portion of the foregut to hindgut, two thirds of stromal tumors originate from the stomach [3]. GISTs are thought to arise from the interstitial cells of Cajal (ICC) [4].
This cKIT immunoreactivity is the best defining feature of GISTs, distinguishing them from true smooth muscle tumors (i.e., leiomyomas and leiomyosarcomas) and tumors arising from neural analysis defining differential diagnosis, prognosis and the need for complex treatment.

Clinical Case
We present a 67-year-old patient with initial bulk complaints in the chest and left lumbar with constant pain and purse secretion.

Objective-local status
Left breast-lumbar area-Swelling, redness, local hyperthermia with blood, pus, and other secretions.
Lung -two-sided purely vesicular breathing without wheezing.

Conclusion from Imaging Diagnostics
Most likely concerns pulmonary carcinoma on the left with engaging mediastalline lymphatic chains, engaging abdominal and mesenteric lymph nodes. А parenchymal mass lesion, originating in the stomach with infiltration of the spleen and gastric fundus is detected. Gastroscopy with biopsy is recommended.

Surgical intervention
An incision on the flender of the left chest followed by fasciotomy with necrectomy and exudat evacuation. Under CT control a percutaneous trans-cut biopsy from the left lung lesion is carried out.         The imaging diagnostics reports local GIST infiltration in spleen with metastases in the lung, liver, mediastinal, abdominal and mesenteric lymph nodes and subcutaneous metastasis.

Immunohistochemical (IHC) analysis from transthoracic lung biopsy
The patient was targeted for specific drug treatment with a tyrosine kinase inhibitor (i.e. Imatinib), which is indicated for inoperable and metastatic GIST.

Discussion
In 2004, Huang XF et al. [10] express an opinion that Leiomyoblastoma, also called bizarre leiomyoma or epithelioid behaviour. Leiomyoblastoma is a rare, smooth muscle tumor of the stomach that occurs chiefly in the antrum [11]. For decades it was thought that the majority of gastrointestinal mesenchymal tumors arose from the smooth muscle, being called "leiomyomas" and "leiomyosarcomas" [12]. Gastric leiomyoblastoma of Martin's myoid tumour or Stout's smooth muscle cell bizarre tumour is a rare benign mesenchymal neoplasia, that may become malignant [13,14]. Leiomyoblastoma and gastrointestinal autonomic nerve tumor (GANT) are old terms no longer used. The new terminology for these tumors is Gastrointestinal stromal tumor (GISTs) [15].
Approximately 60 to 70% of GISTs arise in the stomach, 20 to 30% in the small intestine, 5% in the colon and rectum [4]. The discovery that GISTs could express KIT protein helps establish that GISTs do not originate from smooth muscles. The current thinking is that GIST tumors arise either from stem cells that differentiate towards interstitial cells of Cajal or directly from interstitial cells of Cajal (ICCs) [16]. Only recently it was clarified that this neoplasm is a well-defined disease called GIST, the acronym for gastrointestinal stromal tumor, through the discoveries of its origin from the interstitial cells of Cajal [17] and the expression of c-Kit protein [18].

Diagnosis
Leiomyoblastoma (GIST) is a rare smooth muscle tumor characterized by epithelioid cells with clear cytoplasms and an unknown biological behaviour. Since pre-operative diagnosis is difficult, the optimum strategy during the operation could be determined only by having a thorough knowledge about it beforehand [19]. The most important CT findings for diagnosis of gastric GIST are: location in the body/fundus, predominantly extraluminal growth, peripheral hypervascularity with heterogeneous core [20].
Because most GISTs show an exophytic growth pattern and arise within the muscularis propria of the stomach or intestinal wall, they present as dominant masses outside of the organ of origin [21]. In early disease, the lesion will remain located subepithelially, therefore, the conventional endoscopic biopsy is of value only when positive, since the tumor may be situated deeper. In the endoscopy unit of INCA, the technique was developed to remedy this situation in addition to endoscopic ultrasound [12]. In general, GISTs are characterized by a uniform, monotonous appearance with minimal cytologic atypia or mitotic activity. Nuclear pleomorphism is occasionally evident in a GIST and, when present, is often admixed with the more conventional cytologic features [22]. Many malignant GISTs have areas that appear benign, such that sampling can be a huge problem. It is also conceivable that the area biopsied could be CD117 negative whereas other parts of the tumor are positive, leading to a completely erroneous diagnosis [23]. In our clinical case in the material from the stomach biopsy, we found a slightly pronounced cell dysplasia in single glands, interstitial and Paneth cell metaplasia, hypertrophy of muscularis mucosae with chronically detected inflammation, corresponding to atrophic gastritis without Helicobacter pylori. Paneth cell metaplasia is abnormal and is considered a sign of long-term damage to the tissue and is an indicator of chronic epithelial cell damage [24]. In the clinical case, the endoscopic biopsy of the stomach mucosa is negative. as it is from the stomach mucosa rather than the muscle layer in which the tumor formation expanded (Figure 3). Due to a severe general condition of the patient at a high risk of surgery (gastrectomy), the diagnosis we achieved after a pathochistological and immunohistochemical analysis of the lung biopsy material.

Biological Development
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors in the gastrointestinal tract, form a specific problem as they have the ability to metastasize, even though they may appear to be fully benign [9,25]. GIST often spreads from the original (primary) site to distant locations. If GIST tumors metastasize they usually travel to the liver, or the peritoneum.
Metastases to lymph-nodes and lungs are rare but do occur [16].
A case of recurring GIST of the stomach that metastasized to the spleen and the liver has been published [26]. An interesting pathologist structure we observe in our clinical case is the presence of vorticity cellular pattern (Figure 4 The process of endothelial cell division is essential for angiogenesis and vessel repair [28], as well as for the growth of metastasis from malignant tissue [29]. Tumor vascularization may be a result of a few different potential mechanisms. Apart from angiogenesis, cancer may achieve new vasculature by vessel co-option (using existing vessels), vascular mimicry (the process of forming vessels from tumor cells) and vasculogenesis (involving bone marrow-derived progenitor cells) [30]. In our clinical case, there is no symptoms on the side of the stomach from where the tumor formation originates.
The initial clinical expression of the tumor is by the soft and lung metastasis, followed by liver metastases. In Figure 7/D there is a rich tumor neoangiogenesis, which is one of the causes of rapid hematogenic desimination of a GIST. Tumor blood vessels are type of deer horns, branched and rich blooded, enhancing distant blood metastases. We present an extremely aggressive vascular mimicry GIST, which is manifested by its distant blood metastases in lung, liver and lymph nodes ( Figure 1A/B, Figure 2A/B).

Prognosis
A panel of five criteria (tumor size, mitotic rate, proliferation index, presence of necrosis, and invasion of mucosa or adjacent structures) have been devolped and that permitted distinction between low and high malignant potential GISTs [31]. They are rare disease, however up to 2/3 developed recurrence or metastasis during the follow up. This risk is higher in high potential malignant tumors and the study of tecidual markers as Ki67 may help to decide which patient will have worst prognosis [32]. Mitotic index is by far the most important prognostic feature of GISTs [33]. The literature articles related that up to 20% of GISTs tumors had a high malignant potential [34,35], however this potential arise to 80% [32]. In our clinical case, Ki 67 is quite high (40,39%), which determines the high mitotic activity of tumor cells and their malignant potential (Figure 6/A). Some experts feel that all stromal tumors are potentially malignant and hence that tumors should be classified as low risk and high risk, whereas others prefer not to mention prognosis at all [23].

Histopathological Analysis
Microscopically, most GISTs demonstrate three main histologic subtypes: spindle cell type (most common), epithelioid type, and mixed spindle and epithelioid type [2,9,35]. The mixed type GISTs is the most rarely diagnosed, only 10% of these stromal mesenchymal tumors [36].  [38]. CD 117 is considered the most specific criteria for the diagnosis of GIST [8]. In Figure 9A and Figure 8A/B).

Differential Diagnosis-Leiomyosarcoma (LMS)
It can be categorized into uterine, retroperitoneal, nonretroperitoneal soft tissue, cutaneous, visceral, and osseous anatomic subtypes [39]. LMS is a smooth muscle tumor with atypia plus either mitotic activity, tumor cell necrosis or size > 10 cm.

Tumor cells merge with blood vessel walls. LMS is constructed from
palisading of spindle cells with eosinophilic fibrillary cytoplasm, focal granularity. Nuclei are cigar-shaped and blunt-ended with variable atypia, often with cytoplasmic vacuoles at both ends of nuclei (unlike neural lesions) May have hemangiopericytoma-like vasculature change [40]. The most common cells were spindle cells with elongated, blunt-ended, segmented or fusiform nuclei, and round/polygonal cells, often with rounded or indented nuclei [41]. Microscopically, the tumor cells are spindle-shaped with abundant eosinophilic cytoplasm and elongated nuclei [42,43].
Is reported marked atypia and necrosis; positive IHC for smooth muscle actin or desmin; negative for CD117; no KIT mutations [15]. Most tumors previously diagnosed as gastrointestinal autonomic nerve tumors (GANTs) are now classified as GISTs and contain essentially the identical KIT mutations as GIST [10].
Epithelioid sarcoma (ES) is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features.
It accounts for less than 1% of all soft tissue sarcomas and was first clearly characterized by F.M. Enzinger in 1970 [44]. ESs typically express vimentin, cytokeratins, epithelial membrane antigen, and CD34, whereas they are usually negative for S100, desmin, and FLI1 (FLI-1) [45]. ES demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases) [46]. High-grade spindle cell sarcomas are rare, undifferentiated, pleomorphic sarcomas previously known as malignant fibrous histiocytomas that are rarely found, and present difficult diagnostic and treatment options in clinical practice [47]. Spindle cell liposarcoma (SCLS) is a rare variant of well differentiated liposarcoma characterized by prominent spindle cell component. Previously reported cases originated in the subcutaneous tissues of shoulder girdle and upper limb [13]. It is characterized that SCLS tumor cells are immunohistochemically positive for CD 34 and Vimentin with negative for Keratin and S100 protein, but not expressing SMA [48]. Inflammatory myofibroblastic tumor contains conspicuous inflammatory cells and can be positive for ALK1 and negative for CD117 [15].

Immunohistochemistry (IHC)
Before the advent of immunohistologic methods, most spindle cell sarcomas of the gastrointestinal tract were considered to be leiomyomas or leiomyosarcomas, with occasional examples of neurogenic tumors [8]. Gastrointestinal stromal tumor (GIST) is now defined as a specific, KIT-expressing and KIT-signaling driven mesenchymal tumor of the gastrointestinal (GI) tract [38]. GIST defines a distinct group of gastrointestinal tumors that originate from the intestinal cells of Cajal (ICCs) [8]. The ICCs are responsible for motility [49], show immunophenotypic and ultrastructural features of both smooth muscle and neural differentiation and Am J Biomed Sci & Res express the Kit receptor (CD117) similar to GIST [12]. True GISTs can be identified from other tumors by histological analysis and the expression of KIT (CD117) [23], a tyrosine kinase inhibitor that is present in almost 95% of these tumors [50][51][52]. KIT is a transmembrane protein that stimulate the cell proliferation and inhibit the apoptosis [53,54]. There are rare CD117-negative GISTs but that such a diagnosis should probably only be rendered by an expert [23]. These are rare undifferentiated GIST with marked anaplasia and negative for CD117 [36]. Most GIST patients are CD34 and Vimentin positive [56], but negative for S-100 or desmin [10,26,55,56]. In cases where there is no certainty whether the lesion is a stromal tumor based on the H&E-stained sections, we usually use CD34, S-100, and smooth muscle actin (SMA) (in addition to CD117) [23]. The tumors coexpressed CD34 and KIT and were rarely positive for SMA or desmin and never for S-100 protein [57]. Immunoreactivity for SMA is found in nearly 30% to 40% of GISTs [22].
In the presented clinical case, like Jeffrey AR et al. [58], both

Complex Treatment
GISTs should always be removed, since all of these tumors can potentially metastasize. The laparoscopic and open surgical resection procedure with a "gentle-touch technique" is recommended in order to reduce the risk of hemorrhage and intraperitoneal dissemination, as GISTs tend to have a friable consistency [59]. The principal treatment modality for patients with primary GIST is complete surgical resection [26]. A large surgical resection of the tumor (including the total thickness of the gastric wall) or a partial gastrectomy is recommended [60]. R0 resection (no residual disease) is one of the most important influences for treatment outcome (disease-free interval and survival), and is achieved in around 40% to 60% of all cases of GIST and in more than 70 % in cases of non-metastatic disease [61][62][63][64]. Nodal metastasis is a rare event, there is no data in the literature indicating the conduction of systematic lymphadenectomy [65]. Lymphadenectomy is not routinely performed in patients with GIST [66,67]. Medical treatment with a tyrosine kinase inhibitor (i.e. imatinib) is indicated for recurrent or iresectable GISTs as this treatment has proven very effective, safe and tolerable [59]. Tyrosine kinase inhibitors (TKIs) (sunitinib and sorafenib) are small-molecular-weight drugs that inhibit the kinase activity of different receptors. The mechanism of action of TKIs relies on binding around the ATP binding site of a given receptor and thus hindering phosphorylation of the tyrosine residue of that receptor and subsequent transmission of signaling down the intercellular pathway [68].

Conclusion
Rhabdoid signet-ring mixed (spindle and epithelioid) cell subtype GIST is a rare diagnosed extremely aggressive malignant tumor. This is a third rhabdoid histologic phenotype GIST of the stomach posted in the English medical literature [58,69]. Its diagnosis requires an expert pathohistological and immunohistochemical study to determine the differential diagnosis with a number of other malignant mesenchymal tumors. Due to tumor expansion within the muscularis propria of the stomach, endoscopic biopsy is hampered. To allow biopsy in the depth of the stomach muscle layer, endoscopic ultrasound biopsy or laparoscopic biopsy is required.
Due to the aggressive malignant potential of the represented rhabdoid phenotype GIST, the prognosis is unfavorable. The initial expression of non-operable distant metastases in parenchymal organs and lymph nodes requires chemotherapy and target therapy.
Medical treatment with a tyrosine kinase inhibitor (i.e. Imatinib) is indicated for recurrent or inoperable metastatic GISTs as this treatment has proven very effective.