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  Table of Contents    
CASE REPORT  
Year : 2013  |  Volume : 56  |  Issue : 3  |  Page : 291-293
Hepatic metastasis with heterologous rhabdomyoblastic differentiation in a patient with gastrointestinal stromal tumor treated with imatinib


1 Department of Pathology, Global Hospital and Health City, Chennai, Tamil Nadu, India
2 Liver Transplantation and Heptobiliary Surgery, Global Hospital and Health City, Chennai, Tamil Nadu, India

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Date of Web Publication24-Oct-2013
 

   Abstract 

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the intestinal tract. In patients with locally advanced and/or metastatic GIST, the introduction of tyrosine kinase inhibitor, imatinib mesylate, has transformed the management of this previously untreatable neoplasm into a treatable entity. Approximately 80% of advanced metastatic GISTs respond to imatinib treatment. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. Generally progressing GISTs retain their typical morphology. Herein, we report an extremely rare case of progressive metastatic GIST with heterologous rhabdomyoblastic differentiation after, imatinib mesylate treatment. We also review the relevant literature.

Keywords: Gastrointestinal stromal tumor, imatinib mesylate, metastasis, rhabdomyoblastic differentiation

How to cite this article:
Vij M, Patra S, Rela M. Hepatic metastasis with heterologous rhabdomyoblastic differentiation in a patient with gastrointestinal stromal tumor treated with imatinib . Indian J Pathol Microbiol 2013;56:291-3

How to cite this URL:
Vij M, Patra S, Rela M. Hepatic metastasis with heterologous rhabdomyoblastic differentiation in a patient with gastrointestinal stromal tumor treated with imatinib . Indian J Pathol Microbiol [serial online] 2013 [cited 2020 Sep 20];56:291-3. Available from: http://www.ijpmonline.org/text.asp?2013/56/3/291/120402



   Introduction Top


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract, with an estimated annual occurrence of ~6000 in the United States. [1] In patients with locally advanced and/or metastatic GIST, the introduction of imatinib has transformed the management of this previously untreatable neoplasm into a treatable entity and the paradigmatic model of targeted therapies in a solid tumor. Surgery is now sometimes applied in patients with metastasized GIST. [2] In patients who respond well to systemic therapy, the rationale for combining it with surgery is that by reducing the tumor load, the risk of resistance to systemic therapy may be lowered. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. [2] Generally progressing GISTs retain their typical morphology. Herein, we report an extremely rare case of progressive metastatic GIST with heterologous rhabdomyoblastic differentiation after imatinib treatment. We also review the relevant literature.


   Case Report Top


A 60-year-old male, a known case of GIST stomach with liver metastasis diagnosed in December 2010, was treated with imatinib elsewhere. In view of progression of the tumor, he was referred to us for further management. He also complained of abdominal pain. There was no history of hematemesis or loss of weight and appetite. There was no history of diabetes or hypertension. All the other relevant investigations were normal, expect the liver function test that was mildly deranged. He was planned for extended left hepatectomy and gastric resection. Intraoperatively, a large growth occupying segments II, III and IV of liver was noted. The remaining liver was healthy. A 5 cm × 3 cm lobulated exophytic growth in the posterior wall of the body of the stomach was also identified. No ascites or peritoneal deposits were seen. No lymphadenopathy/splenomegaly and no collaterals were noted. The resected specimen was sent to the Department of Pathology. We received an extended left hepatectomy specimen measuring 16 × 15.5 × 8.5 cm and weighing 1100 g. The external surface of the specimen was smooth and congested. Bosselation were noted on one aspect. Serial slicing of the liver showed a greyish-white to tan fleshy growth with glistening surface, measuring 15.5 × 15 × 8 cm, occupying almost the entire liver specimen. The growth was abutting the capsule of the liver and showed foci of hemorrhage and necrosis. The closest parenchymal margin from the growth measured 0.5 cm. We also received a specimen of the stomach with a greyish-white mass extending from the submucosa to the serosa measuring 6 × 4.4 × 2 cm, which had a smooth, external surface. The overlying mucosa appeared unremarkable. The cut surface of the mass was firm, greyish-white and glistening. The sections from the gastric tumor showed a low cellular neoplasm with large areas of acellular hyalinized material beneath the relatively normal mucosa [Figure 1]a. Very few foci demonstrated groups of viable round to spindle tumor cells displaying ovoid to elongated nuclei and variable eosinophilic cytoplasm [Figure 1]b. Occasional mitotic figures were observed. There were no foci of necrosis. Foci of myxoid degeneration were noted. The resection margins of the stomach were free from tumor. Light microscopy from the metastatic liver tumor revealed a highly cellular malignant neoplasm composed of sheets and vague loose fascicular arrangement of spindle-shaped neoplastic cells having a variable amount of eosinophilic cytoplasm and ovoid to slightly elongated plump nuclei displaying coarse chromatin and prominent nucleoli [Figure 1]c. There were numerous scattered cells throughout the neoplasm having abundant deeply eosinophilic cytoplasm and one or more enlarged eccentrically placed nuclei with prominent nucleoli resembling rhabdomyoblasts [Figure 1]d. Tadpole-like/strap cells were also seen. Nuclear pleomorphism and increased mitotic activity were observed. Foci of coagulative necrosis and hemorrhage were noted. The parenchymal resection margin was free from tumor. Immunohistochemistry of the gastric tumor showed strong positivity of CD117 [Figure 2]a and CD34 [Figure 2]b and negativity for smooth muscle actin (SMA) and desmin. The metastatic tumor cells were strongly immunopositive for desmin [Figure 2]c, with nuclear expression for myogenin [Figure 2]d, and were negative for CD117, CD34 and SMA. We labeled the tumor as gastric GIST with hepatic metastasis containing heterologous rhabdomyoblastic component (probably treatment related change). The patient is doing well at 6 months.
Figure 1: Beneath the relati vely normal mucosa, the primary tumor cells are replaced by a hyalinizing process (hematoxylin and eosin, ×20) (a). Residual primary tumor cells in a hyalinzed background (hematoxylin and eosin, ×40) (b). Metastati c tumor with normal liver interface (hematoxylin and eosin, ×10) (c). The rhabdomyoblasti c component in gastrointesti nal stromal tumor hepati c metastasis (d)

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Figure 2: Primary tumor with strong CD117 immunopositi vty, 10 (a) CD34 immunopositi vty in residual tumor cells, 10 (b). Heterologous rhabdomyblasti c diff erenti ati on in the metastati c tumor with desmin immunopositi vity, x10 (c). Nuclear expression of myogenin, 40 (d)

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   Discussion Top


GIST is a relatively rare neoplasm representing ~0.1-3% of all primary tumors of the gastrointestinal (GI) tract with an incidence of approximately 12.8-16.4 per million. [3] GISTs may occur in the entire length of GI tract from the esophagus to the anus, and sometimes even in the omentum, mesentery, retroperitoneum and pancreas adjacent to but separate from the stomach and the intestine. [4],[5] The clinical behavior of GIST varies according to site. GISTs vary from diminutive to symptomatic tumors that most commonly manifest by occult or visible GI bleeding or vague abdominal complaints, and less commonly by obstruction, perforation or palpable mass. Malignant examples may spread to the liver and abdominal soft tissues, and rarely into the bone and peripheral soft tissue. Lymph node and lung metastasis are exceptional. [4],[5]

Tumor size, perioperative tumor rupture and incomplete resection are factors known to influence the development of metastases after surgery. Conventional chemotherapy has been ineffective in treating metastasized GIST, with disappointing response rates below 10%. [6] Up to 85% of GISTs have activating mutations in tyrosine kinase receptor (KIT) and platelet-derived growth factor receptor alfa (PDFRA) genes, which are responsible for tumor development. Imatinib, a selective inhibitor of several tyrosine kinases (for example, c-KIT and PDGFRA), has provided a generally safe and well-tolerated first-line therapy for patients with primary unresectable and metastatic GIST. [2] Stable disease or tumor shrinkage is achieved in the majority of these patients. Although most patients initially benefit from imatinib, its response is not maintained indefinitely as resistance commonly develops with a median time to progression of 18-24 months, mainly with the acquisition of secondary KIT kinase mutations.

The most frequent changes described in GIST morphology following imatinib treatment are hyalinization and scarring. Large portions of the tumor demonstrate hyalinized stroma containing no viable tumor cells. Additional treatment effects include myxoid degeneration, fibrosis, hemosiderin deposition and infiltrates of inflammatory and foamy histiocytes. [7] Although progressing GISTs usually retain typical morphology, Pauwels et al. previously described changes in the phenotype of GISTs under imatinib treatment. [8] During treatment, two clinically progressive and one clinically stable GIST revealed a diffuse epithelioid, or pseudopapillary epithelioid growth pattern, characterized by rounded cells with eosinophilic cytoplasm and uniform round-to-ovoid nuclei. In addition, GIST specimens from patients on therapy showed complete loss of CD117 immunoreactivity. Remarkably, two of these tumors also became CD34 immunonegative and, in one case, the progression was accompanied by desmin expression. Rhabdomyoblastic differentiation is rarely described in progressive tumors. [9] Liegl et al. also performed mutational testing of samples showing heterologous rhabdomyoblastic differentiation. However, no specific molecular mechanisms were identified. They postulated that this finding, in combination with the loss of KIT expression, suggests the possibility of activation of novel pathways driven by a KIT-independent oncogenic mechanism. [9]

It is of note that other sarcomas may display heterologous differentiation in the form of rhabdomyoblasts, with malignant peripheral nerve sheath tumor (MPNST) with divergent differentiation (so-called malignant Triton tumor) and a dedifferentiated liposarcoma being classic examples. MPNST with heterologous differentiation is more common in patients with neurofibromatosis type 1. The nuclear cytomorphology, biphasic morphological pattern with cellular and less cellular areas, the accentuation of tumor cells around blood vessels, and positivity for S-100 protein can be diagnostically useful. Sampling of fat, immunohistochemical stains for MDM2, and analysis for KIT mutations can help to distinguish GISTs with rhabdomyoblastic differentiation from dedifferentiated liposarcoma. Chemotherapy-related changes in Wilms tumor are well described and include maturation of blastema, epithelial and stromal components, with striated muscle being the most frequent.To pathologists unaware of these treatment-related changes, or if the pathologist has not been given any clinical data, these changes can present as a potential diagnostic pitfall.

In conclusion, the current case demonstrates that pathologists should be aware that heterologous rhabdomyoblastic differentiation may occur in GISTs after imatinib treatment. This unusual finding can represent a diagnostic challenge if proper treatment history is not available. The molecular mechanisms for this form of TKI-resistant clonal evolution remain to be determined.

 
   References Top

1.Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002;33:459-65.  Back to cited text no. 1
    
2.Tielen R, Verhoef C, van Coevorden F, Gelderblom H, Sleijfer S, Hartgrink HH, et al. Surgery after treatment with imatinib and/or sunitinib in patients with metastasized gastrointestinal stromal tumours: Is it worthwhile? World J Surg Oncol 2012;10:111.  Back to cited text no. 2
    
3.Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era - a population-based study in western Sweden. Cancer 2005;103:821-9.  Back to cited text no. 3
    
4.Vij M, Agrawal V, Kumar A, Pandey R. Gastrointestinal stromal tumors: A clinicopathological and immunohistochemical study of 121 cases. Indian J Gastroenterol 2010;29:231-6.  Back to cited text no. 4
    
5.Vij M, Agrawal V, Pandey R. Malignant extra-gastrointestinal stromal tumor of the pancreas. A case report and review of literature. JOP 2011;12:200-4.   Back to cited text no. 5
    
6.Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127-34.  Back to cited text no. 6
    
7.Bauer S, Hartmann JT, de Wit M, Lang H, Grabellus F, Antoch G, et al. Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer 2005;117:316-25.   Back to cited text no. 7
    
8.Pauwels P, Debiec-Rychter M, Stul M, De Wever I, Van Oosterom AT, Sciot R. Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: A potential diagnostic pitfall. Histopathology 2005;47:41-7.  Back to cited text no. 8
    
9.Liegl B, Hornick JL, Antonescu CR, Corless CL, Fletcher CD. Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: A novel form of tumor progression. Am J Surg Pathol 2009;33:218-26.  Back to cited text no. 9
    

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Correspondence Address:
Mukul Vij
Department of Pathology, Global Health City, Chennai, Tamil Nadu - 600 100
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.120402

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This article has been cited by
1 Dedifferentiated gastrointestinal stromal tumor: Recent advances
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