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 Table of Contents  
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 32-36

Double hit: Synchronous gastrointestinal stromal tumour (GIST) & lung neuroendocrine tumour − a rare case of multiple primary malignancies

1 Metro Centre for Respiratory Diseases, Noida, Uttar Pradesh, India
2 Department of Gastroenterology, AIMS, Kochi, Kerala, India
3 Department of Pathology, Metro Group of Hospitals, Noida, Uttar Pradesh, India
4 Metro Centre for Respiratory Diseases & Metro Group of Hospitals, Noida, Uttar Pradesh, India

Date of Submission12-Apr-2020
Date of Decision30-Jun-2020
Date of Acceptance09-Jul-2020
Date of Web Publication15-Feb-2021

Correspondence Address:
Dr. Deepak Talwar
Metro Centre for Respiratory Diseases & Metro Group of Hospitals, Noida, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jacp.jacp_16_20

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Gastrointestinal Stromal Tumours (GISTs) are rare but remain the most common mesenchymal tumour of the Gastrointestinal tract (GIT). The asynchronous occurrence of other malignancies in patients with GIST during the clinical course is relatively common. However, the synchronous coexistence of GIST and lung cancer has only rarely been reported. We report the case of a 65-year-old male, a former smoker, who was diagnosed with synchronous occurrence of mesenteric GIST and Primary Large Cell Neuroendocrine Cancer (LCNEC) of the lung. There are few case reports on synchronous occurrence of GIST with primary lung cancer but till date no case report exists on GIST with primary LCNEC of lung.

Keywords: Gastrointestinal stromal tumour (GIST), histopathological examination (HPE), immunohistochemistry (IHC), large cell neuroendocrine carcinoma (LCNEC)

How to cite this article:
Kumar KS, Prajapat D, Prakash A, Dabral C, Talwar D. Double hit: Synchronous gastrointestinal stromal tumour (GIST) & lung neuroendocrine tumour − a rare case of multiple primary malignancies. J Assoc Chest Physicians 2021;9:32-6

How to cite this URL:
Kumar KS, Prajapat D, Prakash A, Dabral C, Talwar D. Double hit: Synchronous gastrointestinal stromal tumour (GIST) & lung neuroendocrine tumour − a rare case of multiple primary malignancies. J Assoc Chest Physicians [serial online] 2021 [cited 2022 Dec 8];9:32-6. Available from: https://www.jacpjournal.org/text.asp?2021/9/1/32/309468

  Introduction Top

The Gastrointestinal Stromal Tumours (GISTs), being most common mesenchymal tumour of Gastrointestinal tract(GIT), appear in isolation. Earlier GISTs were classified as leiomyomas or leiomyosarcomas due to resemblance with smooth muscle neoplasm histologically, but now GISTs are considered as a separate entity, identified by activating mutations in c-kit.[1]

Although synchronous and metachronous occurrence of unrelated malignancies among GISTs are known, little is known about the significance and prognosis in this scenario.[2]

The association of GIST with abdominal Neuroendocrine Tumor (NET) has been reported.[3] However, the association with lung LCNEC is not reported. We report a synchronous occurrence of GIST with lung LCNEC, a rare case of multiple primary malignancies.

  Case Top

A 65year old male, former smoker (50 pack years), known diabetic, hypertensive, hypothyroid (controlled on treatment) presented with progressive breathlessness and dry cough for 1 month. He gave a history of abdominal distension and pain for 2 months. Evaluation at another center included a Positron Emission Tomography (PET) scan which showed grossly distended Gall Bladder with FDG avid (SUVmax 3.3) wall thickening and non-FDG avid hypodense mesenteric deposits (66 × 55 mm) in epigastric region. Non-FDG avid pulmonary fibrocalcified opacities were also seen in the right upper lobe suggestive of post infective changes [Figure 1]A and 1B. Computed Tomography (CT) guided biopsy from the mesenteric mass showed spindle cell tumor [Figure 2]A and 2B. A diagnosis of GIST was made with Immuneohistochemistry (IHC) markers positive for c-kit (CD-117) [Figure 2]C, CD-34 [Figure 2]D, DOG-1. His respiratory symptoms had resolved with conservative care and was subsequently commenced on Imatinib (IM) (400 mg daily) and discharged. However, patient noticed worsening respiratory symptoms a month later.
Figure 1 A) Non FDG avid fibrocalcified opacities in right lung upper lobe B) Distended FDG avid gall bladder wall thickening (SUV max 3.3), FDG avid hypodense mesenteric deposits

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Figure 2 (A&B) On HPE, Mesentric mass biopsy showing neoplasm composed of bland spindle cells with faintly eosinophilic cytoplasm, elongated nuclei with inconspicuous nucleoli, suggestive of spindle cell tumor (C) Immunohistochemistry (IHC) markers: c-kit positive (D) CD-34 positive. IHC markers confirmed the diagnosis of GIST

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On presentation, he was afebrile, with room air oxygen saturation 90%, blood pressure was 120/90 mmHg and a respiratory rate of 24/min. There was pallor with no clubbing, pedal edema, lymphadenopathy or skin rash. He had decreased breath sounds on right upper anterior wall. Rest of systemic examination was normal. His chest X-ray [Figure 3]A showed right upper lobe (RUL) collapse and consolidation. High Resolution CT revealed a RUL heterogeneous dense mass lesion [Figure 3]B, 3C. Few small lymph nodes were seen in the pre-tracheal, para-tracheal and subcarinal region. In view of disease progression, it was decided to repeat a PET-CT which revealed RUL mass lesion to be metabolically active [Figure 3]D. The Mesenteric and Gall Bladder lesions had reduced in size and had lower uptake than before.
Figure 3 (A) Chest X-Ray showing right upper zone homogenous opacity, (B & C) CT Chest showing heterogenous dense mass lesion, (D) PET-CT: metabolically active RUL mass lesion

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Fibre-optic Bronchoscopy (FOB) revealed endobronchial mass lesion in RUL which had completely occluded the RUL bronchus [Figure 4]A. Endobronchial biopsy showed nests and cords of neoplastic cells with coarse chromatin, inconspicuous nucleoli and extensive necrosis [Figure 4]B, 4C. IHC was negative for c-kit and DOG-1 but was positive for CD-56 [Figure 5]A, Synaptophysin [Figure 5]B, Chromogranin [Figure 5]C, Neuron Specific Enolase (NSE) [Figure 5]D. Presence of TTF-1 & Ki-67 of 60% were suggestive of Large Cell Neuroendocrine lung Carcinoma (LCNEC). He was started on Etoposide and platinum based chemotherapy (Cisplatin). He tolerated the first cycle well and is on follow up.
Figure 4 A) Fibreoptic Bronchoscopy image showing endobronchial growth causing complete occlusion of Right Upper Lobe bronchus; (B&C) Histopathology of endobronchial growth showing nests and cords of neoplastic cells with coarse chromatin and inconspicuous nucleoli

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Figure 5 Immunohistochemistry of Endobronchial growth/mass showing (A) CD-56 positive (B) Synaptophysin positive (C) Chromogranin positive (D) Neuron Specific Enolase positive. All these markers confirming the Large cell neuroendocrine carcinoma of lung

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  Discussion Top

Multiple primary malignancies (MPM) are occurrence of two or more primary malignancies in same patient, each tumor being histologically unrelated to the others.[4] In view of increase in elderly population, improved screening and diagnostic methods and increase in survivors among cancer patients, MPMs are on the rise. Malignancies seen at the same time or within two months interval are called synchronous, while those seen beyond two months are metachronous according to Surveillance, Epidemiology and End Results program (SEER). The interval of six months is recommended as per International agency for research and cancer (IARC) definition.[5]

The index case had gastrointestinal issues to begin with for which diagnosis of GIST was made and treated with Imatinib. A month later, he showed RUL mass lesion which revealed a LCNEC (Large cell carcinoma). The risk of developing a second primary malignancy in an already diagnosed cancer patient is 20% higher than the general population. The risk factors for MPMs are the presence of a past h/o cancer in self or in family, immunologic and genetic disorders, exposure to carcinogens, radiotherapy and chemotherapy for primary malignancy, smoking, alcohol, squamous cell malignancies, and male gender.[6],[7]

In a patient diagnosed with cancer, mere attention to present disease can miss other malignancies. GIST generally has better survival but associated second malignancy may reduce it significantly. In 2017, Danila et al.[8] from Italy reported a case of synchronous GISTs with non-small cell lung cancer and prostatic cancer. Vassos et al.[9] in 2014 found that 5 out of 37 patients (13.5%) diagnosed with GIST in Germany, suffered from more than two other malignancies. In 2010, Pandurengen et al.[10] studying the survival ratio of 783 GIST patients showed that 24 of them (3.1%) had had more than two other primary malignancies.

Romaszkoet al. retrospectively analyzed the records of 1112 cancer patients hospitalized in the period of January 2013–August 2014 and observed 52 cases of lung cancer accompanying different malignancies. Lung cancer was chronologically the first malignancy unraveled in 11 patients, the second in 39, and the third in 2, hence lung cancer being most frequent as a second malignancy. Synchronous cancers became apparent at older age compared to metachronous cancers.[11]

As there is no recommended protocol to address issues related to synchronous malignancies, multidisciplinary discussion and individualized treatment decisions are being practiced to improve outcomes. The differentiation of metastases from primary cancer is important in view of different management strategies and IHC studies aid in this process to provide better line of management.

There is adequate evidence for the presence of Somatostatin Receptors (SSTR) among GISTs[12] and over expression of c-kit in LCNEC (up to 77% in some studies).[13] The likelihood of treatment with targeted therapy for either of them should, given this evidence, be synergistic for the other. In a case report IM was also used to treat NET of the liver where report detailed molecular characterization of the tumor revealed associated activation mutation in exon 11 of the KIT receptor Tyrosine Kinase. This mutation has been previously associated with efficacy of imatinib in GIST patients, thus highlighting common oncogenic mechanisms between NET and GIST. So, detailed molecular characterization of tumors can help in identifying new therapeutic targets.[14] In-vitro drug repurposing trials have shown synergistic effects of combination of IM with Etoposide as well as Cisplatin.[15] No worsening of GIST has been reported with systemic chemotherapy so far. The combination of mammalian Target of Rapamycin (m-TOR) inhibitors and IM has been studied in GIST (Phase I/II) with results showing acceptable safety profiles and moderate benefits.[16] Therefore it appears safe and beneficial to continue IM as a treatment for the underlying GIST alongside systemic chemotherapy for LCNEC.

  Conclusion Top

GIST tumors are associated with other malignancies and any incidental findings in a known GIST patient must be carefully evaluated to rule out associated malignancies. This is being highlighted in our case as lung findings on first PET scan were deemed insignificant. It is also clear that prognosis in GIST depends on the associated malignancy rather than disease itself and treatment algorithms need to be planned accordingly.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Hueman MT, Schulick RD. Management of gastrointestinal stromal tumors. Surg Clin of North Am 2008;88:599-614.  Back to cited text no. 1
Agaimy A, Wünsch PH, Sobin LH, Lasota J, Miettinen M. Occurrence of other malignancies in patients with gastrointestinal stromal tumors. Seminarsin Diagnostic Pathology 2006;23:120-9.  Back to cited text no. 2
Tavares AB, Viveiros FA, Cidade CN et al. Gastric GIST with synchronous neuroendocrine tumour of the pancreas in a patient without neurofibromatosis type 1. Case Reports 2012;2012:bcr0220125895.  Back to cited text no. 3
Williamson CW, Paravati A, Ghassemi M, Lethert K, Hua P, Hartman P et al. Five simultaneous primary tumors in a single patient: A case report and review of the literature. Case Rep Oncol 2015;8:432-8.  Back to cited text no. 4
Vogt A, Schmid S, Heinimann K, Frick H, Herrmann C, Cerny T et al. Multiple primary tumours: challenges and approaches, a review. ESMO Open 2017;2.  Back to cited text no. 5
Testori A, Cioffi U, De Simone M, Bini F, Vaghi A, Lemos AA et al. Multiple primary synchronous malignant tumors. BMC Res Notes 2015;8:730.  Back to cited text no. 6
Jena A, Patnayak R, Lakshmi AY, Manilal B, Reddy MK. Multiple primary cancers: an enigma. South Asian J Cancer 2016;5:29-32.  Back to cited text no. 7
[PUBMED]  [Full text]  
Comandini D, Damiani A, Pastorino A. Synchronous GISTs associated with multiple sporadic tumors: a case report. Drugs Context 2017;6:212-307.  Back to cited text no. 8
Vassos N, Agaimy A, Hohenberger W, Croner RS. Coexistence of gastrointestinal stromal tumours (GIST) and malignant neoplasms of different origin: prognostic implications. Int J Surg 2014;12:371-7.  Back to cited text no. 9
Pandurengan RK, Dumont AG, Araujo DM, Ludwig JA, Ravi V, Patel S et al. Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor. Ann Oncol 2010;21:2107-11.  Back to cited text no. 10
Romaszko Świetlik, Doboszyńska Szpruch, Luks J. Lung cancer and multiple neoplasms: a retrospective analysis. Advances in Experimental Medicine and Biology 2016;911:53-8.  Back to cited text no. 11
Makino T, Mikami T, Hata Y, Otsuka H et al. Comprehensive biomarkers for personalized treatment in pulmonary large cell neuroendocrine carcinoma: a comparative analysis with adenocarcinoma. Ann Thorac Surg 2016;102:1694-701.  Back to cited text no. 12
Araki K, Ishii G, Yokose T, Nagai K, Funai K et al. Frequent overexpression of the c-kit protein in large cell neuroendocrine carcinoma of the lung. Lung Cancer 2003;40:173-80.  Back to cited text no. 13
Perkins J, Boland P, Cohen SJ et al. Successful imatinib therapy for neuroendocrine carcinoma with activating Kit mutation: a case study. J Natl Compr Canc Netw 2014;12:847-52.  Back to cited text no. 14
Groh T, Hrabeta J, Khalil AM, Doktorova H et al. The synergistic effects of DNA-damaging drugs cisplatin and etoposide with a histone deacetylase inhibitor valproate in high-risk neuroblastoma cells. International Journal of Oncology 2015;47:343-52.  Back to cited text no. 15
Agulnik M. New developments in mammalian target of rapamycin inhibitors for the treatment of sarcoma. Cancer 2012;118:1486-97.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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