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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 28-31

ROS1 rearranged pulmonary sarcomatoid carcinoma: A rare clinical presentation


1 Department of Respiratory Medicine, MS Ramaiah Medical College, Bengaluru, Karnataka, India
2 Department of Medical Oncology, MS Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Submission27-Mar-2021
Date of Decision21-Jan-2022
Date of Acceptance31-Jan-2022
Date of Web Publication20-Apr-2022

Correspondence Address:
H J Gayathri Devi
Department of Respiratory Medicine, MS Ramaiah Medical College, Bengaluru - 560 054, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_13_21

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  Abstract 


Pulmonary sarcomatoid carcinoma (PSC) is a rare type of non-small cell lung cancer which contains poorly differentiated cells and sarcoma or sarcomatoid components (spindle and/or giant cells). Most of the cases are peripherally located and usually present as a large lung mass. We report a case of PSC in a 42-year-old male with massive pleural effusion as initial presentation. Therapeutic pleurocentesis showed exudative lymphocyte predominant pleural fluid. The diagnosis of PSC could be arrived at with medical thoracoscopy, biopsy and immunohistochemical staining. The next generation sequencing assay of gene panel revealed ROS1 positive status. The patient responded well to crizotinib, till the last follow-up of 21 months from the start of treatment.

Keywords: Crizotinib, pleural effusion, sarcomatoid carcinoma, thoracoscopy


How to cite this article:
Devi H J, Arjun A S, Maka V. ROS1 rearranged pulmonary sarcomatoid carcinoma: A rare clinical presentation. Oncol J India 2022;6:28-31

How to cite this URL:
Devi H J, Arjun A S, Maka V. ROS1 rearranged pulmonary sarcomatoid carcinoma: A rare clinical presentation. Oncol J India [serial online] 2022 [cited 2022 May 27];6:28-31. Available from: https://www.ojionline.org/text.asp?2022/6/1/28/343569




  Introduction Top


Pulmonary sarcomatoid carcinoma (PSC) is a rare group of non-small cell lung cancer (NSCLC) comprising between 0.3 and 3% of all lung cancers.[1] It is a poorly differentiated NSCLC showing a sarcomatoid or sarcomatous cell component which indicates a divergent tumour cell dedifferentiation from epithelial to mesenchymal phenotype. Majority of tumors have lung mass as initial finding and initial pleural presentation of PSC is an uncommon manifestation. The lack of any specific imaging signs makes the probability of misdiagnosis of PSC high. The prognosis and treatment options for this group of malignancies remains uncertain due to its rarity of presentation. It has more aggressive behaviour and worse prognosis than conventional NSCLC.[2]

We report a case of sarcomatoid carcinoma of lung in a 42-year-old male with the initial rare presentation of massive pleural effusion.


  Case Report Top


A 42-year-old male, businessman by occupation without significant comorbidities or family history, presented with history of breathlessness of 30 days duration and dry cough of 9 days duration. He also gave history of 1 episode of fever before the onset of cough. He is a current smoker and smokes 1-2 cigarettes per week for 15 years.

On physical examination, he was conscious, oriented but tachypneic. There was no pallor, cyanosis, clubbing, pedal oedema and lymphadenopathy. The patient's vital signs revealed normal temperature, heart rate of 120/min, blood pressure was 110/70 mmHg, respiratory rate was 40/min with an initial oxygen saturation of 90% on room air. Respiratory system examination showed reduced breath sounds in right infrascapular and infraaxillary areas on auscultation. Cardiac examination revealed tachycardia without evidence of murmur or rub. Systemic examination was otherwise found to be normal.

Diagnostic Studies

Blood investigations at admission revealed leucocytosis (17,000 cells/mm3) with neutrophilia and an elevated ESR (32mm/hour). Liver and renal function tests were normal.

Chest x ray showed gross pleural effusion on right side and left lung fields appeared normal [Figure 1]. Plain CT thorax done prior to admission elsewhere showed gross right sided pleural effusion with passive collapse of right lung. There was pleural thickening with nodularity noted on the right side. The mediastinum appeared normal and there was no evidence of hilar or mediastinal lymphadenopathy, [Figure 2]a and [Figure 2]b. Initial impression was pleural effusion secondary to tuberculosis/malignancy.
Figure 1: Plain chest X-ray showing massive right-sided pleural effusion

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Figure 2: (a and b) Plain CT thorax showing Pleural Effusion on right Side

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Other investigations like 2-dimensional Echocardiogram, and ultrasound of abdomen and pelvis were normal. Serum CEA and CA19.9 levels were within normal limits.

Patient was started on symptomatic treatment and supportive measures. He was given NIV support in view of tachypnea and hypoxia. Tube thoracostomy was done to relieve his breathlessness. Analysis of pleural fluid revealed exudative lymphocyte predominant pleural effusion with low levels of adenosine deaminase (18.6). Mycobacterium Tuberculosis was negative by CBNAAT and bacterial culture did not yield any growth. Cytology of the pleural fluid revealed atypical cells with large nucleus in clusters in a lymphocyte predominant background.

Based on these features, the clinical impression was of malignant pleural effusion which may be primary/secondary origin, thus triple endoscopy was planned, colonoscopy and upper gastro-intestinal endoscopy were normal, bronchoscopy could not be performed as patient was hypoxic. Patient was subjected to medical thoracoscopy which showed extensive pleural nodules involving both visceral and parietal pleura with adhesions [Figure 3]a and [Figure 3]b. Biopsy of pleural nodules was done and sent for histopathological examination. Histopathological examination revealed a poorly differentiated neoplasm composed of cells arranged in diffuse sheet like growth patterns displaying highly pleomorphic and hyperchromatic nuclei with prominent nucleoli and abundant cytoplasm. Mitosis 0-1/hpf was noted. Occasional cells with bizarre nuclear forms, and areas of necrosis and haemorrhage were also identified [Figure 4].
Figure 3: (a and b) Pleuroscopic images showing thick parietal pleura with pleural nodularity

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Figure 4: Histopathology image showing tumour cells with bizarre nuclei and areas of haemorrhage and necrosis are also seen (Haematoxylin and Eosin stain 40x)

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Immunohistochemical staining of biopsy sections was negative for thyroid transcription factor, synaptophysin, p40 and mesothelin, double stain Desmoglein 3 + and Napsin A were Weak and Variable, essentially ruling out squamous and adenocarcinoma. Vimentin stain was strongly positive, and pan CK was Positive which favoured a diagnosis of sarcomatoid carcinoma of carcinosarcoma subtype, [Figure 5]a and [Figure 5]b.
Figure 5: Immunohistochemistry images shows Pancytokeratin positive tumor cells (a) and Vimentin strongly positive tumor cells (b)

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Staging workup by PET-CT scan revealed diffuse metabolically active heterogeneously enhancing soft tissue thickening along the right pleural reflection and an 8.6cm x 4.8cm metabolically active mass lesion in the right infra-hilar lung parenchyma with metabolically active soft tissue thickening along the right oblique and horizontal fissures. Also seen were discrete enlarged pretracheal, subcarinal, right hilar and right prevascular lymph nodes, [Figure 6]a and [Figure 6]b. With the above findings the patient was finally diagnosed as a case of sarcomatoid carcinoma of lung with pleural metastasis.
Figure 6: PET-CT done at the time of diagnosis, at the level of carina (a) and lower lobes (b) showing metabolically active right infra-hilar lung mass with pleural deposits

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Five gene panel based next generation sequencing assay was used for the identification of clinically relevant and genomic alterations within the five genes EGFR, ALK, ROS 1, MET, and BRAF.

Patient had received broad spectrum antibiotics and other supportive treatment till tissue diagnosis was obtained. With the diagnosis of Sarcomatoid Carcinoma of the lung with pleural metastasis, patient received one course of docetaxel and cisplatin while awaiting 5-gene panel assay report. The gene panel assay report was found to be ROS1 positive. The patient was initiated on Crizotinib tablets and was subjected to talc pleurodesis on 12th February 2020.

Patient has improved clinically and is on regular follow-up with tablet crizotinib taken orally.

At his follow-up, 15 months post diagnosis, the patient was asymptomatic and repeat PET-CT on 3/3/2021 showed marked regression of previously noted diffuse metabolically active heterogeneously enhancing soft tissue thickening along the right pleural reflection and intermediate regression of metabolically active mass lesion and discrete lymph nodes, [Figure 7]a and [Figure 7]b. He is on regular follow-up every 3 months and at his last follow-up, 21 months from the start of tablet crizotinib, he continued to be asymptomatic.
Figure 7: PET-CT done15 months from the start of crizotinib, at the level of carina (a) and lower lobes (b) showing partial response to treatment

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  Discussion Top


PSC is defined as poorly differentiated NSCLC and the histological appearance suggests mesenchymal differentiation. It contains a component of true sarcoma or sarcoma-like elements (at least 10% spindle and/or giant cells) or a carcinoma containing exclusively spindle and giant cells.[1] These are aggressive tumors and are often diagnosed at an advanced stage.

In the 2015 WHO classification, sarcomatoid carcinoma is used to encompass a spectrum of subtypes based on pathological characteristics which are pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma.[3] Pleomorphic carcinoma is the most common subtype consisting of >50% of PSC.[1] The present case was of carcinosarcoma subtype of PSC.

PSC often affects older age groups with a median age at diagnosis being about 65 years. Higher prevalence is seen in male gender, current/former smokers.[1] PSC may also present in patients under the age of 40 years and who are non-smokers.[4] Aketa et al. reported 2 cases of pulmonary pleomorphic carcinoma one case at the age of 44-year and one case at the age of 34-year.[4] Our case is diagnosed at 42-years of age and is a current smoker.

PSC can present as central or a peripheral lung lesion.[1] The clinical presentation is non-specific such as chest pain, cough, hemoptysis, dyspnea, fever, and weight loss as in our case.[5],[6] At presentation, most of the cases present as large sized lung mass on imaging and it progresses by invading the bronchial tree, the pulmonary parenchyma, mediastinum, pleura and chest wall.[5],[6] However, pleural mass with obscure primary lung mass at presentation are rarely seen.[7] PSC with pleural invasion may manifest with pleural thickening and pleural effusion. Our case of PSC had a large size mass at infra-hilar aspect of right lung with pleural involvement. This case was initially suspected as pleural effusion secondary to either tuberculosis or malignancy and after complete evaluation including thoracoscopic biopsy, IHC analysis and PETCT scan imaging the case was confirmed as a case of PSC of right lung with pleural metastasis.

The histopathology followed by specific IHC staining are the key points for the final diagnosis of PSC. The diagnosis of PSC is difficult on small biopsies or cytology and required adequate specimen/sample size to facilitate the diagnosis [5],[8]. Our case was diagnosed on only pleural biopsy sample with IHC analysis. The findings on IHC analysis include epithelial marker expression of cytokeratins, EMA, and CEA and mesenchymal marker expression of vimentin, and fascin positivity. Positive expression of pancytokeratin on IHC is sufficient to confirm carcinomatous component.[1] Our case had positive expression of both pancytokeratin and vimentin.

The treatment of PSC is quite challenging for varied reasons such as identification of the epithelial to mesenchymal transition as a major mechanism of secondary resistance to TKIs, over-expression of PD-L1 and effective treatment with immunotherapy. Moreover, MET exon 14 skipping mutation identification representing an effective target to crizotinib and other specific inhibitors.[1]

KRAS, MET exon 14 skipping, and epidermal growth factor receptor (EGFR) mutations are the common driver oncogenes observed in cases of PSC.[9] Anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusions are rarely observed in PSC.[9] In real world settings, lung adenocarcinoma patients with driver mutations (ROS1) are well studied for treatment response to several TKIs such as crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib and have shown good response. However, their successful administration in PSC patients have been rarely reported. Wu et al. reported a good response to serial ROS1 inhibitors in a case of pulmonary pleomorphic carcinoma[9]. Our case of pulmonary carcinosarcoma with ROS1 positive status responded well to crizotinib and PETCT evaluation after 15 months post diagnosis showing response to crizotinib.

The reported prognosis of PSC is poor, with a median survival of 9.9 months (7-12.6 months) and a 5-year survival of approximately 15% [10].


  Conclusion Top


Sarcomatoid carcinoma of the lung remains poorly explored. Molecular profiles of these tumors need further studies to determine the best therapeutic approach. High index of suspicion for malignancy while evaluating massive pleural effusion in current/former smokers is important.

Acknowledgements

Dr. Palaniappan Ramanathan, Consultant Surgical Oncology.

Dr. Divya Davis, Cardiorespiratory Physiotherapist.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Baldovini C, Rossi G, Ciarrocchi A. Approaches to Tumor Classification in Pulmonary Sarcomatoid Carcinoma. Lung Cancer (Auckl). 2019;10:131-49. doi: 10.2147/LCTT.S186779. PMID: 31824199; PMCID: PMC6901065.  Back to cited text no. 1
    
2.
Cen Y, Yang C, Ren J, Gong Y, Xie C. Additional chemotherapy improves survival in stage II-III pulmonary sarcomatoid carcinoma patients undergoing surgery: a propensity scoring matching analysis. Ann Transl Med. 2021;9:24. doi: 10.21037/atm-20-3226. PMID: 33553317; PMCID: PMC7859755.  Back to cited text no. 2
    
3.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243–60.  Back to cited text no. 3
    
4.
Aketa A, Yamada G, Aketa K, et al. Two younger male patients with rapidly progressing pulmonary pleomorphic carcinoma. Nihon Kokyuki Gakkai Zasshi 2004;42:164-9.  Back to cited text no. 4
    
5.
Wang L, Zhang J, Chen X, Liang M, Li S, Zhou W, Cao J. Pulmonary sarcomatoid carcinoma mimicking pleural mesothelioma: A case report. Medicine (Baltimore). 2021;100:e27813. doi: 10.1097/MD.0000000000027813. PMID: 34766593; PMCID: PMC8589231.  Back to cited text no. 5
    
6.
Arshad HS, Dudekula RA, Niazi M, Malik S, Khaja M. A rare case of sarcomatoid carcinoma of the lung with spine metastasis, including a literature review. Am J Case Rep 2017;18:760–5.  Back to cited text no. 6
    
7.
Inomata M, Kawagishi Y, Yamada T, et al. Two cases of pulmonary sarcomatoid carcinoma mimicking malignant mesothelioma. Nihon Kokyuki Gakkai Zasshi 2010;48:33-8.  Back to cited text no. 7
    
8.
Giuseppe Pelosi AS, Tommaso De Pas, Domenico Galetta, et al. Pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol 2010;18:103–20.  Back to cited text no. 8
    
9.
Wu CW, Yang CY, Chang YL, Shih JY. Successful Management of a ROS1-Rearranged Pulmonary Pleomorphic Carcinoma Using Serial Tyrosine Kinase Inhibitors. Onco Targets Ther. 2020;13:10123-7.  Back to cited text no. 9
    
10.
Maneenil K, Xue Z, Liu M, Boland J, Wu F, Stoddard SM, Molina J, Yang P. Sarcomatoid Carcinoma of the Lung: The Mayo Clinic Experience in 127 Patients. Clin Lung Cancer 2018;19:e323-33. doi: 10.1016/j.cllc. 2017.12.008. Epub 2017 Dec 21. PMID: 29454534.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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