Flawed and Facsimile- Thoracic SMARCA4-Deficient Undifferentiated Tumour

Introduction

Thoracic SMARCA4-deficient undifferentiated tumour emerges as an aggressive neoplasm incriminating the thoracic cavity. Neoplasm configures a distinct entity delineating unique morphological, phenotypic and molecular features and expounds precise diagnostic immunohistochemistry.

Previously designated as SMARCA4-deficient thoracic sarcoma or SMARCA4-deficient thoracic sarcomatoid tumour, tumefaction demonstrates an aggressive clinical course with rapid progression and inferior overall survival. As clinical representation of SMARCA4-deficient undifferentiated tumour is ambiguous, an amalgamation of biochemical evaluation, histopathological assessment and molecular features is necessitated in order to appropriately categorize the neoplasm. Features such as concurrent immune reactivity to CD34, SALL4 and SOX2 in combination with lack of diffuse expression of epithelial markers appear indicative of the neoplasm. Tumefaction is associated with definitive molecular modifications confined to SMARCA4 gene, especially within ATPase subunits of SWI/SNF chromatin modifying complex. Genomic alterations within SWI/SNF complex may be accompanied by ‘rhabdoid’,’ dedifferentiated’ or ‘undifferentiated’ morphological subtypes wherein tumour may emerged within diverse sites. Tumefaction enunciates distinct molecular profile with SMARCA4 genetic mutations and RNA expression disparate from non-small cell pulmonary carcinoma [1, 2].

Tumour mutational burden of SMARCA4-deficient undifferentiated tumour is concordant with SMARCA4- deficient non-small cell carcinoma manifesting as clear cell adenocarcinoma or exceptionally as squamous cell carcinoma. Thus, distinction between aforesaid neoplasms may be challenging. Nevertheless, tumour magnitude of SMARCA4-deficient undifferentiated tumour is significantly enlarged, in contrast to SMARCA4-deficient non-small cell carcinoma. Tumefaction is associated with loss of or diffuse, severe decimated expression of BRG1 or SMARCA4 and loss of BRM or SMARCA2 expression [1, 2].

Tumefaction is commonly discerned within subjects with history of intense cigarette smoking. A male predilection is observed. Thoracic SMARCA4-deficient undifferentiated tumour manifests as an enlarged tumefaction compressing circumscribing thoracic viscera. Pulmonary and mediastinal involvement is frequently encountered. Cytological examination exhibits cellular smears comprised of singular cells or clusters and sheets of non-cohesive tumour cells with spaces between individual tumour cells. Neoplasm may configure glandular structures or papillary articulations. Focal keratinization or tumour necrosis may be encountered [2, 3].

Tumour cells appear as miniature, intermediate or enlarged cells with spherical, elliptical, polygonal, spindle shaped or irregular outline and are permeated with indistinct, pale or densely staining cytoplasm with micro- vacoules. Intracytoplasmic or intra-nuclear inclusions may be exemplified. Cellular perimeter may be distinct or indistinct. Tumour cell nuclei are pervaded with inconspicuous or prominent, centric or eccentric nucleoli. Miniature, intermediate or enlarged tumour cell nuclei configure as spherical, elliptical, polygonal or demonstrate irregular nuclear outline with nuclear moulding. Streaking artefact may be enunciated [2, 3]. Cellular pleomorphism may be absent to significant. Pleomorphic or multinucleated tumour cells may occur. Tumour cells with classic rhabdoid morphology are characteristically imbued with distinct, hyaline cytoplasmic inclusions. Nevertheless, rhabdoid cellular morphology may be absent, infrequent or demonstrate focal areas [2, 3]. Generally, singular cells or non-cohesive sheets of neoplastic cells are predominant and intermingled with focal, non-cohesive rhabdoid tumour cells and disseminated inflammatory cells. Focal tumour necrosis is discerned. Occasionally, mucin rich tumour cells imbued with intracytoplasmic mucin and eccentric nuclei may be delineated.

Features such as focal tumour necrosis and monomorphic tumour cells admixed with foci of pleomorphic tumour cells appear pathognomonic. Exceptionally, composite tumours with thoracic SMARCA4-deficient undifferentiated tumour admixed with non-small cell carcinoma may be encountered [3, 4]. Upon microscopy, neoplasm represents with a population of undifferentiated round cells. Typically, tumefaction is comprised of sheets of non-cohesive, monomorphic cells pervaded with variegated nuclei and prominent nucleoli [3, 4] (Figure 1). Thoracic SMARCA4- deficient undifferentiated tumour mandates discernment of cogent features as ~foci of rhomboid tumour cells or poorly differentiated tumour cell phenotype ~comprehensive or significant loss of expression of SMARCA4 and SMARCA2 ~focal or diffuse immune reactivity to minimally two biomarkers as SOX2, CD34 or SALL4 [3, 4]. Foci of rhomboid tumour cells are observed wherein rhomboid cells appear incorporated with distinct, hyaline cytoplasmic inclusions. Mitotic activity is significant. Tumour necrosis is exemplified (Figure 2). Composite tumours delineate a combined morphology of SMARCA4-deficient undifferentiated tumour admixed with conventional non-small cell carcinoma [3, 4].

Courtesy: Journal of thoracic oncology

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Courtesy: Semantic scholar

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Epithelial Tumours

Papilloma

Squamous cell papilloma NOS

Squamous cell papilloma, inverted

Glandular papilloma

Mixed squamous cell and glandular papilloma Adenoma

Sclerosing pneumocytoma

Alveolar adenoma

Papillary adenoma

Bronchiolar adenoma/ciliated muconodular papillary tumour

Mucinous cystadenoma

Mucous gland adenoma

Precursor glandular lesions

Atypical adenomatous hyperplasia

Adenocarcinoma in situ

Adenocarcinoma in situ, non-mucinous

Adenocarcinoma in situ, mucinous

Adenocarcinoma

Minimally invasive adenocarcinoma

Minimally invasive adenocarcinoma, non-mucinous

Minimally invasive adenocarcinoma, mucinous

Invasive non-mucinous adenocarcinoma

Lepidic adenocarcinoma

Acinar adenocarcinoma

Papillary adenocarcinoma

Micro-papillary adenocarcinoma

Solid adenocarcinoma

Invasive mucinous adenocarcinoma

Mixed invasive mucinous and non-mucinous adenocarcinoma Colloid adenocarcinoma Foetal adenocarcinoma Adenocarcinoma, enteric type Adenocarcinoma NOS Squamous precursor lesions Squamous cell carcinoma in situ Mild squamous dysplasia Moderate squamous dysplasia Severe squamous dysplasia Squamous cell carcinoma Squamous cell carcinoma NOS Squamous cell carcinoma, keratinizing Squamous cell carcinoma, non keratinizing Basaloid squamous cell carcinoma Lympho-epithelial carcinoma Large cell carcinoma Adenosquamous carcinoma Sarcomatoid carcinoma Pleomorphic carcinoma Giant cell carcinoma Spindle cell carcinoma Pulmonary blastoma Carcinosarcoma Other epithelial tumours NUT carcinoma Thoracic SMARCA4-deficient undifferentiated tumour Salivary gland-type tumours Pleomorphic adenoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma Mucoepidermoid carcinoma Hyalinising clear cell carcinoma Myoepithelioma Myoepithelial carcinoma Neuroendocrine tumours of lung Precursor lesion Diffuse idiopathic neuroendocrine cell hyperplasia

Neuroendocrine tumours

Carcinoid tumour NOS/ neuroendocrine tumour NOS

Typical carcinoid/neuroendocrine tumour grade I

Atypical carcinoid/neuroendocrine tumour grade II

Neuroendocrine carcinomas

Small cell carcinoma

Combined small cell carcinoma

Large cell neuroendocrine carcinoma

Combined large cell neuroendocrine carcinoma

Tumours of ectopic tissue

Melanoma

Meningioma

Mesenchymal tumours specific to the lung Pulmonary hamartoma Chondroma

Diffuse lymphangiomatosis

Pleuropulmonary blastoma

Intimal sarcoma

Congenital peribronchial myofibroblastic tumour

Pulmonary myxoid sarcoma with EWSR1-CREB1 fusion PEComatous tumours Lymphangioleiomyomatosis PEComa benign PEComa malignant Haematolymphoid tumours MALT lymphoma Diffuse large B cell lymphoma NOS Lymphomatoid granulomatosis NOS Lymphomatoid granulomatosis, grade I Lymphomatoid granulomatosis, grade II Lymphomatoid granulomatosis, grade III Intravascular large B cell lymphoma Langerhans cell histiocytosis Erdheim-Chester disease Table1: Classification of Lung Tumours World Health Organization 2021[4].

Discussion

Tumour cells appear immune reactive to synaptophysin and chromogranin. Stem cell markers as CD34, SALL4 and SOX2 appear immune reactive. Tumefaction is immune non- reactive to cytokeratin and Claudin 4. Majority (~95%) of tumour cells appear immune non-reactive to Claudin 4 and exhibit a concurrent loss of expression of BRG1 and BRM, a feature which is pathognomonic of thoracic SMARCA4- deficient undifferentiated tumour. Neoplastic cells appear immune non-reactive to POU2F3 [5, 6]. Fine needle aspiration cytology (FNAC) or endobronchial ultrasound (EBUS) guided fine needle aspiration cytology may be optimally adopted to appropriately discern the predominantly central neoplasms. Morphological assessment of obtained surgical tissue samples is optimal and recommended [5, 6]. Evaluation of SMARCA4 genetic alteration by molecular assay may be beneficially adopted for categorizing thoracic SMARCA4- deficient undifferentiated tumour as well as non-small cell pulmonary carcinoma. Cogent genetic analysis may be contemplated for additional neoplastic categorization [5, 6].

Thoracic SMARCA4-deficient undifferentiated tumour requires segregation from high grade, undifferentiated neoplasms confined to pulmonary parenchyma or thoracic cavity demonstrating monomorphic, round cell morphology or neoplasms with rhabdoid morphology which are immune non-reactive to cytokeratin [5, 6]. Generally, demarcation is necessitated from lesions such as diverse vascular tumours, epithelioid angiosarcoma, epithelioid sarcoma, liposarcoma, gastrointestinal stromal tumour, malignant melanoma, NUT pulmonary carcinoma, malignant peripheral nerve sheath tumour, large cell lymphoma, germ cell tumours, rhabdomyosarcoma, Ewing’s sarcoma, CIC-DUX4 sarcoma, various undifferentiated sarcomas, mesothelioma and anaplastic or undifferentiated carcinomas devoid of keratin expression [5, 6]. Thoracic SMARCA4- deficient undifferentiated tumour may be challenging to alleviate as therapeutic targets appear difficult to obtain. However, possible adoption of precise targeted chemotherapy requires additional evaluation. Neoplasms of advanced grade appear unamenable to comprehensive surgical eradication. SMARCA4-deficient undifferentiated tumour may exhibit predilection for lymphatic dissemination, an exceptionally discerned feature of sarcomas [5, 6].