Primary Pulmonary Epithelioid Inflammatory Myofibroblastic Sarcoma With SQSTM1::ALK Fusion

ABSTRACT

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and aggressive variant of inflammatory myofibroblastic tumor (IMT) characterized by epithelioid morphology, atypical features, ALK rearrangements, and early metastatic potential. Primary pulmonary EIMS is exceptionally uncommon, and diagnosis on cytologic specimens can be challenging. A 58‐year‐old woman presented with cough and shortness of breath and was found to have a right lung mass. Transbronchial needle aspiration revealed scattered spindle cells in a lymphoplasmacytic background on the smears. Cell block sections demonstrated mainly spindle to few epithelioid cells with focal necrosis. Immunohistochemistry showed diffuse ALK positivity with focal SMA and desmin expression. The lesion was diagnosed as a spindle cell neoplasm concerning for an IMT with possible malignant transformation. Subsequent lobectomy revealed epithelioid morphology, marked atypia, increased mitotic activity, and extensive necrosis, establishing the diagnosis of EIMS. Molecular testing identified an SQSTM1::ALK fusion and a TERT promoter mutation. The patient developed metastatic disease and showed a limited response to ALK inhibitor therapy. This case highlights the diagnostic challenges of EIMS on cytology and underscores the importance of integrating cytomorphology, immunohistochemistry, and molecular testing for accurate diagnosis and management. It also expands the molecular spectrum of EIMS by demonstrating a rare SQSTM1::ALK fusion in a primary pulmonary tumor.

1. Introduction

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate biological potential characterized by neoplastic myofibroblastic spindle cells accompanied by a prominent inflammatory infiltrate composed of lymphocytes and plasma cells [1]. IMT most commonly affects children and young adults and arises in a wide range of anatomic sites, with the lung representing one of the most frequent locations [2]. Although historically regarded as a reactive process, IMT is now recognized as a true neoplasm, frequently driven by clonal cytogenetic rearrangements involving chromosome band 2p23 and resulting in ALK gene fusions [3, 4, 5, 6]. IMTs typically exhibit low‐grade spindle cell morphology without significant atypia, mitotic activity, or necrosis and generally follow an indolent clinical course [1, 2].

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and aggressive malignant variant of IMT, first recognized as a distinct entity in 2011 by Mariño‐Enríquez et al. In contrast to conventional IMT, EIMS is characterized by sheets of round to epithelioid cells with prominent nucleoli, increased mitotic activity, and necrosis. Clinically, EIMS is associated with rapid recurrence and early metastasis [7]. Nearly all cases harbor ALK rearrangements, most commonly involving RANBP2 or RRBP1, which are associated with characteristic nuclear membrane and perinuclear accentuated cytoplasmic ALK staining patterns respectively [7, 8]. Mostly reported in mesentery and abdomen; primary pulmonary EIMS is exceedingly rare with few reported cases [9, 10, 11, 12, 13, 14].

SQSTM1 encodes a multifunctional scaffold protein involved in autophagy and intracellular signaling. SQSTM1::ALK fusion has been reported in a limited number of tumors, including IMT, large B‐cell lymphoma, epithelioid fibrous histiocytoma, and epithelioid cell histiocytoma, but remains an uncommon fusion partner in EIMS [15, 16, 17, 18, 19, 20].

Here, we report a rare case of primary pulmonary EIMS harboring a SQSTM1::ALK fusion, initially identified on cytology and biopsy and subsequently confirmed on resection, highlighting the diagnostic and molecular features of this unusual entity.

2. Case Presentation

A 58‐year‐old woman with a persistent cough and shortness of breath following a syncopal episode was found to have a 5.3 × 4.6 × 4.5 cm right lung mass and tree‐in‐bud nodularities in the left lower lobe, favored to represent infectious bronchiolitis. She was treated with antibiotics, and follow‐up imaging showed interval growth of the mass (5.7 × 5.0 × 4.7 cm) with improvement of nodularities. PET‐CT demonstrated an intensely hypermetabolic mass with central necrosis and calcifications (SUVmax 29.3).

A transbronchial needle aspiration (TBNA) and transbronchial biopsy with touch preparations were performed. Smears were paucicellular, showing few spindled cells with crush artifact in a lymphocytic background. Touch preparations showed scattered spindle cells with elongated nuclei, vesicular chromatin, inconspicuous nucleoli, and variable cytoplasm in a polymorphous lymphocytic background. Cell block and biopsy sections showed spindle to epithelioid cells in a mixed inflammatory background with focal necrosis. Immunohistochemical studies demonstrated diffuse ALK positivity and focal SMA and desmin expression in the lesional cells (Figure 1); while AE1/AE3, keratin 8/18, calponin, S100, SOX10, CD21, CD23, and CD68 and special stains for microorganisms including GMS and AFB, were negative. The lesion was diagnosed as a spindle cell neoplasm, concerning for IMT with possible malignant transformation.

FIGURE 1.

Cytologic and histologic findings of transbronchial needle aspiration (TBNA) and biopsy. TBNA smears show scant spindle cells with crush artifact in a lymphocytic background (A). Touch preparations demonstrate scattered spindle cells with elongated nuclei in a lymphocytic background (B, C). Cell block section shows spindle to epithelioid cells in a mixed inflammatory background with focal necrosis (D). Immunohistochemistry demonstrates diffuse cytoplasmic ALK positivity (E) and focal SMA (F) and desmin (G) expression.

The patient subsequently underwent right upper and middle lobectomy, which revealed a 7.3 × 5.2 × 5.0 cm well‐circumscribed, solid mass. Histology showed low‐grade spindle cell areas similar to the cell block and the biopsy and epithelioid areas with prominent nucleoli and abundant cytoplasm, along with marked atypia including pleomorphism, binucleation, mitoses, and necrosis. A broader immunohistochemical panel was repeated and showed findings like the initial studies, with focal SMA and desmin and diffuse ALK positivity (Figure 2). Given the malignant cytologic features, increased mitotic activity, and extensive necrosis, the resection specimen was ultimately diagnosed as EIMS.

FIGURE 2.

Resection findings. Gross examination shows a tan‐white, homogenous, well‐circumscribed mass (A). Histologic sections demonstrate areas with low‐grade spindle cell morphology (B) and epithelioid cells showing round nuclei, prominent nucleoli and abundant granular cytoplasm (C). Marked atypia is present, including pleomorphic cells (D), binucleation (E), increased mitotic activity (F), and extensive necrosis (G).

Comprehensive molecular testing, including the MayoComplete Sarcoma Panel, identified an SQSTM1::ALK fusion and detected a TERT promoter mutation.

Three months later, the patient developed back pain, and imaging revealed lumbar and sacral metastases. She received palliative radiation and was started on alectinib. Follow‐up imaging showed stable disease without new lesions or significant size reduction.

3. Discussion

EIMS is a rare and aggressive malignant variant of IMT, characterized by rapid progression, frequent recurrence, and early metastasis. Pulmonary involvement is uncommon, with only a limited number of cases reported. Yang et al. recently summarized thoracic EIMS cases and highlighted their aggressive behavior and near‐universal ALK rearrangement [14].

Histologically, EIMS is characterized by sheets of epithelioid and spindle cells with enlarged vesicular nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and a prominent inflammatory background. Increased mitotic activity and necrosis help distinguish EIMS from conventional IMT [7]. Immunohistochemically, most cases demonstrate diffuse ALK positivity, with variable expression of desmin, SMA, and CD30. Molecularly, ALK rearrangements are a defining feature, most commonly involving RANBP2 and RRBP1, although rare fusion partners continue to be identified.

From a cytopathologic perspective, recognition of EIMS on limited samples remains particularly challenging. Lee et al. provided the first comprehensive description of the cytologic features of EIMS in FNA smears, imprint preparations, and effusion specimens, emphasizing the rarity of this entity and the difficulty in establishing a definitive diagnosis based on cytology alone [10].

In the present case, cytologic evaluation demonstrated scattered spindle cells in a lymphoplasmacytic background, with limited cellularity and crush artifact. Although the epithelioid morphology was very focal in the smears and touch preparation, the presence of necrosis with diffuse ALK positivity on cell block material raised suspicion for an ALK‐driven malignant neoplasm. This highlights the variability of cytologic presentations in EIMS and reinforces the importance of careful morphologic assessment combined with targeted ancillary studies.

The differential diagnosis of EIMS on cytology and small biopsies is broad and includes inflammatory pseudotumor, pleomorphic carcinoma, epithelioid leiomyosarcoma, malignant mesothelioma, and EBV‐positive inflammatory follicular dendritic cell sarcoma (Table 1). Key features favoring EIMS include epithelioid cells in an inflammatory background, lack of cohesive epithelial groups, and ALK positivity. In our case, the integration of cytology, immunohistochemistry, and molecular testing was essential. The initial diagnosis on limited material reflected the difficulty in recognizing malignant transformation, while resection demonstrated overt epithelioid morphology, increased mitotic activity, and necrosis, establishing the diagnosis. This stepwise diagnostic evolution illustrates the value of cytology and small biopsy specimens in guiding early workup while acknowledging their limitations in fully characterizing tumor grade.

TABLE 1.

Differential diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS).

Entity	Cytologic features	Immunohistochemistry	Key distinguishing features
Inflammatory myofibroblastic tumor	Bland spindle cells with inflammatory background, minimal atypia	ALK positive (majority), SMA/desmin variable	Lacks significant atypia, mitoses, and necrosis
Inflammatory pseudotumor	Spindle cells in a background of mixed inflammatory cells, occasional granulomas	ALK negative Depending on etiology, special stains ike AFB and GMS might be positive	No clonal features, lack ALK expression
Pleomorphic carcinoma	Atypical spindle/giant cells, possible necrosis, variable cohesion	Cytokeratins variably positive	Epithelial differentiation, keratin positivity
Epithelioid leiomyosarcoma	Spindle to epithelioid cells, nuclear atypia, inflammatory subtype present	SMA, desmin, caldesmon positive	Strong smooth muscle differentiation; ALK negative
Malignant mesothelioma	Epithelioid cells with windows, cohesive clusters	Calretinin, WT1, D2‐40 positive. Loss of BAP1 or MTAP expression	Mesothelial markers; lacks inflammatory background; ALK negative
EBV‐positive inflammatory follicular dendritic cell sarcoma (FDC)	Spindle to ovoid cells in a lymphoplasmacytic background	CD21, CD23, SMA positive; EBV positive	FDC markers positive; typically, liver/spleen location; ALK negative

The identification of a SQSTM1::ALK fusion in this case further expands the molecular spectrum of EIMS. Although RANBP2 and RRBP1 remain the most common fusion partners [8], recent studies have demonstrated increasing molecular heterogeneity [21, 22]. Comprehensive genomic profiling is therefore critical for identifying different partner genes and potentially targetable alterations.

Therapeutically, ALK inhibitors have shown variable efficacy in EIMS. Yang et al. reported partial responses to alectinib and crizotinib in thoracic EIMS, although progression‐free survival remains limited in many cases [14]. Our patient demonstrated metastatic progression within months of resection and was subsequently treated with alectinib. Follow‐up imaging showed stable disease without new lesions or meaningful regression, reflecting a limited therapeutic response.

This case highlights the critical role of cytologic evaluation in the diagnosis of rare thoracic neoplasms, as well‐sampled smears and cell block material can enable early immunophenotypic and molecular characterization. Increased awareness of the cytomorphologic spectrum of EIMS may improve recognition in minimally invasive specimens and reduce diagnostic delay.

In conclusion, we report a rare pulmonary EIMS with SQSTM1::ALK fusion. This case highlights diagnostic challenges on limited material and the importance of integrating cytomorphology, immunohistochemistry, and molecular testing for accurate diagnosis and management.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.