Pediatric Non-Myofibroblastic Primitive Spindle Cell Tumors with <i>ALK</i> Gene Rearrangements and Response to Crizotinib

Rakheja, Dinesh; Park, Jason; Fernandes, Neil; Watt, T; Laetsch, Theodore W.; Collins, Rebecca

doi:10.1177/10668969221080072

Cited by 4 publications

(12 citation statements)

References 56 publications

(67 reference statements)

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“…The tumor in case 2 showed moderate to high cellular proliferation and stromal and perivascular hyalinization, which are consistent with morphological features reported by Suurmeijer et al (15). Similar to other reported S100-and CD34-co-expressing mesenchymal tumors harboring ALK rearrangement (6,8,9,12,13), inflammatory infiltration was found in both our cases. However, case 1 even showed IMT-like morphology, suggesting IMT in the differential diagnosis, but then we discarded the hypothesis due to the absence of myogenic expression and S100 and CD34 co-expression.…”

Section: Discussionsupporting

confidence: 92%

“…( 15 ). Similar to other reported S100- and CD34-co-expressing mesenchymal tumors harboring ALK rearrangement ( 6 , 8 , 9 , 12 , 13 ), inflammatory infiltration was found in both our cases. However, case 1 even showed IMT-like morphology, suggesting IMT in the differential diagnosis, but then we discarded the hypothesis due to the absence of myogenic expression and S100 and CD34 co-expression.…”

Section: Discussionsupporting

confidence: 91%

“…The kinase domain is reserved, and the partner gene is responsible for dimerization or other ways to mediate the activation of the kinase domain. Third, kinase fusion–positive neoplasms have been proven to be effective for targeted therapy ( 13 , 27 ), not only in mesenchymal tumors but also in various epithelial neoplasms. Finally, these kinase fusion–positive mesenchymal neoplasms share similar clinicopathological features with NTRK -rearranged spindle cell tumors.…”

Section: Discussionmentioning

confidence: 99%

“…According to the 2020 WHO classification of soft tissue tumors (STTs), NTRK-rearranged spindle cell tumors are an emerging entity, which spans a wide spectrum of morphologies and histologic grades, with frequent immunohistochemical coexpression of S100 and CD34. Notably, the family of this entity is expanding, as tumors with similar clinicopathological features and morphology but alternative kinase genes fusions are constantly identified; among them, STTs with ALK gene rearrangement have emerged as a recent hot spot (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Oncogenic activation of ALK kinase following ALK rearrangement has been reported in a variety of tumors, including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), IMT, epithelioid fibrous histiocytoma (EFH) (21), ALK-positive histiocytosis (22), renal cell carcinoma (23), thyroid cancer (24), secretory carcinomas (25), and gastrointestinal stromal tumor (GIST) (26). Recently, ALK rearrangements have been reported in S100-and CD34-coexpressing soft tissue tumors (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). A provisionally termed entity, superficial ALK-rearranged myxoid spindle cell neoplasm, has been coined to emphasize the characteristic swirling pattern of spindle cells arranged in myxoid or myohyaline stroma (6).…”

Section: Introductionmentioning

confidence: 99%

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Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion–positive soft tissue tumors

Sheng

Qiu

et al. 2022

Front. Oncol.

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ALK rearrangements have rarely been reported in S100- and CD34-co-expressing soft tissue neoplasms with lipofibromatosis-like neural tumor (LPFNT) pattern or stromal and perivascular hyalinization, mimicking NTRK-rearranged spindle cell tumors. Here, we reported ALK fusions involving related partner genes in two adult soft tissue tumors with S100 and CD34 co-expression, and conducted a literature review of mesenchymal tumors harboring ALK or other kinase fusions. Case 1 was a 25-year-old female who underwent excision of a soft tissue mass in the anterior thigh region. Morphologically, the tumor was composed of spindle cells adjacent to epithelioid cells embedded in myxedematous and hyalinized stroma, with infiltrative boundary. Spindle cells mixed with inflammatory infiltration resembling inflammatory myofibroblastic tumor (IMT) were seen sporadically. However, brisk mitosis and focal necrosis was also observed, indicating an intermediate-grade sarcoma. In case 2, the left side of the neck of a 34-year-old man was affected. The tumor was composed of monomorphic spindle cells arranged in fascicular growth or patternless pattern, with stromal and perivascular hyalinization. Sparse inflammatory cell infiltration was also observed. Both tumors showed CD34, S100, and ALK-D5F3 immunoreactivity. Next generation sequencing (NGS) test identified a PLEKHH2::ALK fusion in case 1, which was confirmed by RT-PCR and Sanger sequencing, whereas the RT-PCR (ARMS method) test detected an EML4::ALK fusion in case 2. In conclusion, this study expands the morphological and genetic landscape of tumors with S100 and CD34 co-expression harboring kinase fusions, and suggests that kinase fusion–positive mesenchymal neoplasms are becoming an enlarging entity with a variety of morphological patterns.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion–positive soft tissue tumors

Sheng

Qiu

et al. 2022

Front. Oncol.

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ALK‐rearranged Mesenchymal Neoplasms: A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors

Dermawan

DiNapoli

Mullaney

et al. 2022

Genes Chromosomes & Cancer

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Anaplastic lymphoma kinase (ALK) fusions are oncogenic drivers in diverse cancer types. Although well established in inflammatory myofibroblastic tumor (IMT) and epithelioid fibrous histiocytoma (EFH), ALK rearrangements also occur in the emerging family of kinase fusion-positive mesenchymal neoplasms. We investigated 9 ALKrearranged mesenchymal neoplasms (exclusive of IMT and EFH) arising in 6 males and 3 females with a wide age range of 10 to 78 years old (median 42 years). Tumors involved superficial and deep soft tissue (6) and viscera (3). Three were myxoid or collagenous low-grade paucicellular tumors with haphazardly arranged spindled cells.Three were cellular tumors with spindled cells in intersecting short fascicles or solid sheets. Three cases consisted of uniform epithelioid cells arranged in nests or solid sheets, with prominent mitotic activity and necrosis. Band-like stromal hyalinization was present in 6 cases. All tumors expressed ALK; four were positive for S100 and five were positive for CD34, while all were negative for SOX10. By targeted RNA sequencing, the breakpoints involved ALK exon 20; the 5 0 partners included KLC1, EML4, DCTN1, PLEKHH2, TIMP3, HMBOX1, and FMR1. All but two patients presented with localized disease. One patient had distant lung metastases; another had diffuse pleural involvement. Of the six cases with treatment information, five were surgically excised [one also received neoadjuvant radiation therapy (RT)], and one received RT and an ALK inhibitor. Of the four patients with follow-up (median 5.5 months), one remained alive with stable disease and three were alive without disease. We expand the clinicopathologic spectrum of ALK-fused mesenchymal neoplasms, including a low-grade malignant peripheral nerve sheath tumor-like subset and another subset characterized by epithelioid and high-grade morphology.

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ALK-rearranged mesenchymal neoplasms: a clinicopathological and molecular study of eight additional cases of an emerging group of tyrosine kinase fusion mesenchymal tumours

Zhao,

Song,

Yin

et al. 2024

J Clin Pathol

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AimsMesenchymal neoplasms characterised byALKfusions mainly include inflammatory myofibroblastic tumour (IMT) and epithelioid fibrous histiocytoma (EFH). Most recently,ALK-rearranged mesenchymal tumours that are not IMT or EFH have been reported. Our aim is to further characterise eight such neoplasms, with a detailed clinicopathological, immunohistochemical and molecular analysis.MethodsClinicopathological features were assessed and partner agnostic targeted RNA-sequencing on clinically validated platforms was performed.ResultsThe patients consisted of seven males and one female with a median age of 47 years (28 –59 years). The tumours ranged in size from 2.0 to 10.0 cm (mean=3.0 cm) and involved superficial and deep soft tissue (n=6) and visceral locations (n=2). Of the seven patients with follow-up (9–130 months), two developed distant metastases and five had no disease recurrence or metastasis. The tumours demonstrated diverse architectures and variable cellularity and cellular morphologies. The main constitutive cells appeared in elongated spindled in three, primitive to ovoid in two and round to epithelioid in three cases. We expanded the histopathological spectrum to include mildly to moderately cellular spindled to stellate cells in a multinodular growth in a prominent myxoid and vascularised stroma (n=2). All tumours expressed ALK(D5F3); seven were positive for S100 protein and six were positive for CD34. By fluorescence in situ hybridisation,ALKrearrangement was identified in all eight tumours.ALKfusion partners were identified by RNA-sequencing in all cases, including previously reported:EML4(n=3), DCTN(n=1), CLIP1(n=1) andPLEKHH2(n=1), and also two novel fusion partners:TKT(n=1) andMMP2(n=1).ConclusionsOur study expands the clinicopathological and molecular spectrum ofALK-rearranged mesenchymal neoplasms.

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Pediatric Non-Myofibroblastic Primitive Spindle Cell Tumors with ALK Gene Rearrangements and Response to Crizotinib

Cited by 4 publications

References 56 publications

Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion–positive soft tissue tumors

Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion–positive soft tissue tumors

ALK‐rearranged Mesenchymal Neoplasms: A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors

ALK-rearranged mesenchymal neoplasms: a clinicopathological and molecular study of eight additional cases of an emerging group of tyrosine kinase fusion mesenchymal tumours

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