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ALK Gene Fusions in Epithelioid Fibrous Histiocytoma

A Study of 14 Cases, With New Histopathological Findings

Kazakov, Dmitry V., MD, PhD*,†; Kyrpychova, Liubov, MD*,†; Martinek, Petr, PhD*,†; Grossmann, Petr, PhD*,†; Steiner, Petr*,†; Vanecek, Tomas, PhD*,†; Pavlovsky, Michal, MD; Bencik, Vladimir, MD§; Michal, Michael, MD*,†; Michal, Michal, MD*,†

The American Journal of Dermatopathology: November 2018 - Volume 40 - Issue 11 - p 805–814
doi: 10.1097/DAD.0000000000001085
Original Study

Abstract: Previous studies showed that ALK is often positive in epithelioid fibrous histiocytoma (EFH). Two cases of EFH with ALK gene fusions have been recorded. Our objective was to study a series of EFH to present histopathological variations of EFH, identify novel ALK gene fusions, and determine whether there is a correlation between histopathological features and particular gene. We investigated 14 cases of EFH, all ALK immunopositive. The cases were assessed histopathologically as well as for ALK and TFE-3 rearrangements using FISH and ALK gene fusions using next-generation sequencing. The analysis of the sequencing results was performed using the Archer Analysis software (v5; ArcherDX Inc). The study group consisted of 8 female and 6 male patients, ranging in age from 18 to 79 years (mean 42 years; median 37.5 years). All presented with a solitary lesion. Microscopically, most lesions were polypoid and composed of epithelioid cells with ample cytoplasm. In addition, a variable number of bi-, tri-, or multinucleated, spindled, multilobated, cells with eccentric nuclei, cells with nuclear pseudoinclusions, mucinous, and grooved cells were admixed. In 5 cases, the predominant epithelioid cell component consisted of rather small cells, whereas spindled cells dominated in 3 cases. Of these, 2 lesions were composed rather of pale eosinophilic to clear cells, occasioning a resemblance to PEComa or leiomyoma. Immunohistochemically, all cases expressed ALK and 11 were positive for TFE-3. The break apart test for ALK was positive in 11 cases, whereas specimens from the remaining 3 cases were not analyzable. ALK genes fusions were found in all but 3 cases and included SQSTM1-ALK (3), VCL-ALK (3), TMP3-ALK (2), PRKAR2A-ALK (1), MLPH-ALK (1), and EML4-ALK (1). No correlation between histological features and type of ALK fusion was found. TFE-3 break apart test was negative. It is concluded that ALK-immunopositive EFH shows ALK gene fusions that involve various protein-coding genes, implicated in a variety of biological processes. Rare variants of EFH rather consist of spindled “non-epithelioid” cells.

*Sikl's Department of Pathology, Medical Faculty in Pilsen, Charles University in Prague, Pilsen, Czech Republic;

Bioptical Laboratory, Pilsen, Czech Republic;

Department of Pathology, Regional Hospital Most, Czech Republic; and

§Ben Labor, Ostrava, Czech Republic.

Corresponse: Dmitry V. Kazakov, MD, PhD, Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Alej Svobody 80, 304 60 Pilsen, Czech Republic (e-mail:

Supported in part by a Charles University project (SVV 260 391/2017).

The authors declare no conflicts of interest.

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