Molecular or morphology? Challenges in pathologic diagnoses

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Recurrent PHF1 gene rearrangements have been detected in a significant proportion of ossifying fibromyxoid tumor (OFMT), while those with a PHF1-TFE3 fusion are associated with an aggressive clinical behavior.⁴ The same fusion has also been found in soft tissue myoepithelial carcinoma⁵ and malignant chondroid syringoma (cutaneous mixed tumor).⁶ These entities also have overlapping immunophenotypes, including variable expression of keratins, EMA, S-100 protein, SOX10, and GFAP, as well as myogenic markers including calponin, SMA, and desmin, and thus are difficult (if not impossible) to distinguish, especially when presented as a cytologically atypical or malignant form. These findings may provoke further reclassification of the group of lesions with a PHF1-TFE3 fusion to reflect their frequent malignant biologic behavior, whether of myoepithelial or of OFMT origin.

The same challenge is not limited to mesenchymal tumors but can also be encountered in epithelial neoplasms. Adnexal-type and salivary gland-type tumors may rarely arise in breast parenchyma. Distinguishing a clear cell hidradenoma and a low-grade mucoepidermoid carcinoma of the breast poses a significant diagnostic challenge. They demonstrate overlapping histomorphologic features, including squamoid differentiation, mucus cells and clear cells, cyst formation, and, rarely, a papillary growth pattern. Both neoplasms also have significant overlapping immunophenotypes (co-expression of low- and high-molecular-weight keratins and p63, albeit with different patterns) and share identical cytogenetic alterations, principally MAML2 gene rearrangement.⁷ Thus, interpretation of the molecular findings should be closely incorporated with the salient histologic features (i.e. cytologic atypia) and the pattern of biomarker expression to reach the correct diagnosis. Inclusion of these rare tumor types in the WHO classification may prompt their recognition and avoid overdiagnosis and overtreatment.

Third, different tumor types may share identical molecular alterations. One such example is low-grade fibromyxoid sarcoma/sclerosing epithelioid sarcoma. These tumors consistently show a similar immunophenotype (MUC4) and frequently have either FUS-CREB3L2 or FUS-CREB3L1 gene fusions. In some cases, tumors with hybrid features are present, reflecting the overlap between the two entities. Another instance is the identification of t(1;10)(p22;q24) or OGA and TGFBR3 rearrangement in a number of entities, including pleomorphic hyalinizing angiectatic tumor (PHAT), hemosiderotic fibrolipomatous tumor (HFLT), and myxoinflammatory fibroblastic sarcoma (MIFS).^8,9 These tumors most commonly involve the ankle and foot. Tumors showing histologic overlap with HFLT and MIFS (so-called hybrid HFLT-MIFS) have been reported. Moreover, changes identical to those seen in HFLT are present at the periphery of some PHATs (also known as early PHAT). The findings suggest a similar pathway in the pathogenesis among these tumor types and thus merit further exploration.

In short, a growing number of benign and malignant neoplasms share many histomorphologic similarities and immunophenotypes but carry characteristic genetic alterations, leading to specific diagnoses of some entities with potential novel therapeutic targets emerging. On the other hand, distinct neoplasms with diverse histologic features may harbor identical molecular characteristics, suggesting a similar histogenesis. This has resulted in a great deal of diagnostic challenge in current pathology practice. Recognition of salient histologic features and astute use of biomarkers are crucial. Molecular genetic studies are often needed, especially for those entities with an unusual histomorphology and typical histologic features but unusual clinical presentation, or with an uncommon immunoprofile. The advances in molecular techniques are certain to lead to further changes and refinement of classifications in the pursuit of precision medicine.

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9. Boland JM, Folpe AL. Hemosiderotic fibrolipomatous tumor, pleomorphic hyalinizing angiectatic tumor, and myxoinflammatory fibroblastic sarcoma: related or not? Adv Anat Pathol. 2017;24(5):268–277.

Dr. Wei is professor of pathology; associate director, Division of Anatomic Pathology; and senior scientist, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham. Dr. Siegal, also of the University of Alabama at Birmingham, is executive vice chair, Department of Pathology; UAB distinguished professor; Robert W. Mowry endowed professor of pathology; and professor of surgery, genetics, and cell, developmental and integrative biology.