A case of primary angiomatoid fibrous histiocytoma in the lung

Abstract

Background

Angiomatoid fibrous histiocytoma (AFH) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects young adults. The aim of this study was to highlight the clinicopathological features of AFH to assist with establishing a differential diagnosis.

Case presentation

A 28-year-old female was referred to our department for diagnosis and treatment following identification of a 2.5 cm nodule near the hilum of the left upper pulmonary lobe on a computed tomography (CT) scan. She underwent a left upper lobe lobectomy via video-assisted thoracoscopy. On pathologic examination, the lesion measured 2.5 × 2.0 × 0.6 cm with a mitotic count of 0–2/10HPF, tumor necrosis of 0% and marked increased cellularity and spindle cell morphology. The final pathology revealed an AFH. Immunohistochemistry was negative for CK and CD34, focally positive for EMA, CD99, and Desmin, and positive for ALK, CD31, and CD163. Fluorescence in situ hybridization (FISH) and next-generation sequencing analysis were subsequently performed, identifying EWSR1 gene rearrangement. No recurrence or distant metastases were observed during two months of follow-up.

Conclusions

We encountered a rare case of AFH arising from the left upper pulmonary lobe. Its diagnosis required a combination of histopathological examination, immunohistochemistry, and FISH. ALK protein expression is commonly observed in AFH; however, the underlying mechanism remains unclear, as it does not appear to result from ALK rearrangement or amplification.

Background

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor of intermediate biological behavior with uncertain differentiation, which rarely metastasizes [1]. It typically presents in the superficial extremities of children and young adults but may arise in diverse anatomical locations and exhibit numerous uncommon histologic features. Characteristic histologic features include nodular proliferations of oval and spindle cells associated with blood-filled pseudocystic spaces surrounded by dense lymphoplasmacytic infiltrates [2]. Diagnosis is challenging, given the morphologic variation, low incidence, and paucity of specific immunohistochemical (IHC) markers. In fact, AFH is defined by FET::CREB family gene fusions, most commonly EWSR1::CREB1, followed by EWSR1::ATF1 and the rare FUS::ATF1 [3]. Despite genetic analysis, other tumors sharing those genetic fusions exist, which can cause diagnostic difficulties [4, 5]. Herein, we present a challenging case of AFH arising in the lung that presented diagnostic difficulties.

Case presentation

A 28-year-old previously healthy woman presented with a one-month history of cough. History was negative for cigarette smoking, hypertension, coronary heart disease, diabetes mellitus, and tuberculosis. Her family medical history and health history were non-contributory. Approximately one month prior to presentation, she developed paroxysmal dry cough without an obvious cause accompanied by bright red bloody sputum (approximately 5–10 ml per day). She reported no fever, chills, chest pain, or night sweats. A chest CT scan (Fig. 1) revealed a 2.5 cm nodule near the hilum of the left upper pulmonary lobe, exhibiting irregular margins, adjacent pleural thickening, and spiculation, consistent with a central-type lung carcinoma in the left upper lobe. Subsequently, in mid-June 2025, she underwent a left upper pulmonary lobectomy via video-assisted thoracoscopy. In line with general oncologic principles for localized pulmonary tumors of intermediate malignancy, the choice of procedure was tailored to ensure complete excision. For this case, lobectomy was selected considering the tumor’s central location within the lobe.

Fig. 1.

Contrast-enhanced CT images reveal a 2.5 cm nodule near the hilum of the left upper pulmonary lobe. A Pulmonary window (axial view). B Mediastinal window (axial view). C Pulmonary window (Coronal View). D Mediastinal window (Coronal View)

The nodule was located in the left upper lobe; the cut surface was grayish-white to grayish-red, solid, moderately firm, and friable. Histopathological examination revealed nodular proliferations of eosinophilic cells, histiocytoid cells, and myoid-appearing cells. The tumor cells were uniform in size, with oval nuclei containing vesicular chromatin and well-differentiated features. Characteristic pseudoangiomatous spaces were present, filled with erythrocytes but lacking an endothelial lining. The tumor nodules were surrounded by the characteristic dense fibrous pseudocapsule, which was infiltrated by lymphocytes and plasma cells. Lymphoid follicles with occasional germinal center formation were observed within the fibrous cuff (Fig. 2).

Fig. 2.

Analysis of the resected specimen. The images show the tumor surrounded by foci of lymphoplasmacytic cuffs, with a pseudocapsule and multiple heterogeneous spindle cells showing nuclear atypia without mitotic activity (A,×40 B,×200 C,×200 D,×200)

Pathologically, nodular proliferations of histiocytoid cells and chronic inflammatory cell infiltration in the stroma were identified. At low-power magnification, the tumor demonstrated well-demarcated boundaries with a thick fibrous pseudocapsule. Stromal lymphocytes and plasma cells were identified in distinctive “cuff-like” structures surrounding tumor nodules. The neoplastic cells, arranged in nodules or sheets, exhibited histiocytic or dendritic cell morphology with focal whorled or storiform patterns. Under high-power examination, round, oval, or fusiform nuclei featuring visible nucleoli and nuclear grooves were observed in the tumor cells, faintly eosinophilic cytoplasm and well-defined nuclear membranes. Mitotic figures were infrequent (0–2/10 HPF), with occasional abnormal mitoses observed.

IHC was negative for CK and CD34; focally positive for EMA, CD99, and Desmin; and diffusely positive for CD31 and CD163 expression. ALK1 expression was less clear, as divergent results were obtained with different antibodies. The ALK1 clone (Ventana) revealed weak-to-moderate patchy staining, while the D5F3 clone (Roche) exhibited diffuse strong positivity in tumor cells (Fig. 3). FISH analysis using an EWSR1 break-apart probe showed a split red and green signal, indicating EWSR1 gene rearrangement (Fig. 4B), and also demonstrated an EWSR1::CREB1 rearrangement (Fig. 4A). An EWSR1::CREB1 (E7; C7) rearrangement was detected by next-generation sequencing at the DNA and RNA levels (Fig. 4D). However, no ALK gene translocation was observed in this case (Fig. 4C). Taken together, a final diagnosis of AFH was made.

Fig. 3.

Immunohistochemical staining of AFH. Tumor cells are positive for CD163, ALK1, ALKD5F3, CD31 (A-D), focally positive for Desmin, CD99, and EMA (E-G), and negative for CK and CD34 (H-I). (magnification, ×200 for all, tumor cells with brownish − yellow staining are immunohistochemically positive)

Fig. 4.

Fluorescence in situ hybridization and next-generation sequencing of AFH. A Fluorescence in situ hybridization analysis showing fusion of EWSR1 and CREB1. The red fluorescence signal is the CREB1 (2q33) probe, and the green fluorescence signal is the EWSR1 (22q12) probe. The arrow indicates the yellow fluorescence signal, indicating fusion of EWSR1 and CREB1. B FISH analysis revealing a split signal of EWSR1. C FISH analysis showed absence of a split signal for ALK. D EWSR1-CREB1 (E7; C7) was detected by next-generation sequencing DNA and RNA level test

During the 5-month postoperative follow-up period, no tumor recurrence or development of metastasis was observed by imaging examinations (including ultrasonography, CT scan, and MRI).

Discussion

AFH, which occurs predominantly in children and adolescents, typically presents as a painless nodular, indolent mass in the superficial regions of the limbs, trunk, and head and neck, often in lymph node-rich areas. Less common sites include the lung, mediastinum, vagina, retroperitoneal space, and ovary.

In 2020, the World Health Organization (WHO) classified AFH as a soft tissue tumor of uncertain differentiation [6]. The solid variant of AFH is characterized histologically by the absence of hemorrhagic pseudocysts and pseudovascular spaces. Our patient presented with a mass of the lung, a rare anatomical site for AFH. AFH demonstrates histological heterogeneity: tumors lacking hemorrhagic pseudocystic spaces are classified as the solid variant; cases with prominent stromal sclerosis or myxoid degeneration constitute sclerosing or myxoid subtypes; occasional tumors exhibit predominantly small round cells (small cell variant), while focal vacuolated or rhabdoid cytoplasm may rarely occur [7].

There are no specific diagnostic immunophenotypic markers for AFH. Vimentin, which is non-specific, appears to be the only consistently positive marker reported in AFH. Myoid cells within the tumor may demonstrate Desmin and SMA positivity. CD99 and CD68 are present in 40–50% of cases. The neoplastic cells consistently express no cytokeratin, S-100 protein, or vascular endothelial markers such as CD31 and CD34 [8, 9]. In this case, IHC findings consistent with the diagnosis of AFH include diffuse expression of Desmin, CD99, ALK, and CD68, scattered expression of EMA, and absence of both MYOD1 and Myogenin. FISH has recently been recommended as an additional diagnostic tool for AFH, primarily to detect rearrangements in genes involved in its characteristic FET::CREB family fusions [10]. The most common of these, EWSR1::CREB1, accounts for > 90% of molecularly confirmed cases [10, 11] and is a key target for FISH analysis. In this case, where IHC was non-contributory, FISH for EWSR1 provided critical diagnostic information. However, as these fusions are not completely specific for AFH [10], definitive diagnosis requires correlative assessment of histopathological features together with molecular findings.

Primary pulmonary solid-variant AFH requires differentiation from the following tumors:

1. Inflammatory myofibroblastic tumor (IMT) is composed of spindled fibroblastic and myofibroblastic cells within a stroma infiltrated by lymphocytes and plasma cells, but lacks the characteristic cuff-like structures of AFH. Tumor cells exhibit vesicular nuclei with small nucleoli. Immunohistochemically, IMT staining for SMA and ALK is observed, accompanied by ALK gene rearrangements [12]. Recent investigations by Cheah et al. [13] have reported aberrant ALK immunoreactivity in AFH, with robust cytoplasmic staining in nine of 11 cases using high-sensitivity antibodies (clones D5F3 and 5A4). A subsequent validation study [14] confirmed this unexpected immunophenotypic profile, suggesting its diagnostic utility in this histologically ambiguous entity. Notably, ALK expression in AFH is not associated with underlying ALK gene translocations or copy number alterations, this “protein-positive, gene-fusion-negative” discrepancy may stem from non-fusion biological mechanisms, such as activating point mutations (as in neuroblastoma), transcriptional upregulation by the primary driver (e.g., EWSR1::CREB1), or subtle copy number gains. Parallels exist in other tumors, like ALK-overexpressing alveolar rhabdomyosarcoma linked to FOXO1 rearrangements [15]. Thus, while ALK IHC is a valuable diagnostic marker for AFH, it does not necessarily indicate a targetable ALK fusion, highlighting the need for precise molecular interpretation. Our case further substantiates the diagnostic value of ALK immunohistochemistry as a complementary marker for AFH in morphologically ambiguous contexts, corroborating prior evidence of its paradoxical expression pattern. In contrast to IMT, AFH may express ALK protein without associated ALK gene rearrangements, a critical molecular discriminator.

2. Primary pulmonary myxoid sarcoma (PPMS) is molecularly defined by the EWSR1::CREB1 gene fusion. This shared genetic alteration underlies the substantial clinicopathological similarities between PPMS and the pulmonary solid-variant of AFH, including overlapping histological patterns and immunophenotypic profiles. The key distinguishing features are morphological and clinical: PPMS typically presents with endobronchial localization (70–80% prevalence), infiltrative borders, extensive myxoid stroma (> 50% tumor volume), frequent geographic necrosis, a reticular growth pattern of pleomorphic round-to-spindle cells, and high-grade nuclear atypia. In contrast, the solid-variant AFH typically exhibits well-circumscribed margins, uniform histiocytoid cells with low-grade cytomorphology, and characteristic peripheral cuff-like lymphoid aggregates. These morphological discriminators carry critical diagnostic and prognostic implications [16].

3. Follicular dendritic cell sarcoma (FDCS) demonstrates spindle-shaped tumor cells arranged in whorled or storiform patterns, with interspersed lymphocytes and characteristic nuclear grooves. By IHC, FDCS expresses the follicular dendritic cell markers CD21, CD23, and CD35, but not CD68. Molecularly, it lacks associated EWSR1 gene rearrangements [17]. In contrast, pulmonary solid-variant AFH shows CD68 immunoreactivity but is consistently negative for CD21, CD23, and CD35, providing critical immunohistochemical discrimination.

In summary, primary pulmonary solid-variant AFH, though exceptionally rare in the lung, demonstrates a characteristic constellation of clinicopathological features. Definitive diagnosis requires an integrated assessment of the clinical presentation, histological morphology, targeted IHC profiling, and confirmatory molecular testing in uncertain/difficult cases. Our case validates the recently documented phenomenon of aberrant ALK immunoreactivity in AFH, reinforcing its utility as a diagnostic adjunct when integrated with molecular confirmation of EWSR1 rearrangements in morphologically ambiguous tumors.

Author contributions

Chao Liu: Conceptualization, Investigation, Methodology, Writing Original Draft, Writing - Review & Editing. Yong Wang: Investigation, Methodology, Conceptualization. Xiaoyu Long: Investigation, Methodology. Fingping Xu: Project Administration, Supervision, Data Curation, Review Editing, Funding Acquisition.

Funding

Not applicable.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Guangdong General Hospital (KY-Z-2021-626). This study adhered to the Declaration of Helsinki. Written informed consent to participate was obtained from the patient.

Consent for publication

Informed consent for the publication of this case report, including any potentially identifiable information, was obtained in writing from the parents.

Competing interests

The authors declare no competing interests.