From skin to lung: a rare case of PDZRN3/RAF1 fusion in recurrent dermatofibrosarcoma protuberans with lung metastasis

Abstract

Dermatofibrosarcoma protuberans (DFSP), a soft tissue neoplasm of intermediate grade not commonly encountered in oncology clinics, has been traditionally known for its locally aggressive nature and recurrence after surgical excision. This spindle cell neoplasm of fibro-histiocytic origin has one of its rare aggressive variants, pronounced by a high risk of local relapse and metastasis, recognized as fibrosarcomatous transformation of dermatofibrosarcoma protuberans (FS-DFSP). Here, we present a novel case of DFSP of the scalp which, after repeated local recurrences, transformed into an aggressive variant (FS-DFSP) with metastasis to the lungs. After comprehensive molecular profiling of the tumor, an infrequent PDZ Domain-Containing RING Finger 3-Rapidly Accelerated Fibrosarcoma 1 (PDZRN3/RAF1) gene fusion was identified, suggesting a plausible targetable chemotherapeutic option in the era of precision medicine. This case report also highlights the diagnostic conundrum faced by medical oncologists and radiologists, who, at first glance, thought of an invasive lung primary malignancy encasing the bronchus, but the histopathological findings turned out to be a flabbergasting surprise.

Background

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma of the skin, constituting 0.1% of all malignancies and 1% of all soft tissue sarcomas [1]. It arises from dermal fibroblasts and commonly exhibits recurrence, its metastatic potential is quite rare, and the literature on metastatic DFSP is conspicuously sparse [2–5]. If distant metastasis does occur, it typically develops following repeated local recurrences and commonly involves the lungs, bones, or locoregional lymph nodes. This spindle cell neoplasm has a rare aggressive variant, characterized by a significant risk of local recurrence and metastasis, known as fibrosarcomatous transformation in dermatofibrosarcoma protuberans (FS-DFSP). We report a unique case of DFSP located on the scalp that underwent multiple local recurrences before evolving into its aggressive fibrosarcomatous form, ultimately metastasizing to the lungs.

Case report

A 48-year-old lady noticed swelling behind her right ear in the scalp region back in 1993, but did not seek medical evaluation until later. In the preceding decade, she underwent excision of the swelling twice, but there were no available records of these procedures. A contrast-enhanced computed tomography (CECT) scan of the head conducted in 2021 revealed a 4.3 × 2.8 cm ill-defined, lobulated mass lesion with heterogeneous enhancement in the suboccipital region on the right side, extending to the skin surface without evidence of bony erosion. Last year marked her initial presentation to our hospital, where she returned due to the recurrence of the lesion at the same site. Over the course of a few months, the lesion had gradually enlarged. Subsequently, it was completely excised, and pathological examination identified an unencapsulated fibro-histiocytic tumor in the dermis, diagnosed as DFSP. Given the history of prior resections and the scalp being a cosmetically sensitive area where achieving wide excision and clear deep margins was previously challenging, the current surgery achieved an R0 resection. As DFSP has a high inherent tendency for local recurrence, adjuvant radiation therapy (RT) was administered to the local site at a dose of 60 Gray (Gy) in 30 fractions to further reduce the risk of recurrence. She was doing well, until recently, she revisited the emergency department, reporting shortness of breath, chest pain, and one episode of hemoptysis. Oxygen support via mask, antibiotics, and analgesics were initiated. Laboratory investigations, including complete blood count, liver, and kidney function tests, were unremarkable. The chest X-ray indicated near-complete opacification of the left thorax. Pulmonology consultation was requested, and intermittent overnight bilevel positive airway pressure (BiPAP) therapy was initiated, but she tolerated it poorly. Bronchoscopy revealed an endobronchial growth which was partially occluding the left lower lobe of the lung. A bronchoalveolar lavage (BAL) sample was sent for gene xpert, acid-fast bacilli (AFB) culture, and cytology, all of which yielded normal results. Additionally, 1200 ml of hemorrhagic pleural fluid was aspirated. A whole-body positron emission tomography-computed tomography (PET/CT) scan revealed an F-18 fluorodeoxyglucose (FDG) avid, heterogeneously enhancing large soft tissue mass measuring approximately 7.8 × 8.5 cm with a standardized uptake value (SUV)max of 7.2 detected in the left lung lower lobe, encompassing the basal segmental divisions of the left lung lower lobe bronchus (Fig. 1a, b). The mass is adjacent to the mediastinal, costal, and diaphragmatic pleura, with associated left pleural thickening and mild left pleural effusion. Multiple subpleural and parenchymal nodular lesions were observed in both lungs, including tiny nodules in the right lung upper lobe and right middle lobe, a large nodule measuring 1.0 × 1.2 cm in the right lung lower lobe, and nodules in the lingual segment of the left upper lobe and left lung lower lobe. An FDG avid left hilar and subcarinal lymph node measuring 1.0 × 1.9 cm with an SUVmax of 4.7 and subcentimetric right paratracheal lymph nodes were also noted. The histopathological examination of the lung lesion revealed an unencapsulated tumor comprised of uniform spindle cells arranged in a short storiform pattern, intersecting fascicles dispersed in a myxoid matrix (Fig. 2a, b). There was evidence of focal sarcomatous transformation, characterized by a focal herringbone pattern of tumor cells demonstrating marked nuclear pleomorphism, and increased mitoses (10–12/high-power field (HPF)), with areas of necrosis (Fig. 2c). These findings indicated a recurrence of DFSP with focal sarcomatous transformation. The resection margins were clear. Immunohistochemical stains were positive for Vimentin, Cluster of Differentiation (CD) 34, and S-100 (focal), and negative for Cytokeratin (CK), Desmin, Signal Transducer and Activator of Transcription 6 (STAT6), and Smooth Muscle Actin (SMA), supporting the diagnosis of metastatic DFSP with fibrosarcomatous transformation (Fig. 2d–f). In the interim, the patient was started on a once-daily dose of 400 mg imatinib tablets, and a sample of the lung tumor tissue was sent for next-generation sequencing (NGS), which identified a PDZ Domain-Containing RING Finger 3-Rapidly Accelerated Fibrosarcoma 1 (PDZRN3/RAF1) gene fusion in the metastatic tumor. Despite 3 weeks of imatinib therapy, the symptoms persisted. Following an extensive review of literature on this rare gene fusion, the treatment strategy was adjusted. This involved administering 90 mg of doxorubicin every 3 weeks and 1 mg of trametinib tablets once daily. After completing six cycles of doxorubicin in combination with a mitogen-activated protein kinase (MEK) inhibitor, the patient underwent a re-evaluation with a PET scan, which showed stable disease. Clinically, the patient remained asymptomatic. Due to the near-cumulative dose of doxorubicin and the associated risk of developing dilated cardiomyopathy, it was decided to discontinue doxorubicin while continuing the MEK inhibitor therapy. The patient achieved a progression-free survival of 8.3 months on MEK inhibitor monotherapy. However, disease progression was subsequently observed in the lungs, along with hemoptysis resulting from tumor-induced bronchial bleeding. Bronchoscopy was done, which revealed endobronchial growth with bleeding; electrocautery and fulguration were done as a temporary measure. To palliate her symptoms, the patient was scheduled for hemostatic radiation to the affected area (30 Gy in 10 fractions).

Fig. 1.

a, b Positron emission tomography-computed tomography scan image showing a fluorodeoxyglucose avid, heterogeneously enhancing large soft tissue mass in the left lung lower lobe (arrow), encompassing the basal segmental divisions of the left lung lower lobe bronchus

Fig. 2.

a, b Low-power view of the lung lesion showing an unencapsulated tumor composed of uniform spindle cells arranged in a short storiform pattern, intersecting fascicles dispersed in a myxoid matrix (hematoxylin and eosin (H&E) 40 ×, 100 ×). c Focal sarcomatous transformation, characterized by a focal herringbone pattern of tumor cells demonstrating marked nuclear pleomorphism and increased mitoses (H&E 400 ×). d Vimentin-positive (40 ×). e Cluster of Differentiation (CD)34-positive (40 ×). f S-100 focal patchy-positive (40 ×)

Discussion

FS-DFSP is marked by a herringbone pattern, increased cellularity, larger and more atypical cells, and heightened mitotic activity [2]. It often shows reduced or absent CD34 immunoreactivity. Poor prognosis has been linked to older age, high cellularity, mitotic index > 10/HPF, and close surgical margins. These findings highlight the need for thorough local and systemic evaluation, especially in aggressive cases of FS-DFSP. While ordinary DFSP rarely metastasizes (< 1%), FS-DFSP has a metastasis rate of up to 33% [3]. Tumors over 10 cm, especially FS-DFSP, are more likely to metastasize, as shown in K. Hayakawa’s study, where 4 of 5 metastatic cases had tumors ≥ 10 cm [4].

Molecular profiling has transformed soft tissue sarcoma management by identifying driver mutations and enabling targeted therapies. However, many variants remain of uncertain significance (VUS) due to limited data [5]. In DFSP, a Collagen Type I Alpha 1 Chain-Platelet-Derived Growth Factor Beta (COL1 A1-PDGFβ) fusion leads to Platelet-Derived Growth Factor-β (PDGFβ) receptor overactivation, promoting tumor growth [6]. Imatinib, a PDGFβ receptor inhibitor, blocks this pathway, inducing apoptosis [7]. Despite its efficacy, reports on imatinib use in DFSP are limited due to the tumor’s rarity. McArthur et al. reported a 90% response rate in 10 advanced DFSP cases treated with 800 mg/day of imatinib [8]. Recently, spindle cell tumors co-expressing S100 and CD34 (SOX-10 negative) have been identified as a distinct group with recurrent Rapidly Accelerated Fibrosarcoma 1 (RAF1), BRAF, and NTRK1/2 fusions [9]. These tumors range from benign to malignant, with high cellularity and mitoses suggesting aggressive potential. Differential diagnoses include pulmonary fibrosarcoma, synovial sarcoma, radiation-induced sarcoma, sarcomatoid carcinoma, and metastases such as leiomyosarcoma (LMS), malignant peripheral nerve sheath tumor (MPNST), or epithelioid sarcoma.

Surgical resection with adjuvant radiotherapy remains the mainstay for localized DFSP. Recurrences can often be managed with re-excision. Importantly, current data do not support a causal link between adjuvant RT and the induction of driver mutations or fibrosarcomatous transformation in DFSP. Studies have shown no association between RT and increased tumor aggression, and genomic analyses have not identified mutational signatures, characteristic of radiation-induced deoxyribonucleic acid (DNA) damage [10, 11]. In FS-DFSP or metastatic DFSP, treatment is less defined and requires multidisciplinary input. Options include chemotherapy, targeted agents, and anti-angiogenesis therapy [12]. Next-generation sequencing (NGS) enables rapid identification of rare mutations and gene fusions, offering critical insights into treatment decisions.

In this case, despite imatinib and radiotherapy, the patient developed recurrences and lung metastases. NGS identified a rare PDZRN3/RAF1 fusion. RAF1 fusions activate the mitogen-activated protein kinase (MAPK) pathway, driving proliferation [13, 14]. As PDGFR lies upstream and MEK downstream in this pathway, therapy was switched from imatinib to a MEK inhibitor. Doxorubicin was added to enhance cytotoxicity. Although MEK inhibitors are not standard for DFSP, they have shown promise in other MAPK-driven cancers. Trametinib, a selective MEK1/2 inhibitor approved for RAS/MAPK-activated tumors, was chosen. The patient showed dramatic tumor regression, underscoring the potential of MEK inhibitors and the value of genomic testing. Without NGS, this effective therapeutic avenue might have been missed [15].

Conclusion

In conclusion, the NGS analysis of the metastatic DFSP in our patient proved pivotal in identifying the clinically relevant genetic alteration, PDZRN3/RAF1 fusion. This analysis guided the selection of MEK inhibitor treatment, resulting in significant tumor regression and improvement in symptoms. Additional basic and clinical research on MEK inhibitor–based therapy in malignancies with RAF1 fusions is warranted.

Author contribution

The concept for the study was developed by RC and MAO. The study design was formulated by RC, SR, KB, JS, and MAO. The definition of intellectual content was contributed by RC, SR, KB, and JS. Literature searches were conducted by RC and MAO. Clinical studies were carried out by RC, SR, KB, JS, and MAO. Experimental studies were performed by RC, SR, KB, JS, and MAO. Data acquisition was managed by RC, SR, KB, and JS. Data analysis was conducted by RC, SR, KB, and JS. Statistical analysis was not applicable. Manuscript preparation was completed by RC, SR, KB, JS, and MAO. Manuscript editing was undertaken by RC, SR, KB, JS, and MAO. The final draft of the manuscript was reviewed and approved by RC, SR, KB, JS, and MAO. All authors take responsibility for the integrity of the work from its inception to the published article.

Funding

None.

Data availability

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

Declarations

Use of artificial intelligence (AI)–assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)–assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.

Patient consent

The authors certify that they have obtained the appropriate consent from the patient. The patient has given his consent for the images and other clinical information to be reported in the journal. The patient understands that the name and initials will not be published, and due efforts have been made to conceal the same.

Ethical statement

The ethical approval was exempted for this case report.

Conflict of interest

The authors declare no conflicts of interest.