Abstract
Background: Dermatofibrosarcoma protuberans (DFSP) is an uncommon, low-grade, dermal soft-tissue neoplasm with high recurrence, but low metastatic potential. It mainly occurs on the trunk, proximal extremity, head and neck, but rarely on the toes. Herein we report a case of DFSP on the right hallux. Case Report: A 39-year-old male presented with a mass in the right great toe of 3.5 years. After surgical excision, histopathological evaluation of the mass showed elongated monomorphic spindle cells arranged in a storiform pattern. The tumor cells infiltrated into adjacent adipose tissue in a honeycomb formation. Immunostaining for CD34 showed diffuse and strong cytoplasmic expression in neoplastic cells, whereas that for alpha smooth muscle actin, factor XIIIa, S-100 and melan-A were negative. The tumor was diagnosed as DFSP. We further reviewed the literature of DFSP on the toes with the aim to reveal, for the first time as far as we are aware, its clinical presentations, histopathology, differential diagnosis and treatment options. Conclusion: DFSP on adult toes is a rare neoplasm characterized by monomorphic spindle cells arranged in storiform pattern, and can be treated with partial or total toe amputation, or wide local excision after primary excision, with excellent prognosis.
- Dermatofibrosarcoma protuberans
- excision
- pathology
- toes
- tumorigenesis
Dermatofibrosarcoma protuberans (DFSP) is an uncommon and indolent dermal soft-tissue sarcoma. Two large epidemiological studies in the United States demonstrated that the annual incidence of DFSP was 42 per 10 million patients, studied in a 30-year period from 1973 to 2002 (1), and 41 per 10 million patients in a 10-year period between 2000 and 2010 (2). Both studies showed that the incidence was higher in women than in men, and higher in Black populations than White populations. DFSP comprises fewer than 0.1% of all malignancies and fewer than 1% of all soft-tissue sarcomas (3-5). It most often occurs on the trunk (40-50%), followed by proximal extremities (30-40%), and the head and neck (10%15%) (6-8). It is rarely located on the toes, with only a few cases reported (9-13). Here we report the clinical manifestation, histopathology, and treatment of a 39-year-old male with DFSP on the right hallux, and review the literature of DFSP on toes.
Case Report
A 39-year-old Asian male presented with a complaint of a large bump on the right dorsal hallux of about 3.5 years. He felt pain in the bump area, which was aggravated by footwear, but was not generally painful otherwise. The mass had grown gradually and slowly. He reported that a doctor had removed some tissue from the same location in his home country many years earlier but he was unsure of the reason and did not know any of the specifics of the procedure. Medical, surgical and social histories were unremarkable. In particular, he denied any personal or family history of malignancy. He denied any systemic symptoms.
Physical examination revealed a skin-colored, raised, round, subcutaneous, soft-tissue mass with some overlying telangiectasias on the right dorsolateral hallux. It was located near the dorsal sulcus and measured approximately 3.5×2.5×2.5 cm (Figure 1). On palpation it was slightly firm and loculated, and movable with flexion and extension of the hallux. Standard weight-bearing radiographs of the right foot revealed an increase in soft-tissue density at the site of the observed mass. Neither osseous involvement, erosion, fracture, subluxation and dislocation underlying the mass nor intra-lesional calcifications were seen. The alignment of the forefoot and midfoot were generally within normal limits.
After discussion of suspected diagnosis, treatment options and prognosis, the patient decided the mass should be excised. At the time of surgery, a linear incision was made lateral to the extensor hallucis tendon and directly over the soft-tissue mass. The mass was found to be almost directly subcutaneous with very thin overlying fascia. Dissection was performed to free it from the surrounding tissue. The mass was largely encapsulated and appeared to arise from the first intermetatarsal space. It did not appear that it directly adhered to or arose from the extensor hallucis tendon, the first metatarsophalangeal joint capsule, or the hallux interphalangeal capsule. There was apparent deep attachment to the plantar ligamentous and capsular structures. The mass was firm at the superior aspect, but at the inferior aspect it was poorly encapsulated, and infiltrated locally into the surrounding soft tissue. Upon removal, the mass (Figure 1) was immediately fixed in 10% neutral buffered formalin and submitted to pathological evaluation. The surgical site was primarily closed and good approximation was achieved.
Gross pathological examination revealed a white to yellow soft-tissue measuring 35×25×25 mm at the greatest dimension. The tissue was soft, smooth outside, well circumscribed and was serially cut. The cut surface showed a white to yellow, well-encapsulated, solid, fishmeat-like textured lesion. No hemorrhage or cyst was noticed. Histopathological examination revealed that the tumor was composed of elongated, monomorphic spindle cells arranged in a storiform pattern in subcutaneous and dermal layers (Figure 2). The elongated nuclei had mild hyperchromasia, small to inconspicuous nucleoli and moderate eosinophilic cytoplasm. The tumor cells infiltrated adjacent adipose tissue forming honeycomb-like fat entrapment. No necrosis, hemorrhage, or cyst were observed. Tumor cells were noticed at the margins of the excision. Immunostaining for CD34 showed diffuse and strong cytoplasmic expression in neoplastic cells, while that for other biomarkers including alpha smooth muscle actin, factor XIIIa, S-100, melan-A were negative (Figure 2). The tumor was diagnosed as DFSP in-house and outside on consultation with Dr Christopher D.M. Fletcher (Department of Pathology, Brigham & Women's Hospital, Harvard University, Boston, MA, USA).
The patient was seen at 4 days and 2 weeks postoperatively, and had recovered well at that point without any significant complications. The patient missed several appointments and did not return phone messages after this. He was contacted by certified mail to inform him of his diagnosis and the need for further evaluation.
Literature Review
We reviewed the English literature and found reports of another 10 adult patients with DFSP on the toes. Other reports of DFSP on the toes without detailed clinical information were excluded from analysis. Table I summarized the findings from these 10 patients in addition to the one reported here, for a total of 11 tumors. The median age at presentation was 41 years, and the ratio of males to females was 8:3. Nine out of 11 tumors were located on the dorsal side of the toes, while that for two was not specified. Gross tumor presentation ranged from multinodular violaceous plaque to projecting multinodular mass. The growth period varied from 5 months to 31 years, with a median of 3.5 years. The size of the tumor ranged from 2.5-8 cm in diameter, with a median of 3.5 cm. Histologically, nine out of 11 cases were typical DFSP, while one showed fibrosarcomatous changes, and one showed myxoid changes. All cases tested for CD34 showed diffuse and strong expression. Eight out of 11 primarily excised tumor margins contained neoplastic cells, including the case reported here. Seven patients were further treated with partial or total amputation of the affected toes and two patients were treated with wide local excision after primary excisional biopsy. One patient did not pursue further treatment after primary excisional biopsy and was lost to follow-up. The patient reported here is also currently lost to follow-up.
Discussion
Clinically, DFSP on the toes has similar features to those lesions on other sites. These tumors are characterized by a long history of indolent and slow growth. The development from an indurated dermal plaque or nodule to a noticeable, symptomatic, projecting multinodular mass on the toes usually takes several years. The incidence of DFSP on toes is male predominant (M/F=2.67/1). In our review, the patient's median age at presentation was 41 and the median size of the tumor was 3.5 cm in diameter.
Histologically, DFSP on the toes typically presents with uniformly monomorphous spindle cells with little atypia and mitotic activity arranged in storiform fascicles. The cellular nuclei are elongated with even chromatin, and low to moderate quantities of cytoplasm. The neoplastic cells often infiltrate the surrounding adipose tissue in a honeycomb pattern. Variants including fibrosarcomatous and myxoid types were reported (9, 13). DFSP with a fibrosarcomatous component has been associated with higher tendencies of local recurrence, metastasis, and death (14). Immunohistochemically, DFSP tumors typically show strong and diffuse expression of CD34 but negative expression for other biomarkers including alpha smooth muscle actin, factor XIIIa, S-100, and melan-A, as we demonstrated here. Cytogenetic and molecular studies show that more than 90% of DFSPs carry either supernumerary ring chromosomes derived from chromosomes 17 and 22, or chromosomal translocation t(17;22)(q22;q13), leading to the fusion of collagen type 1-alpha 1 (COL1A1 at 17q22) and platelet-derived growth factor beta (PDGFB at 22q13) genes. The gene fusion places the PDGFB gene under the control of the COL1A1 promoter (15-17), leading to PDGFβ overexpression (18) and dimerization, and subsequently resulting in continuous activation of the PDGF receptor β protein-tyrosine kinase. Interaction of PDGFβ and PDGF receptor β is involved in multiple signaling pathways including Ras mitogen-activated protein kinases (RAS-MAPK) and phosphatidylinositol 3-kinase-AKT serine/threonine kinase-mechanistic target of rapamycin kinase (PI3K-AKT-MTOR) (19-22). Deregulation of PDGFβ thus drives the tumorigenesis of DFSP. Gene fusion of COL1A1–PDGFB can be detected by either fluorescent in situ hybridization or reverse transcriptase-polymerase chain reaction in formalin fixed, paraffin embedded tissues (13, 18), which provides a useful tool for differential diagnosis of DFSP. DFSP needs to be differentiated from other tumors including dermatofibroma, Schwannoma, solitary fibrous tumor, fibrosarcoma, leiomyosarcoma, and spindle cell or desmoplastic melanoma. Profiling of morphological features and immunohistochemistry will aid in making an accurate diagnosis (Table II).
The treatment options for DFSP on the toes include wide local excision (WLE) with tumor-free margin, Mohs micrographic surgery (MMS), partial or total amputation and adjuvant radiation- and immunotherapy after primary excisional biopsy. Multiple studies demonstrated that MMS can significantly lower the risk of recurrence of DFSP compared to WLE (23, 24). Since both MMS and WLE usually require wide and deep excision of the tumor with at least 2 to 3 cm free margins from the periphery of the tumor, this poses a challenge for the DFSP on the toes due to the limited space and the complex structures surrounding the toes. Therefore, partial or total amputation of the involved toe becomes a favored option to obtain tumor-free margins and allow for primary closure and faster return to function. Among the 10 patients reviewed here, seven patients were treated with partial or total amputation of the involved toe and no recurrences for these patients with a median follow-up of 19.5 months. Multiple studies have shown that DFSP is a radio-responsive tumor and adjuvant radiation therapy is effective in the local control and in the reduction of the postoperative recurrence (25-28). Radiation therapy should be considered for patients with positive margins in which WLE or MMS becomes difficult due to the location of DFSP or subtotal or total toe amputation would significantly affect the patient's quality of life. Imatinib, a potent and specific protein tyrosine kinase inhibitor interfering with the phosphorylation and activation of PDGF receptor β, has growth-inhibitory effects on DFSP demonstrated in both in vitro and in vivo studies (29, 30). The efficacy of imatinib was observed in localized and metastatic DFSP with t(17;22), but not in fibrosarcomatous variants of DFSP lacking t(17;22) (31-34). Further studies showed that imatinib used as a preoperative adjuvant therapy in DFSP to reduce tumor volume (32, 35, 36) can transform a very large, unresectable tumor into a resectable one. These studies provide new treatment options for patients with unresectable, recurrent, advanced, and metastatic DFSP.
In conclusion, DFSP on the adult toes is a rare tumor with similar clinical characteristics to that on the other parts of the body. It is male-predominant, slow-growing tumor, most often occurring around 40 years of age, and histologically composed of monomorphous spindle cells arranged in a storiform growth pattern. Treatment with either partial or total amputation of the affected toe or WLE after primary excision achieve excellent prognosis. Adjuvant therapies including radiation- and immuno-therapy provide options for patients unsuitable for surgical removal.
Acknowledgements
The Authors thank Dr Christopher D.M. Fletcher's help for making the diagnosis and Dr David Freeman for proofreading.
Footnotes
‡ Current address: Podiatry Care Specialists, 1953 McDaniel Dr., West Chester, PA 19380, U.S.A.
Authors' Contributions
Caitlin Madden: Patient care, data collection, analysis and interpretation, article revision; Adam Spector: Patient care, data collection, analysis and interpretation, article revision; Sarwat Siddiqui: Data collection, analysis and interpretation, article revision; Gene Mirkin: study design, article revision; Joon Yim: data collection, analysis and interpretation, article revision; Xingpei Hao: study design, data collection, analysis and interpretation, writing and revising the article.
Conflicts of Interest
None reported.
- Received February 23, 2019.
- Revision received March 18, 2019.
- Accepted March 20, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved