Atypical fibrous histiocytomas and pleomorphic fibroma-type lesions in a patient with li-fraumeni syndrome

Abstract

Atypical fibrous histiocytomas are an uncommon but benign variant of dermatofibroma where the neoplastic cells can feature cytological atypia constituted by prominent nuclear enlargement, pleomorphism and multinucleated giant cells. Though these can have a degree of atypia, they have a benign course and a failure to recognize these tumors as benign can lead to misdiagnosis and overtreatment, particularly in patients with Li-Fraumeni syndrome who are known to be predisposed to various malignancies. Here, we report a patient with atypical fibrous histiocytomas and multiple pleomorphic fibroma-type lesions in the setting of Li-Fraumeni syndrome.

Introduction

Atypical fibrous histiocytomas are an uncommon but benign variant of dermatofibroma, pathologically characterized by a proliferation of spindled fibroblastic cells with admixed atypical cells, centered in the dermis and set in a collagenous stroma. The neoplastic cells with cytological atypia feature prominent nuclear enlargement, pleomorphism and multinucleated giant cells. ¹ Despite the atypia, these tumors are known to have a mostly benign clinical course, with only rare instances of recurrences and metastases where a complete excision has been performed. ² We report a patient with multiple atypical fibrous histiocytomas and pleomorphic fibroma-type lesions in the setting of Li-Fraumeni syndrome.

Case report

The patient is a 37-year-old Chinese woman with an oncological history significant for juvenile granulosa cell tumor in the right ovary, invasive ductal carcinoma of the left breast and recurrent leiomyosarcoma of the back, in the setting of Li-Fraumeni syndrome with a NM_000546.6(TP53): c.743G >A (p.Arg248Gln) pathogenic variant. No familial history of a genetic cancer syndrome was identified.

She presented to the dermatology clinic as part of her regular annual dermatological examination in view of her underlying syndrome. On examination, there was an irregularly shaped, erythematous to brown, rubbery nodule on the left shoulder (Figure 1(a)). A punch biopsy of the lesion showed hyperplasia of the epidermis with a poorly circumscribed proliferation of spindled and stellate fibroblasts in the superficial to mid dermis, with surrounding of the collagen fibers at the edge of the lesion (Figure 1(b)). A significant proportion of the admixed cells had irregular, enlarged and pleomorphic nuclei with prominent nucleoli (Figure 1(c)). Multinucleated giant cells were also present. No atypical mitotic figures were identified.

Figure 1.

Clinical, histological and immunohistochemical findings of atypical fibrous histiocytoma. (a) Clinical image of the lesion showing a brown rubbery nodule on the left shoulder. (b) H & E at ×2 magnification: There is a dermal based lesion with pseudoepitheliomatous hyperplasia of the overlying epidermis. (c) H&E at ×20 magnification: the lesion is composed of atypical spindled to stellate cells with hyperchromic, pleomorphic nuclei. (d) The spindled cells are diffusely positive for Factor XIIIA. (e) Positivity for CD10. (f) CD34 immunohistochemical stain is negative in the lesional cells. (g) The pleomorphic cells show p16 positivity. (h) Increased expression of p53.

The spindle cells were diffusely positive for Factor XIIIa (Figure 1(d)), smooth muscle actin (SMA) and CD10 (Figure 1(e)) on immunohistochemical staining. Focal positivity for CD68 and CD163 were also present and CD34 (Figure 1(f)) was negative. The Ki-67 proliferative index was less than 1% in both the bland spindled cells and the pleomorphic cells. The pleomorphic cells were largely positive for p16 (Figure 1(g)) and showed overexpression of p53 (Figure 1(h)). Melanocytic markers and cytokeratins were negative. RB1 was preserved in the tumor on fluorescence-in-situ-hybridisation (FISH). There was no MDM2 amplification on FISH. Taken together, the morphological and immunohistochemical findings were compatible with a diagnosis of an atypical fibrous histiocytoma.

Additional right medial calf and left lateral ankle lesions (Table 1) were later biopsied. These showed a similar morphology of a spindled cell tumor in the dermis with collagen trapping at the periphery, an epidermal collarette and interspersed pleomorphic and giant cells, consistent with atypical fibrous histiocytomas.

Table 1.

Soft tissue lesions listed in chronological order.

Diagnosis	Age at diagnosis	Location	Morphological features	Immunohistochemical features
Leiomyosarcoma	14	Left back	• Cellular spindled cell tumor arranged in fascicles with eosinophilic cytoplasm, cigar-shaped nuclei.	• Not performed
			• Significant cytological atypia, a high mitotic rate and venous invasion.
Pleomorphic fibroma-type lesion	34	Upper back	• Paucicellular spindle cell lesion with occasional atypical stromal cells.	• Positivity for p16 Focal staining for p53 (‘Focal staining for p53' should be a separate bullet point like the next row)
			• Occasional lipomatous cells.
			• No peripheral collagen trapping.
Pleomorphic fibroma-type lesion	35	Left shoulder	• Spindle cell lesion with occasional atypical cells.	• Positivity for p16
			• No peripheral collagen trapping.	• Focal staining for p53
Pleomorphic fibroma	35	Right shoulder	• Spindle cell lesion with atypical stromal cells in a collagenous stroma.	• Positivity for CD34, Positivity for p16 and Overexpression of p53
			• No peripheral collagen trapping.
Atypical fibrous histiocytoma	37	Left shoulder	• Spindled cell lesion with interspersed pleomorphic and giant cells.	• Positivity for Factor XIII, SMA and CD10
			• Collagen trapping present at the periphery.	• Focal positivity for CD68 and CD163.
			• Epidermal collarette was present.	•Negativity for CD34.
				• Pleomorphic cells mostly positive for p16.
				• Overexpression of p53.
Atypical fibrous histiocytoma	37	Right medial calf	• Spindled cell lesion with interspersed pleomorphic and giant cells.	• None performed
			• Collagen trapping present at the periphery.
			• Epidermal collarette was present.
Atypical fibrous histiocytoma	37	Left lateral ankle	• Spindled cell lesion with interspersed pleomorphic and giant cells.	• None performed
			• Collagen trapping present at the periphery.
			• Epidermal collarette was present.

The patient’s prior upper back, left and right shoulder tumors were also reviewed (Table 1). The upper back tumor showed a paucicellular dermal lesion composed of atypical spindled stromal cells and occasional lipomatous cells (Figure 2(a)) without peripheral collagen trapping. No mitotic activity was seen. The atypical cells showed positivity for p16 (Figure 2(b)) and overexpression of p53 (Figure 2(c)). The prior left shoulder lesion, located more medially than the more recent left shoulder lesion, showed similar histological findings as the upper back tumor (Figure 3(a)). These showed positivity for p16 (Figure 3(b)) and only focal staining for p53 (Figure 3(c)). MDM2 FISH amplification on both these tumors were negative. The features of both the prior upper back and left shoulder lesions were consistent with pleomorphic fibroma-type lesions. The right shoulder tumor was classified as a pleomorphic fibroma. It showed a dermal lesion with occasional atypical stromal cells in a collagenous stroma, with no lipomatous component. The atypical cells demonstrated diffuse, strong positivity for CD34, positivity for p16 and overexpression of p53. Additionally, all 3 prior lesions also demonstrated preserved RB1 on FISH.

Figure 2.

Histopathological and immunohistochemical findings of the upper back lesion. (a) H&E at ×20 magnification: atypical stromal cells. (b) Pleomorphic cells positive for p16. (c) Overexpression of p53.

Figure 3.

Histopathological and immunohistochemical findings of the prior left shoulder lesion. (a) H & E at ×10 magnification: Dermal tumor composed of spindled to stellate cells. (b) Strong and diffuse p16 staining. (c) Only focal expression of p53.

Review of the most recent recurrence of the leiomyosarcoma from 1999 showed a cellular spindled cell tumor arranged in fascicles with eosinophilic cytoplasm, cigar-shaped nuclei displaying significant cytological atypia, a mitotic rate of more than 65 mitoses per 10 HPF and venous invasion. The cellularity, cytological atypia, and mitotic rate set this tumor apart from the patient’s other benign spindled cell tumors and demonstrated unequivocal features of malignancy. Notably, there was also p53 overexpression.

No recurrence of any of her atypical fibrous histiocytomas, pleomorphic fibromas and pleomorphic fibroma-type lesions was noted over a period of at least 18 months.

Discussion

Atypical fibrous histiocytomas have not previously been known to have an association in patients with Li-Fraumeni Syndrome or mutations in the TP53 gene in reported literature. While a benign tumor, the atypical population of cells and occasional mitoses may cause concern for a pleomorphic sarcoma, ³ atypical fibroxanthoma, ¹ or pleomorphic fibroma, ⁴ all of which are known to occur in young patients with Li-Fraumeni syndrome. ⁵ Distinguishing features on histology include the presence of an overlying epidermal hyperplasia, a relatively well-circumscribed border and the peripheral entrapment of dermal collagen. The presence of a more uniform spindled cell component similar to conventional dermatofibroma is also helpful. ³

Histologically, a sarcoma would display poorer circumscription, more widespread atypia and mitoses. ⁴ An atypical fibroxanthoma would show prominent solar elastosis, an epidermal collarette, more abundant atypical cells and atypical mitoses. ⁴ On immunohistochemical staining, there is conflicting evidence as to whether atypical fibrous histiocytomas show a consistent staining pattern. ⁶ Compared to atypical fibroxanthomas and sarcomas, they demonstrate a significantly lower Ki-67 proliferative index of <1%. ³ Recurrent gene fusions have been identified in only a subset of dermatofibromas and are yet to be incorporated into clinical practice. ³

In contrast to the above morphological differentials, pleomorphic fibromas and atypical fibrous histiocytomas share the similar histomorphological features of a dermal based tumor with pleomorphic cells ⁷ and occasionally, even multinucleated giant cells. Atypical fibrous histiocytomas display increased cellularity with more ill-defined borders, ⁸ areas of typical dermatofibroma admixed with the more pleomorphic cells, peripheral collagen trapping and overlying epidermal hyperplasia. ⁴ Apart from the morphological feature of pleomorphic cells, all the above-mentioned features were seen in the most recent left shoulder, right calf and left ankle lesions, and were consistent with atypical fibrous histiocytomas on H&E. As noted by Potts et al. in their case series of 18 pleomorphic fibromas, 17 of their cases were at least focally positive for CD34 which is negative in atypical fibrous histiocytomas, ⁸ highlighting its use as a supportive feature.

The treatment of atypical fibrous histiocytoma is complete excision. In keeping with the other types of dermatofibromas, incomplete excision may result in recurrence. Rare cases of metastases have also been reported. ²

Conclusion

There is a suggestion of a predilection for pleomorphic fibromas and possibly atypical fibrohistiocytomas in patients with Li-Fraumeni syndrome. Though these can have a degree of atypia, they have a benign course and a failure to recognize these tumors as benign can lead to misdiagnosis and overtreatment, particularly in this group of patients known to be predisposed to various malignancies.