Progression of the atypical fibroxanthoma to pleomorphic dermal sarcoma in a heart transplant patient

Abstract

An 82-year-old man presented with a right scalp lesion which had been increasing in size. The patient’s medical history was significant for a heart transplant 25 years before, and he was on chronic immunosuppression. Biopsy of the lesion showed atypical fibroxanthoma. The patient underwent an excision of the lesion with split thickness skin graft. Pathology showed fibroxanthoma with negative margins. Over the next 9 months, the patient developed new lesions, which were also excised to negative margins. However, with each new lesion, the histology demonstrated increasing dysplasia and ultimately pleomorphic sarcoma. The patient had a metastatic workup with CT of the chest, which was negative, and he underwent a radical scalpectomy, split thickness skin graft placement and adjuvant radiation therapy. The patient has not developed any new scalp lesions and no evidence of metastasis.

Background

This paper illustrates the progression from atypical fibroxanthoma (AFX) to high-grade pleomorphic dermal sarcoma (PDS). This case is important, as to our best knowledge, this is the first known reported incidence of the rare PDS in a postcardiac transplant patient. Previous cases of this rare tumour have been reported in kidney transplant patients only. Given the increase in transplant surgeries performed worldwide and increased overall survival in this population, one challenge is the management of rare malignancies in this population.

Secondary, this case serves to illustrate the importance of frequent surveillance of the biology of the tumour and prompt intervention in immunosuppressed patients with cutaneous malignancies. A tertiary, multidisciplinary approach was implemented to eradicate the malignancy despite multiple reoccurrences and the aggressive nature of the tumour. Radical surgical resection and adjuvant radiation were able to produce long-term disease control. Lastly, no modification to immunosuppression was done.

Organ transplantation is one of the most successful and remarkable therapeutic developments. With the development of immunosuppressive therapy and the establishment of effective antiviral, antifungal, antibacterial and pre-emptive prophylaxis strategies,^{1 2} patients who have undergone transplant are experiencing significantly increased survival rates than they used to. With increased longevity and allograft survival in transplant recipients, it has become apparent that neoplasm is one of the major threats to life expectancy in these patients.³

Case presentation

An 82-year-old man presented with a right scalp lesion. The patient had an extensive medical history including basal cell carcinoma, heart transplantation 25 years (on immunosuppression) earlier due to heart failure from coronary artery disease, hypercholesterolaemia and hypertension. The patient reported that the lesion was slowly growing; he denied pain or other symptoms. The pathology was significant for atypical spindle cell permeating through the dermis, most consistent with a superficial malignant histiocytoma.

Treatment

The patient underwent an excision of the lesion with split thickness skin graft. The final pathology showed fibroxanthoma, and squamous cell carcinoma and negative surgical margins. However on 6 months of postsurgical resection, the patient developed a new skin lesion adjacent to the lateral side of the healed skin graft. It was resected to negative margins and no residual disease. Pathology of the lesion showed a spindle cell neoplasm.

At the 3-month follow-up visit, the patient developed a new right frontal scalp lesion which was excised to negative margins. Histopathology revealed atypical spindle cell neoplasm consistent with fibroxanthoma. The patient underwent a wide right scalp local excision and split thickness skin graft (figure 1). The pathology report was positive for spindle cell fibroxanthoma, which consisted of malignant spindle and epithelioid cells focally ulcerating the epidermis. All lateral margins of resection were negative. The lesional cells displayed a significant degree of atypia with numerous mitotic figures scattered throughout, up to four mitotic figures per high-power field (figure 2). There was no necrosis identified as well as no evidence of lymphovascular invasion. The lesion cells were positive for vimentin, SMA and desmin but negative for factor VIII, CD34, cytokeratin AE1/AE3, cytokeratin Cam 5.2, Ck7, CK20, 34betaE12, S100 and HMB45. In addition, the patient had left preauricular area biopsy that was proven to be invasive squamous cell carcinoma, acantholytic type.

Figure 1.

Right scalp lesion postresection with split thickness skin grafts showing good adherence.

Figure 2.

Low-power magnification shows cells with a significant degree of atypia, numerous mitotic figures scattered throughout, up to four mitotic figures per high-power field, and high-power magnification shows malignant spindle and epitheloid cells.

Four new discrete scalp lesions surrounding his original surgical site were identified on follow-up 3 months later (figure 3). CT of the chest with contrast was negative for metastasis. The patient underwent the fourth resection. Pathology was significant for a high-grade pleomorphic sarcoma and focal positive margins. The tumour had invaded to the skeletal muscle without lymphovascular or perineural infiltration. Background of the lesion was significant for focal squamous cell carcinoma in situ. Altogether, the invasive tumour cells show scant patchy nuclear positivity for keratin 903 and keratin AE1/3 in association with a faint cytoplasmic blush. However, demonstrable cytoplasmic staining was absent. The tumour cells were negative for p53.

Figure 3.

Scalp lesions with four new discrete lesions surrounding the original surgical site.

The increase in the rate of the development of recurrences and changes in the tumour behaviour with progression to a pleomorphic sarcoma supported the decision to proceed with a radical resection. The final pathology was negative for tumour surgical margins. In addition, pathology was significant for residual squamous cell carcinoma in situ in a background of actinic keratosis. The patient’s age and comorbidities precluded a free flap. He received reconstruction with a wound vac followed by Integra and finally skin graft (figure 4). Subsequently, the patient underwent radiation therapy and remained cancer free on 4 years of follow-up.

Figure 4.

Scalp wound covered by Integra.

Outcome and follow-up

Given the progression of the malignancy to a more aggressive tumour histology, multifocality and involvement of the deep margin, radical excision in combination with radiation therapy provided the best option for long-term management. The patient has remained recurrence-free in the scalp and has not developed metastatic disease on 4 years of follow-up.

Discussion

Malignancy is one of the major complications of long-term immunosuppression following transplantation. The incidence varies based on patient-related and donor-related factors.³ These neoplasms may manifest as the newly developed malignancies, as a recurrence of pre-existing cancer or transmitted with the transplant organ.³ The major risk factors include the immunosuppressive agent therapy, the organ used as a transplant and current malignancies in the patient receiving the organ.³ Studies showed that heart transplant recipients are particularly at a higher risk of cutaneous neoplasm because of more intense immunosuppression and older mean age at transplantation.⁴ Due to immunosuppressive treatment, there is an increased frequency of rare malignancies that tend to behave more aggressively. These tumours can be more resistant to therapy and reoccur more frequently.⁵ This trend was observed in our case when the tumour reoccurred multiple times despite adequate resection with negative margins. In addition, with each reoccurrence, the biology of the tumour progressed to be more aggressive and invasive in nature.

Overall, malignant soft tissue tumours have been estimated to develop 7.3 times more frequently in organ transplant patients in comparison to the general population.⁶ The key factors of the increased neoplastic occurrence in transplant patients seem to be related to the dose and duration of immunosuppressive therapy.^{7 8} The pathogenesis of such effect could be attributed to suppression of antiviral immune response, direct oncogenic effect and a significant disruption in immune system capacity to identify tumour cells.^{7 8} The first study mentioning a high incidence of cutaneous malignant fibrous histiocytoma (MFH) (also known as undifferentiated pleomorphic sarcoma (UPS)) and AFX in renal transplant patients was published in 1999.⁷ AFX and UPS, also known as an MFH or PDS, are rare cutaneous malignancies that exhibit common histopathological and clinical features.⁸ Histopathology of, these soft tissue tumours demonstrates pleomorphic epitheloid cells, atypical spindle cells and multinucleated giant cells in varying proportions derived from mesenchymal cells of origin.⁸ The tumours frequently manifest as a single, pink to red, asymptomatic nodule on the head and neck, this was observed in our patient. The median age of presentation is 69–72 years.^{9 10} Risk factors associated with this type of malignancy are male sex, history of ultraviolet exposure, radiotherapy, previous skin cancers and trauma, as well as immunosuppressive therapy playing the biggest role.¹¹ Because of the histological, etiological and clinical resemblance to UPS, many believe that AFX is a less-aggressive, superficial variant of UPS.⁸ UPS has the following additional features that distinguish it from AFX: deep invasion of the superficial subcutis, tumour necrosis or vascular/perineural infiltration.¹² In our case, we observed how AFX progressed to a deeper variant, UPS, in a short amount of time. The initial specimen had skin with atypical spindle cell proliferation. The lesion had significant degree of atypia, with numerous mitotic figures scattered) throughout up to four mitotic figures per high-power field. No necrosis was identified. No lymphovascular or perineural invasion was identified. The tumour cells extended to the superficial subcutis. Based on the mentioned histological findings, the lesion was classified as AFX (figures 5 and 6). The subsequent resection specimen received showed infiltration of the skeletal muscle by the tumour. Based on the depth of infiltration and histological parameters, the tumour progressed and was categorised as PDS (figures 7 and 8). In combination with a previous series of similar cases,¹¹ we believe that there is the possibility that immunosuppression influences the biological behaviour of AFX and UPS.

Figure 5.

Low power depicting atypical spindle cell proliferation extending to the superficial subcutis.

Figure 6.

High power depicting atypical spindle cell proliferation along with scattered mitotic figures.

Figure 7.

Low power depicting the tumour invading into the skeletal muscle.

Figure 8.

High power depicting sheets of pleomorphic cells with cytological atypia and scattered mitotic figures.

Metastatic behaviour in not typical for AFX, although metastasis has been reported and is commonly observed with vascular or deep tissue invasion, tumour necrosis, and impaired host immunity.¹¹ Usual prognosis for AFX is favourable, with many patients being treated successfully without recurrence or metastasis. Rare incidences of metastasis are identified, and many are believed to be due to the overlap between AFX and UPS.⁸ However, case series shows that AFX and UPS in immunocompromised organ transplant patients exhibit more frequent recurrence and metastasis, altogether increasing mortality that is otherwise not commonly observed in an immunocompetent population.¹¹ As mentioned previously, AFX commonly arises in sun-exposed skin of elderly patients; given the history of basal cell carcinoma in our patient and newly developed squamous cell carcinoma in situ in a background of actinic keratosis, we developed a high suspicion of the presence of UV-signature p53 mutations. This is one of the best studied tumour suppressor genes, and the frequency of its mutation was reported to be from 25.7% to 65% in malignant soft tissue tumours.^{13 14} Fortunately, this patient’s histopathology was negative for this mutation, which is known to be associated with tumour progression and poor prognosis.¹⁴

The pathological examination did not reveal evidence of lymphovascular or perineural invasion in our patient’s case. However, since the tumour grew in size, invaded through the skeletal muscle and showed necrotic features, the diagnosis changed from AFX to UPS based on the currently accepted criteria for UPS mentioned earlier. Taking all aspects of the tumour behaviour such as the involvement of the deeper tissue, the gross size, frequent multiple recurrences and the acquisition of the new mutations into consideration, the radical excision in combination with adjuvant radiation became the evident treatment approach.

Literature review shows that current treatment options for AFX are cryotherapy, radiation and surgical excision.^9–15 The surgical treatment includes wide local excision and Mohs micrographical surgery, which is the gold standard treatment today, given a high rate of recurrence postcryotherapy and upregulated tumour DNA mutations that are associated with irradiation causing a transformation to more aggressive malignancy.¹⁶

Given the rare incidence rate of pleomorphic sarcoma, there is less known regarding the best treatment option. The most common practice today is a treatment with complete surgical excision with absolute margin control, since positive margins left behind are well known risk factors for recurrence.^17–19 In addition, radiation therapy may be beneficial for these tumours when surgical margins are not obtainable or disease recurrence.²⁰ The role of traditional chemotherapy is mostly ineffective and not commonly recommended.²⁰ In certain situations, the dose or regimen of immunosuppressive medications may be downgraded in order to strengthen the organisms’ innate defences against tumour.

In conclusion, post-transplant malignancy is still a significant health problem despite advanced development in the use of immunosuppressive pharmacotherapy. It may place these patients at higher risk of developing malignancy that is most likely to behave aggressively. The case presentation illustrates the absolute necessities in frequent monitoring and close follow-up for tumour recurrence. It is necessary to use a multidisciplinary team approach in the management of these patients, which include a dermatologist, a pathologist, a transplant physician, an oncologist, a surgeon and a radiation oncologist.

Learning points.

• Immunosuppressed patients have an increased frequency of considerable rare malignancies that tend to behave more aggressively and to be biologically resistant to the treatment.

• Immunosuppressed patients require more frequent and longer follow-up periods to monitor for recurrence.

• Due to risk of progression to undifferentiated pleomorphic sarcoma, aggressive surgical resection to negative margins should be performed for the fibroxanthomas whenever possible.

• In cases of recurrence, the addition of radiation therapy may be considered early in the course of disease.

Ethics statements

Patient consent for publication

Obtained.