Undifferentiated pleomorphic sarcoma: Factors predictive of adverse outcomes

ORIGINAL

ARTICLE

Undifferentiated pleomorphic sarcoma: Factors predictive of adverse outcomes Daniel Winchester, MD,a Julia Lehman, MD,a Tiffany Tello, MD,b Nicolette Chimato, MS,c Thomas Hocker, MD,a Sunhee Kim, MD,b Joseph Chang, MD,b Jeffrey Markey, MD,b Sue S. Yom, MD,b William Ryan, MD,b Thaddeus Mully, MD,b David Hodge, MS,c Clark Otley, MD,a and Sarah T. Arron, MD, PhDb Rochester, Minnesota; San Francisco, California; and Jacksonville, Florida Background: Undifferentiated pleomorphic sarcoma (UPS) encompasses rare neoplasms that can arise either in the dermis or in the subfascial soft tissue. The behavior of UPS ranges from indolent to aggressive, but data predicting outcomes are limited. Objective: Identify predictors of poor outcomes by analyzing a large collection of UPS cases. Methods: We evaluated all available cases of UPS (including those termed atypical fibroxanthoma, malignant fibrous histiocytoma, pleomorphic dermal sarcoma, and subfascial UPS) across 3 tertiary care centers. Results: Among the 319 patients, 45 experienced recurrence, 33 experienced metastasis, and 96 died of any cause. Risk factors for recurrence were clinical tumor size larger than 5 cm and invasion beyond subcutaneous fat. Risk factors for distant metastases were tumor site, tumor size larger than 2 cm, invasion beyond subcutaneous fat, and lymphovascular invasion. Risk factors for overall mortality were age, immunosuppression, tumor size larger than 2 cm, and lymphovascular invasion. History of skin cancer was associated with a lower risk of recurrence and metastasis. Limitations: This was a retrospective study. Conclusions: Using the unbiased approach of pooling all UPS cases regardless of terminology, we identified clinical and histologic factors predicting poor outcomes. We propose subcategorization of UPS (into superficial versus deep UPS), which is consistent with the American Joint Committee on Cancer staging of soft-tissue sarcoma. ( J Am Acad Dermatol https://doi.org/10.1016/j.jaad.2018.05.022.) Key words: atypical fibroxanthoma; malignant fibrous histiocytoma; pleomorphic dermal sarcoma; undifferentiated pleomorphic sarcoma.

ndifferentiated pleomorphic sarcomas (UPSs) of the skin and soft tissue are rare spindle cell neoplasms that despite their similar microscopic appearance, can have divergent patient outcomes.1-3 The terminology used to differentiate these neoplasms can be confusing. Generally,

U

when arising in the dermis, they are referred to as atypical fibroxanthoma (AFX), superficial UPS, or pleomorphic dermal sarcoma. However, microscopically similar neoplasms arising deep to the superficial fascia are typically classified as UPS or deep UPS. Though these neoplasms are included in the broader

From the Department of Dermatology, Mayo Clinic, Rochestera; Department of Dermatology, University of California San Franciscob; and Department of Health Sciences Research, Mayo Clinic, Jacksonville.c Funding sources: None. Conflicts of interest: None disclosed. Accepted for publication May 15, 2018. Correspondence to: Sarah T. Arron, MD, PhD, Department of Dermatology, University of California San Francisco, 1701

Divisadero St, San Francisco, CA 94115. E-mail: sarah.arron@ ucsf.edu. Published online September 11, 2018. 0190-9622 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. https://doi.org/10.1016/j.jaad.2018.05.022

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category of malignant fibrous histiocytoma (MFH), centers. A retrospective chart and histopathologic the latter term is no longer favored given the more review was performed on all confirmed cases on the precise classifications brought about by advances in basis of readout description by a board-certified immunohistochemistry.1,2 Though UPS can rarely dermatopathologist. The clinical variables assessed arise in the retroperitoneum, bone, and other interwere tumor size, location, patient age, and immunal organs, this study focused on UPS of the skin and nosuppression, with the latter defined as a solid soft tissue. organ transplant, bone marrow transplant, or HIV Cutaneous or superficial infection at any stage of disUPS most frequently occurs ease. Outcomes evaluated CAPSULE SUMMARY in chronically sun-exposed were rates of local and skin of elderly white regional recurrence, metasUndifferentiated pleomorphic sarcoma males.2,4 These tumors tasis, and death. To avoid (UPS) embodies various spindle cell show marked cytologic pleobias, outcomes were studied tumors; we sought to identify those with morphism, bizarre cellular in a single collective group of aggressive behavior. forms, atypical mitoses, and UPS cases, rather than by ulceration.2,5,6 When a UPS is Invasion beyond subcutaneous fat and separating them according confined to the dermis, the tumor size larger than 2 cm predicted to diagnostic terminology. A tumors rarely metastasize.7,8 more aggressive behavior. total of 90 patients were When cutaneous UPS origiincluded in a previous study We propose subcategorization into nates or extends below the from one of our institutions.2 superficial UPS and deep UPS. subcutaneous fat, more The histopathologic feaaggressive behavior is chartures of each case were reacteristic, with an increased viewed by using the existing risk of metastasis and death.9-11 The current standard histopathology slides and paraffin-embedded tissue. of care for cutaneous UPS is primarily surgical with Glass slides for re-review were available for 170 the overarching goal of establishing clear margins.2 cases (53%). Cases were included only if they lacked This goal can be achieved with either wide local cytomorphologic or immunophenotypic features of excision or Mohs micrographic surgery.2,12 other differentiated tumors. The characteristics evalDifferentiating between indolent cutaneous UPS uated were the depth of invasion, the presence of and more aggressive cutaneous UPS with histopathlymphovascular invasion (LVI), and the predominant ologic staining has been challenging.13 Though cytomorphology. The cytomorphology was classitumor depth has been utilized as an indicator of fied as pleomorphic/anaplastic, epithelioid, or spinadvanced disease,14,15 many skin biopsies transect dled. Immunostains available from the time of these tumors, leaving out critical tumor depth inforinterpretation were reviewed. Available specimens mation. Thus, it would be useful to identify other and the accompanying stains performed at the time clinical, microscopic, or immunophenotypic predicof initial interpretation were reviewed. Cases were tors of poor prognosis. included only if histomorphologic and immunopheWe designed this study to analyze a large number notypic features were compatible with those of AFX/ of UPS cases to further validate the importance of UPS and no other diagnosis was probable. For cases depth as a key prognostic factor and to identify in which the tumor extended beyond the depth of additional clinical, microscopic, or immunophenothe biopsy, if the tumor showed invasion into or typic predictors of poor prognosis in UPS. This study below the subcutis, this information was included. combined the experience of 3 large tertiary medical Cases in which depth of the biopsy finished in the centers to identify the clinical and histopathologic dermis, the base of the tumor was indeterminate, and predictors of local recurrence, metastasis, and death re-excision specimens did not clearly demonstrate due to UPS. an ultimate depth of the tumor (as in the case of preoperative curettage or a clear first stage on Mohs micrographic surgery) were not included in the METHODS statistical analysis of tumor depth. In the absence of Institutional review board approval was obtained microscopic information, tumor depth was deterat all institutions before this study. Electronic medical mined clinically and radiologically when data were records, institutional cancer registry data, and paavailable. Overall, data on tumor depth were availthology databases were used to identify all adult able for 247 cases (77%). patients who received a diagnosis of UPS, AFX, The cumulative probability of each of the followpleomorphic dermal sarcoma, or MFH from 1980 to up end points was estimated by using the Kaplan2013 and were evaluated across 3 tertiary medical d

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Abbreviations used: AFX: AJCC: CI: HR: LVI: MFH: UPS:

atypical fibroxanthoma American Joint Committee on Cancer confidence interval hazard ratio lymphovascular invasion malignant fibrous histiocytoma undifferentiated pleomorphic sarcoma

Meier method. Potential risk factors for each end point were evaluated by using Cox proportional hazards models with univariate and multivariate models where appropriate. Analyses were completed with SAS software (version 9.4, SAS Institute Inc, Cary, NC).

RESULTS Clinical predictors A total of 319 cases of UPS were identified. The median patient age at diagnosis was 72 years (range, 18-94 years), and 259 patients (81.2%) were male. Of the cases, 235 (73.7%) occurred on the head and neck, 20 (6.3%) occurred on the trunk, 22 (6.9%) occurred on an upper extremity, and 34 (10.7%) occurred on an lower extremity (Table I). The median follow-up time was 4.1 years. Among the subjects studied, 45 (14.1%) developed a local recurrence. The median time to recurrence was 1.2 years (range, 1 month-30.1 years). A total of 33 patients (10.3%) developed distant metastatic disease. The median time to nodal and distant metastasis was 1.2 years, ranging from the time of diagnosis to 19.7 years after surgery with a wide local excision. In all, 96 subjects (30%) died during the follow-up period. (Table I). In our univariate analysis, tumor location on the trunk or extremities was associated with a trend toward increased hazard for recurrence, but this trend did not achieve statistical significance. Subjects with a history of other skin cancers had a lower hazard for local recurrence (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.26-0.85; P = .012). In all, 13 tumors (15.9%) with a preoperative tumor size between 2 cm and 5 cm had a local recurrence. Of the 18 tumors larger than 5 cm, 6 (33.3%) recurred (P \.001). Of the tumors larger than 2 cm, 18.3% metastasized, and at 10 years, 43.9% of these patients had died. After adjustment for age in our statistical model, this tumor size predicted risk of metastasis and overall mortality. Tumor site on the trunk or extremities also had an increased risk of metastasis (P \.001) (Table II).

Other clinical predictors of overall mortality were older age at diagnosis (HR, 1.07; 95% CI, 1.05-1.10; P \ .001) and history of immunosuppression (HR, 2.58; 95% CI, 1.65-4.02; P \ .001). Site and history of other skin cancers were not significantly associated with death (Table II). In our multivariate analysis, both older patient age and history of immunosuppression (HR, 1.11; 95% CI, 1.07-1.15; P \ .001 and HR, 3.65; 95% CI, 3.05-4.25; P \ .0001, respectively) and tumor size larger than 5 cm (HR, 3.20; 95% CI, 2.44-3.96, P \.002) were clinical predictors of death. Histopathologic predictors By univariate analysis, depth of invasion beyond the subcutaneous fat (as determined histopathologically, clinically, or by specimen examination in surgical reports) was the primary predictor of local recurrence (HR, 3.3; 95% CI, 1.55-7.05; P \ .002). A total of 53 cases invaded beyond the subcutaneous tissue, with 17 (32.1%) recurring. Deeper tumors trended towards increased hazard for nodal/ in-transit metastasis, but this was not statistically significant (HR, 2.65; 95% CI, 0.99-7.14; P = .054). Depth of invasion beyond the subcutaneous fat was also a strong predictor of distant metastasis in the univariate and multivariate models (depth HR, 24.90; 95% CI, 5.85-106.00; P\.001); metastasis occurred in 23 of these cases (43.4%) (Table II). The presence of LVI was associated with a significantly higher rate of both metastatic disease (HR, 8.22; 95% CI, 2.48-27.22; P \ .0006) and death (HR, 5.59; 95% CI, 2.03-15.35; P \ .0008). The presence of LVI was not significantly associated with increased rate of local recurrence (HR, 1.90; 95% CI, 0.26-13.86; P \.53) (Table II). According to multivariate analysis, tumor depth was a significant risk factor for local recurrence (HR, 3.30; 95% CI, 1.55-7.05) and distant metastasis (HR, 23.09; 95% CI, 21.59-24.59; P \.0001). LVI was also a significant predictor of death (HR, 6.87; 95% CI, 5.55-8.18); however, the number of cases was small (n = 6). Other histopathologic variables (CD31, epithelial membrane antigen, p63, s100, desmin, and CD34 levels; cytomorphology; and ulceration) did not affect outcomes (Table I). The predominant cytomorphologic subtype (in a comparison of the categories epithelioid, spindled, and anaplastic/pleomorphic) did not significantly affect the rate of local recurrence, metastasis, or death.

DISCUSSION Prior studies attempted to characterize cutaneous UPS through differentiation into subtypes of

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Table I. Clinical and histologic variables with related outcomes in undifferentiated pleomorphic sarcoma Variable

Clinical Age at diagnosis, y Mean (SD) Median Q1, Q3 Range History of immunosuppression History of skin cancer Treatment site Head and neck Trunk and extremities Preoperative tumor size (continuous) Mean (SD) Median Q1, Q3 Range Preoperative tumor size \2 2-5 [5 Histologic Depth of invasion beyond subcutaneous fat Intravasular lymphatic invasion CD31 EMA Desmin Predominant cytomorphology Anaplastic/pleomorphic Spindled/epitheliod Ulceration None Focal Broad

Total (n = 319)

First local recurrence (n = 45)

Nodal/in-transit Met (n = 24)

All Met (n = 33)

Death (n = 96)

71.2 (13.2) 72 66.0, 80.0 (18.0-94.0) 77 183

71.7 (11.6) 72 68.0, 80.0 (34.0-94.0) 8 (10.4%) 19 (10.4%)

68.4 (14.6) 70.5 59.0, 81.0 (34.0-87.0) 6 (7.8%) 10 (5.5%)

66.4 (13.2) 68 55.0, 75.0 (39.0-94.0) 8 (10.4%) 9 (4.9%)

75.1 (10.4) 74 69.0, 83.0 (45.0-94.0) 31 (40.3%) 61 (37.7%)

235 76

28 (11.9%) 17 (22.4%)

11 (4.7%) 13 (17.1%)

12 (5.1%) 21 (27.6%)

67 (28.5%) 27 (40.3%)

2.3 (3.0) 1.5 1.0, 2.3 (0.3-25.0)

3.5 (3.3) 2 1.5, 5.0 (0.6-15.0)

2.9 (2.6) 2.2 1.4, 3.2 (0.7-10.0)

6.6 (6.4) 4.5 2.3, 10.0 (1.3-25.0)

3.2 (4.1) 2 1.2, 3.0 (0.3-25.0)

147 64 18

12 (8.2%) 7 (10.9%) 6 (33.3%)

5 (3.4%) 5 (7.8%) 2 (11.1%)

3 (2.0%) 7 (10.9%) 8 (44.4%)

34 (23.1%) 26 (40.1%) 10 (55.6%)

53

17 (32.1%)

10 (18.9%)

23 (43.4%)

22 (41.5%)

6 5 1 1

1 (16.7%) 1 (20.0%) 0 (0.0%) 0 (0.0%)

1 (16.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

3 (50.0%) 1 (20.0%) 1 (100.0%) 1 (100.0%)

4 (66.7%) 2 (40.0%) 0 (0.0%) 0 (0.0%)

52 118

9 (17.3%) 12 (10.2%)

4 (7.7%) 7 (5.9%)

2 (3.8%) 8 (6.8%)

19 (36.5%) 26 (22.0%)

222 8 17

29 (13.1%) 1 (12.5%) 1 (5.9%)

14 (6.3%) 0 (0.0%) 1 (5.9%)

22 (9.9%) 0 (0.0%) 0 (0.0%)

81 (36.5%) 5 (62.5%) 5 (29.4%)

Overall, information is unavailable for treatment site (n = 8), preoperative tumor size (n = 90), depth (n = 151), CD31 (n = 307), EMA (n = 317), p63 (n = 311), s100 (n = 262), desmin (n = 301), CD34 (n = 314), predominant cytomorphology (n = 149). Met, Metastasis; Q1, first quartile; Q2, second quartile; SD, standard deviation.

superficial UPS/AFX or deep UPS/MFH with the aid of histopathologic and immunohistochemical assessment.6,16,17 However, differentiation based on clinical, histopathologic, or immunohistochemical parameters has been challenging given the limited data available. With the large number of cases in this collective experience, more reliable conclusions are possible. The diagnosis of UPS requires extensive histopathologic evaluation to exclude melanoma, squamous cell carcinoma, angiosarcoma, leiomyosarcoma, or other poorly differentiated neoplasms.18-20 Once the diagnosis of UPS has been established, the histopathologic similarity of deep and superficial tumors creates uncertainty as to whether the tumor will behave as an indolent tumor or a rapidly spreading, aggressive

tumor with high mortality.11 Determination of tumor prognosis is particularly challenging if the lesion is transected during biopsy, thus limiting assessment of tumor depth and extent of invasion. Our data confirm that the behavior of cutaneous undifferentiated pleomorphic sarcoma appears to be closely related to tumor depth. Tumor invasion beyond the subcutaneous fat was associated with increased rates of local recurrence, nodal disease, and distant metastasis, supporting the findings from prior studies.14,15 When the tumor is transected, if determination of tumor depth is not possible in re-excision specimens, then the other factors outlined later in this discussion can be used to aid in clinical judgment. The most prominent of these would be tumor size, which was also significantly

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Table II. Univariate hazard ratios for clinically and histologically relevant factors in undifferentiated pleomorphic sarcoma Variable

Clinical Age at diagnosis History of immunosuppression History of skin cancer Treatment site (head and neck vs trunk and extremities) Preoperative tumor size (continuous) Preoperative tumor size \2 cm 2-5 cm [5 cm Histologic Depth of invasion beyond subcutaneous fat Lymphatic or vascular invasion AJCC Stage

Recurrence

P value

Metastasis

P value

Overall death

P value

1.10) 4.02) 1.84) 1.63)

\.001 \.001 .36 .86

\.001 1.07 (1.02, 1.13)

.008

1.00 (ref) NA 1.00 (ref) NA 1.00 (ref) 1.40 (0.55, 3.55) .48 5.77 (1.49, 22.32) .011 2.31 (1.37, 3.91) 5.53 (2.07, 14.79) \.001 29.02 (7.67, 109.80) \.001 2.89 (1.42, 5.89)

NA .002 .003

1.01 0.76 0.47 1.75

(0.98, (0.35, (0.26, (0.96,

1.03) 1.64) 0.85) 3.19)

.59 .49 .012 .070

0.98 1.19 0.25 5.15

1.09 (1.01, 1.18)

.027

1.17 (1.11, 1.24)

3.30 (1.55, 7.05)

(0.96, (0.53, (0.12, (2.53,

1.00) 2.67) 0.54) 10.50)

.075 .67 \.001 \.001

1.07 2.58 1.21 1.04

(1.05, (1.65, (0.80, (0.66,

.002 24.90 (5.85, 105.99) \.001 1.14 (0.65, 2.01)

1.90 (0.26, 13.86) .53 3.71 (1.77, 7.79) \.001

8.22 (2.48, 27.22) 4.13 (1.79, 9.54)

.65

\.001 5.59 (2.03, 15.35) \.001 \.001 1.10 (0.52, 2.32) .81

AJCC, American Joint Committee on Cancer; NA, not applicable.

Table III. Hazard ratios for clinical and histologic factors associated with poor outcomes in undifferentiated pleomorphic sarcoma Factor

Clinical Age History of immunosuppression History of skin cancer Treatment site (trunk/extremities) Preoperative tumor size Histologic Depth of invasion beyond subcutaneous fat Lymphatic or vascular invasion

Recurrence, HR (95% CI)

1.01 (0.98-1.03) 0.76 (0.35-1.64) 0.47 (0.26-0.85) 1.09 (1.01-1.18) 3.3 (1.55-7.10) 1.90 (0.26-13.86)

Metastasis, HR (95% CI)

0.98 1.13 0.25 5.15 1.17

(0.96-1.01) (0.51-2.53) (0.12-0.54) (2.53-10.50) (1.10-1.24)

24.90 (5.85-106.00) 8.22 (2.48-27.22)

Overall death, HR (95% CI)

1.07 (1.05-1.10) 2.58 (1.65-4.02) 1.34 (0.88-2.02) 1.06 (1.01-1.12) 0.97 (0.45-2.10) 5.59 (2.03-15.35)

Other factors evaluated without statistical evidence of associated outcomes are as follows: CD31, EMA, p63, s100, Desmin, CD34, cytomorphology, and ulceration. CI, Confidence interval; HR, hazard ratio.

correlated with worse outcomes, showing increased rates of local recurrence, metastasis, and death. Tumor size and tumor depth are the main criteria used in the American Joint Committee on Cancer (AJCC) staging of soft-tissue sarcomas.15 These factors were the 2 most consistent predictors of poor outcomes in this study. AJCC tumor stage correlated with adverse outcomes of recurrence and distant metastases (Table II). Although tumor depth and anatomic location seemed to play a consistently strong role in recurrence and metastasis, there was no association with all-cause mortality; rather, death was predicted by tumor size, age at diagnosis (with a 7% increased hazard with each additional year), and immunosuppression (which was associated with a

2.6-fold increased hazard for death). LVI was also associated with increased rates of all-cause mortality. However, the tumor’s cytomorphologic subtype was not correlated with difference in outcomes (Table III). Clinical risk factors are better defined for the superficial, indolent forms of UPS/AFX than for the less common deep aggressive UPS.2,3,18 Studies have shown evidence of ultraviolet radiationeinduced mutations with superficial UPS/AFX12,18 but not for the deep, aggressive UPS.21 The literature is mixed as to whether aggressive tumors occur more often on the head and neck versus on other body parts,21 but most studies have demonstrated a predominance of superficial UPS/AFX in sun-exposed areas.1,7,9 Our study demonstrated an increased risk of local

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recurrence for tumors located on the trunk or extremities. Combined with the lower risk of recurrence in patients with a history of skin cancer, these 2 findings lend evidence to the idea that superficial tumors arising from ultraviolet radiation may be more indolent.2,18 Another potential explanation for these findings is that more frequent or thorough follow-up skin examinations in patients with a history of skin cancer may allow for earlier detection of these tumors and, therefore, less opportunity for deeper invasion of the tumor. Evidence that convincingly differentiates histopathologically between superficial indolent UPS/AFX and aggressive forms of UPS is growing but still limited.22-26 To date, a reliable stain to differentiate between a UPS that behaves aggressively and a UPS with indolent behavior has yet to be discovered,16 and accordingly, we did not identify any immunophenotypic differences between the 2 entities. The lack of differentiating immunohistochemical findings may argue that the tumors derive from the same mesenchymal cells but with different initiators of tumorigenesis.27-30 Recent studies have explored the use of next-generation sequencing to help differentiate these tumors.31,32 Limitations of this study include its retrospective nature; the lack of a uniform prospective histopathologic and immunohistochemical evaluation; the referral bias present at large academic institutions; and the fact that over the decades spanning this study, analysis of tumors in this differential has improved, as a result of which some of the earlier tumors could have been incorrectly deemed AFX or UPS. When available, these tumor specimens were re-evaluated by a board-certified dermatopathologist (J.L. or T.M.). Referral bias and temporal bias may also explain the relatively high recurrence and metastasis rates in this study, as our institutions see many aggressive deep tumors. The primary goal of this study was to assess the clinical and histopathologic features of UPS that predict aggressive behavior. Previous studies relied on series of fewer than 100 patients. Our multicenter study of 319 patients has allowed us to clearly identify some new or clearer findings: tumor behavior is most reliably predicted by the presence of invasion beyond subcutaneous fat, preoperative tumor size larger than 2 cm, immunosuppression, and the presence of LVI. This study also supports the use of the AJCC soft-tissue sarcoma staging for UPS, including the superficial AFX type. These clinical and histopathologic characteristics may help guide clinicians in making decisions regarding the adjuvant treatment and frequency of surveillance for these tumors.

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