Dermatology

Malignant Fibrous Histiocytoma (undifferentiated pleomorphic sarcoma, not otherwise specified)

Malignant Fibrous Histiocytoma [MFH, undifferentiated pleomorphic sarcoma, not otherwise specified]

Are You Confident of the Diagnosis?

Malignant fibrous histiocytoma (MFH) is the third most common malignant soft tissue tumor of the skin, after dermatofibrosarcoma protuberans (DFSP) and dermal sarcoma (former atypical fibroxanthoma) (AFX). Its exact incidence is unknown, but it certainly is very rare. In Tübingen (Germany), 2.5 times more DFSP than MFH have been treated in the same period.

The definition of MFH is based on the studies of Weiss and Enzlinger. Despite its relative rarity, MFH represents the most frequent soft tissue sarcoma diagnosed in adults. A pleormorphic-storiform type (82%) can be distinguished from a myxoid type (18%). The latter is more often superficially located and of lower grade, and therefore, associated with a better prognosis.

The superficial type of MFH involves exclusively the skin up to the investing fascia. It carries a relatively good prognosis. Particularly primary (nonrecurrent) MFH that can be treated with a microscopically complete surgical resection carries a 10-year survival rate of almost 100%. Therefore, micrographic surgery (synonymously: 3D-histologically evaluated surgery) represents the treatment of choice for superficial MFH. The superficial type has to be distinguished from the deep type of MFH involving fascia and deeper layers (muscle, bone or neurovascular structures), which carries a poorer prognosis.

MFH has been described to occur on the lower extremities (48%), upper extremities (16%), trunk including the retroperitoneum (29%), and the head and neck region (6%]. When a department of dermatology represents the referral center, 44% of MFH are located at the head and neck region, 23% at the lower extremity, 15% at the upper extremity, and 18% at the trunk.

MFH, like other cutaneous soft tissue tumors, typically presents as nonspecific, skin-colored, indurated nodule or plaque, which initially grows slowly with an irregular pattern of extension (Figure 1). Often it takes a long delay of months or even years until the diagnostic biopsy is taken.

Figure 1.

Eroded plaque on the scalp. Biopsy showed MFH. (Courtesy of Bryan Anderson, MD)

Typical histology is illustrated in Figure 2 and Figure 3. Histological subtypes are categorized in Table I.

Table I.

Histological subtypes
Storiform (pleomorphic) - most frequent
Giant Cell
Myxoid
Inflammatory

Figure 2.

MFH histology, low power. (Courtesy of Bryan Anderson, MD)

Figure 3.

MFH histology, high power (Courtesy of Bryan Anderson, MD)

Who is at Risk for Developing this Disease?

MFH affects males slightly more than females. It is most common in the 6th to 8th decade of life, and is rarely seen in individuals less than 20 years of age.

What is the Cause of the Disease?

Etiology

The etiology is unknown.

Pathophysiology

The pathophysiology is likewise unknown.

Systemic Implications and Complications

Recurrence in up to one-third of cases, typically in the first 1-2 years. Systemic implications/complications include metastasis and death.

Treatment Options

--Surgery

--Radiation

--Chemotherapy

The first-line treatment is based on surgical resection aiming at microscopically tumor-free excisional margins (R0 resection). In dermatology, this technique is called Mohs’ micrographic surgery (then conventionally referring to the fresh frozen technique that uses “instant” cryostat sections) or “Slow Mohs,” applying the micrographic technique on formalin-fixed and paraffin-embedded slides that require at least 1 day delay until reading.

The term “3D-histological evaluation of surgery” coined by the Tübingen group lumps all micrographic excisional techniques together. The Tübingen group and the Zürich group agree that formalin-fixed and paraffin-embedded sections are more suitable for diagnosing excisional margins of cutaneous soft tissue tumors, particularly when deep anatomical structures or scar tissue have to be distinguished from fine strands of tumor extensions.

The old surgical dogma proposes to use wide surgical margins to treat cutaneous soft tissue tumors, ie, wide excision with 2-cm or 3-cm lateral margins measured from the macroscopically visible or palpable tumor delineation. It has been shown by several authors that recurrence rates after wide excision tend to be higher than with micrographic surgery. This has been explained by long, unidirectional tumor protrusions that may exceed the empirically chosen “wide” surgical margin.

The technique of 3D-histological evaluation of surgery to treat MFH of the skin is explained in the comprehensive paper by Häfner et al. They resect the tumor with lateral margins of 6-10 mm, including the subcutis to the underlying anatomical layer, commonly the fascia. The specimen is prepared and encapsuled by the surgeon himself, and after a formalin fixation at 60°C the specimens can be processed using paraffin sections that are ready 20 hours after the first excision.

They continue to reexcise tumor-positive margins until they reach R0 margins in all directions. An R0 resection is mandatory before repair, even if the excisional procedure may extend over multiple steps on several consecutive days.

Häfner et al treated 31 patients with cutaneous MFH, amongst whom 26% had recurrent tumors. They were able to achieve R0-resections in 90% of patients. At 5 years follow-up they observed eight recurrences (26%). All three patients (10%) with a noncompletely resectable MFH had died after an observational period of 5 years.

The effectiveness of adjuvant radiotherapy in the treatment of MFH is not yet completely clarified. In the French study, postoperative radiotherapy decreased the local relapse risk (p = 0.002). It should probably be reserved for patients with a more serious prognosis based on the risk factors at initial presentation. In other words, patients with a superficial type of MFH with a diameter less than 5 cm that can be totally removed (R0-resection) can avoid postoperative radiotherapy.

The effectiveness of adjuvant chemotherapy is unknown. In both the French study and the Memorial Sloan-Kettering Cancer Center study a fraction of patients (9% and 23%, respectively) had postoperative chemotherapy. The decision for adjuvant chemotherapy was made by a multidisciplinary tumor board. A variety of regimens that usually contained doxorubicine were applied.

It is likely that both studies reserved adjuvant chemotherapy for patients with a high-risk profile at study entry. It was not used in a controlled study setting and therefore it is hardly possible to draw any conclusions on its effectiveness.

Optimal Therapeutic Approach for this Disease

In summary,, MFH of the skin should be first treated with micrographic surgery. It should be emphasized that the use of “wide surgical margins” (2 cm or 3 cm) leads to higher recurrence rates than the use of the more tissue-sparing micrographic (“3D-histologically evaluated”) surgical techniques. It is probably advisable to use formalin-fixed and paraffin-embedded sections instead of cryostat sections to control the surgical margins. Patients presenting with a superficial MFH of less than 5-cm diameter who can be treated with a R0 resection can expect a 10-year survival rate of almost 100%, and do not require adjuvant radiotherapy or adjuvant chemotherapy.

Patient Management

The French, Memorial Sloan-Kettering Cancer Center, and Tübingen studies are summarised in Table II, Table III, and Table IV, respectively.

Table II.

French National League Against Cancer Study (1980-89)
n = 216 ; 195 (90%) R0 or R1 resection ; 78 (36%) adjuvant radiotherapy ; 61 (28%) adjuvant radio- and chemotherapy; 19 (9%) adjuvant chemotherapy
 
Five-year actuarial rates of
- disease-specific survival (DSS)   70%
- metastasis-free survival (MFS)   63%
- local recurrence-free survival (LRFS)  63%
 
Adverse prognostic factors 
- UICC/AJC stage III + IVA   p = 0.00001  *
- macroscopic incomplete (R2) resection p = 0.00024
- tumor size >8 cm    p = 0.0012  *
- deep tumor location    p = 0.0045 
- nonmyxoid histology    p = 0.0056
- >50 years old     p = 0.037 
- No adjuvant radiotherapy (for LRFS)  p = 0.0043

Table III.

Memorial Sloan-Kettering Cancer Center Study (1982-96)
n = 239, extremity ; 203 (85%) R0 resection ; 42 (18%) presented with local recurrence; 45 (19%) adjuvant radiotherapy ; 54 (23%) adjuvant chemotherapy
 
Prognostic factors
- UICC/AJC stage III + IVA
- tumor size >5 cm (and >10 cm)
- deep tumor location
- presentation with local recurrence
 
Superficial* versus deep** location: Actuarial survival rates
- superficial, low grade, <5 cm diameter  100%
- superficial, high grade, <5 cm diameter    93%
- superficial, high grade, >5 cm diameter    40%
- deep, low grade, <5 cm diameter   100%
- superficial, high grade, <5 cm diameter    52%
- superficial, high grade, >5 cm diameter    38%
 
Superficial*: To the investing muscular fascia (n = 56; 23%)
Deep**: Involving muscular fascia or deeper compartments (n = 183;77%)

Table IV.

University Dermatology Department of Tübingen Study (1982-2004): Summary of outcome (Häfner HM et al.: EJSO 2008;34:680-686)
n = 31; 28 (90%) R0 resection ; 8 (26%) presented with local recurrence; 3 (10%) with R1 resection had adjuvant radiotherapy ;none (0%) adjuvant chemotherapy
 
Prognostic factors
- R1 resection (all of whom had postoperative adjuvant radiotherapy) Actuarial disease-specific survivial rate (DSS)
- actuarial 10-year survival rate  89%
- 3 fatal outcomes, all of them with incomplete resection and adjuvant radiotherapy
 
Actuarial recurrence-free survival rate (RFS)
- actuarial   5-yearsrecurrence-free survival rate 71%
- actuarial 10-year recurrence-free survival rate 65%

Patients should be seen every 3-6 months for 2 years and every 6 months for another 3 years, then annually thereafter for at least 10 years. History and physical examination, including review of systems, should be done at each visit.

Unusual Clinical Scenarios to Consider in Patient Management

MFH is rarely seen in children. Unusual locations have been reported. It is most frequently seen on the extremities or in the retroperitoneum.

What is the Evidence?

Hafner, J, Schütz, K, Morgenthaler, W, Steiger, E, Meyer, V, Burg, G. "Micrographic surgery (“Slow Mohs”) in cutaneous sarcomas". Dermatology. vol. 198. 1999. pp. 37-43.

(Discusses the treatment of cutaneous sarcomas including MFH with the “slow” Mohs technique.)

Häfner, HM, Moehrle, M, Eder, S, Trilling, B, Röcken, M, Breuninger, H. "3D-histological evaluation of surgery in dermatofibrosarcoma protuberans and malignant fibrous histiocytoma: differences in growth patterns and outcome". Eur J Surg Oncol. vol. 34. 2008. pp. 680-6.

(Article discussing the differences between DFSP and MFH using 3D evaluation models.)

Weiss, SW, Enzinger, FM. "Malignant fibrous histiocytoma: an analysis of 200 cases". Cancer. vol. 41. 1978. pp. 2250-66.

(Overall excellent review of 200 cases of MFH, including characteristics, therapy and outcomes.)

Le Doussal, V, Coindre, JM, Leroux, A, Hacene, K, Terrier, P, Binh Bui, N. "Prognostic factors for patients with localized primary malignant fibrous histiocytoma: a multicenter study of 216 patients with multivariate analysis". Cancer. vol. 77. 1996. pp. 1823-30.

(Excellent review looking at prognostic indicators of disease.)

Salo, JC, Lewis, JJ, Woodruff, JM, Leung, DH, Brennan, MF. "Malignant fibrous histiocytoma of the extremity". Cancer. vol. 85. 1999. pp. 1765-72.

(Nice review of MFH. Discusses a case of MFH on the extremity.)
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