悪性線維性組織球腫

アクセイセンイセイソシキキュウシュ

【英】malignant fibrous histiocytoma（MFH）

異型性の強い線維芽細胞様細胞と組織球様細胞からなり，奇異な形の巨細胞や炎症性細胞浸潤を混じえてきわめて多彩な像を示す悪性度の高い肉腫＊sarcoma

である．1960年代以前にはmalignant fibroxanthoma, fibroxanthosarcomaなどの名で呼ばれていたが，1967年Stoutらが悪性線維性組織球腫（MFH）の名称を提唱した．その後1978年にはEnzinger，　Weissによる多数例の臨床病理学的検討に基づく報告が出され，一つの疾患単位として広く受け入れられるようになった．分類亜型として， 1)花むしろ状‐多形型， 2)粘液型， 3)巨細胞型， 4)炎症型， 5)類血管腫型の5型に分けられるが，同一腫瘍内でもこれらの組織型が混在していることが多い．50歳代から70歳代の中高齢者に多くみられ，体幹や四肢の軟部組織や後腹膜に分葉状・多結節性の腫瘤として発生するが，近年，肺，心，肝，脾，骨などさまざまな臓器での発生も報告されている．この腫瘍が提唱されてからは，軟部組織肉腫（→軟部組織腫瘍）の中での発生頻度はMFHが脂肪肉腫＊liposarcomaや平滑筋肉腫＊leiomyosarcomaを抜いて第1位を占めるようになったが，かつて多形性の強い脂肪肉腫，横紋筋肉腫＊rhabdomyosarcoma，線維肉腫＊fibrosarcomaとされてきた症例の一部は，MFHであろうと推定されている．しかし1980年代後半からの研究によって，MFHを構成する腫瘍細胞には真の組織球の性格が判然としないこと，非腫瘍性の反応性組織球や巨細胞が混在していることが明らかとなってきており，FletcherらはMFHの疾患単位としての独立性を疑問視している．現在MFHの組織発生については， 1)未分化間葉系細胞が一定の形態的表現を示さずに最も未熟で低分化な肉腫として発生してきたもの，あるいは， 2)いったん脂肪肉腫，平滑筋肉腫など一定方向への分化を示して発生してきた腫瘍の一部が，いわゆる脱分化dedifferentiation（→前〔進〕形成）によって未分化な肉腫の形態をとって増殖してきたもの，などの説明がなされているが，いずれにしてもEnzinger, Weissらがこの腫瘍を整理した時期に比べると，MFHはかなりheterogenousな性格の強い腫瘍グループとする意見が強まってきている．→黄色線維腫，細網組織球腫

悪性線維性組織球腫（Malignant Fibrous Histiocytoma; MFH）

概念・定義

悪性線維性組織球腫は、脂肪組織や骨、筋肉など軟部組織から発生する代表的な高悪性度軟部肉腫の一種です。腫瘍細胞は線維芽細胞様の細胞と組織球様の細胞が混在し、急速に増大する性質を持ちます。

好発部位・好発年齢・性差

• 好発年齢：50～70歳代に最も多く発症します
• 性差：男性にやや多く（男性：女性＝2：1）認められます
• 好発部位：下肢（特に大腿部）、腹部、肩背部などの深部軟部組織に発生しやすいです

病因・リスク因子

原因は完全には解明されていませんが、以下の因子が関連すると考えられています：

• 遺伝子異常：TP53やRB1遺伝子変異の関与が示唆されます
• 放射線被曝や化学療法既往：治療目的の放射線や抗がん剤への暴露後に発生することがあります
• 慢性の外傷・炎症：傷や慢性炎症部位で好発するケースがあります

症状

• 初期は無痛性のしこり（腫瘤）で発見されることが多く、自覚症状に乏しい場合があります
• 腫瘤が大きくなると、局所圧迫による痛みや可動域制限が出現します
• 骨への浸潤で病的骨折を来すことがあります
• 肺転移を起こしやすく、呼吸困難や胸痛を契機に発見される場合もあります

診断

1. 画像検査

1. X線検査：腫瘤の位置・石灰化の有無を評価
2. CT／MRI：腫瘍の大きさ・浸潤範囲を詳細に把握
3. PET-CT：全身への転移検索・病期診断に有用

1. 病理検査

• 針生検または開放生検により組織を採取し、鏡検で腫瘍細胞の形態・細胞分裂像を評価します

治療

• 外科的切除
  腫瘍周囲の正常組織を含めた広範囲切除が基本です。十分なマージンを確保することで再発リスクを低減します。
• 補助療法

• 放射線療法：切除困難な部位や術後補助として適応
• 化学療法：高悪性度例や転移例で行われることがあります

• 再発・転移例
  再手術、追加の放射線／化学療法を検討します。肺転移に対しては肺切除術が選択される場合もあります。

予後

• 一般に進行が速く、5年生存率は骨転移がある例で不良です。
• 以下の因子が良好予後とされます：

• 腫瘍径が小さい
• 悪性度が低い（細胞異型度・分裂能が低い）
• 完全切除が可能
• 発症年齢が60歳未満

さらに詳しく知りたい場合は、以下のテーマもご参照ください：

• 他の軟部肉腫（例：平滑筋肉腫、脂肪肉腫）との鑑別
• 分子標的治療・免疫チェックポイント阻害剤の臨床試験動向
• 術後リハビリテーションと生活指導のポイント

【参考文献】

1. MEDLEY「悪性線維性組織球腫の基礎知識」2022.03.11
2. Medical Note「悪性線維性組織球腫について」2017.04.25

Prognosis of Malignant Fibrous Histiocytoma (MFH)

5-Year Survival Rates

• MFH of bone treated with adequate surgical resection shows a 5-year survival rate of 63 %.
• In contrast, patients receiving inadequate or palliative surgery have a 5-year survival of only 17 %.
• Among a small cohort of bone MFH patients who underwent both intensive chemotherapy and adequate surgery, 100 % were alive and well at 5 years.

Key Prognostic Factors

Recurrence and Metastatic Risk

• Local recurrence rates for MFH range up to 30–50 %, especially when margins are positive or narrow.
• Distant metastases most commonly involve the lungs; pulmonary spread is the chief cause of MFH-related mortality.

Subtype-Specific Considerations

• Storiform-pleomorphic MFH: most common, high-grade, intermediate prognosis.
• Myxoid MFH: less aggressive course, often low-grade, best overall survival among MFH subtypes.
• Giant cell and inflammatory types: rare; inflammatory MFH in retroperitoneum may have variable outcomes.

Clinical Implications

• Achieving a wide surgical margin is the single most important modifiable factor.
• In bone MFH, adjuvant intensive chemotherapy shows promise but requires validation in larger soft-tissue cohorts.
• Histopathologic review for desmoplasia and inflammatory infiltrates can refine individual risk stratification.

Next Steps for Deeper Insight

• Investigate molecular markers (e.g., TP53, RB1) for personalized prognosis.
• Review evolving roles of radiation therapy and targeted agents in high-risk MFH.
• Explore surveillance protocols (imaging intervals, duration) tailored by histologic risk features.

References

1. UCSF Department of Surgery. Malignant Fibrous Histiocytoma. (undifferentiated pleomorphic sarcoma)
2. Yokoyama R, Tsuneyoshi M, Enjoji M, et al. Prognostic Factors of Malignant Fibrous Histiocytoma of Bone. Cancer. 1993;72(6):1902–1908.

Summary of Key Prognostic Factors in MFH

Here’s a concise overview of the factors that most strongly influence outcomes in malignant fibrous histiocytoma:

• Surgical margin status
  Wide, negative margins after resection dramatically lower the risk of local recurrence and improve overall survival.
• Tumor size
  Lesions larger than 5 cm correlate with higher rates of recurrence and poorer long-term survival.
• Histologic grade
  High-grade features—marked pleomorphism and elevated mitotic rate—predict more aggressive behavior.
• Patient age
  Patients older than 60 typically fare worse than younger counterparts.
• Anatomic depth
  Deep-seated tumors carry a greater risk of both local relapse and distant metastasis compared to superficial lesions.
• Histologic subtype
  Myxoid variants often behave less aggressively, whereas storiform-pleomorphic types exhibit intermediate prognosis.
• Microenvironmental features
  – Desmoplastic stroma is linked to poorer outcomes.
  – Chronic inflammatory infiltrates tend to portend a more favorable course.
• Adjuvant therapy
  In bone MFH, combining intensive chemotherapy with surgery has yielded up to 100 % 5-year survival in small series; its role in soft-tissue MFH is under active investigation.

Beyond the Basics

• Molecular markers such as TP53 and RB1 mutations are emerging as tools for personalized risk stratification.
• Advanced imaging protocols—including interval PET-CT or MRI—can catch early recurrences before clinical symptoms arise.
• Novel therapies, from targeted molecular agents to immunomodulators, are being trialed to improve outcomes in high-risk patients.
• Tailored surveillance schedules and rehabilitation strategies play a key role in maintaining quality of life and functionality post-treatment.

Influence of Prognostic Factors on Treatment Decisions

Surgical Margin Status

Wide, negative surgical margins guide toward limb-sparing wide excisions with the goal of complete tumor removal and minimal functional loss.

When margins are close or positive, postoperative radiotherapy is often added to reduce local recurrence risk, or a re-excision is considered to achieve clearer margins.

Tumor Size

Lesions larger than 5 cm frequently prompt neoadjuvant (preoperative) chemotherapy or radiotherapy to shrink the tumor and facilitate a safer, more conservative resection.

Smaller tumors (< 5 cm) without high-risk features may proceed directly to surgery, reserving adjuvant therapies for unexpected adverse findings.

Histologic Grade

High-grade MFH with marked pleomorphism and rapid mitotic activity typically warrants multimodal treatment: neoadjuvant chemotherapy, wide resection, and postoperative radiotherapy.

Low-grade variants often achieve durable control with surgery alone, minimizing exposure to systemic agents.

Patient Age and Performance Status

Younger patients (< 60 years) and those with good performance status can tolerate more aggressive chemotherapy regimens (e.g., doxorubicin-based combinations) and dose-intense radiotherapy.

In older or frail patients, treatment is tailored to balance efficacy and quality of life, often favoring less intensive systemic therapy and prioritizing functional preservation.

Anatomic Depth

Deep-seated tumors adjacent to neurovascular bundles or vital structures may receive neoadjuvant therapy to reduce size and improve the likelihood of a complete resection.

Superficial MFH lesions generally follow a standard surgical pathway, with radiotherapy reserved for cases with narrow margins or recurrent disease.

Histologic Subtype

Myxoid MFH, behaving like a low-grade tumor, often relies on surgery as the mainstay; adjuvant therapy is considered only for large or recurrent lesions.

Storiform-pleomorphic MFH, being more aggressive, usually triggers a combination approach: chemotherapy, wide excision, and radiotherapy for optimal control.

Microenvironmental Features

A desmoplastic stroma can indicate radioresistance, encouraging dose escalation or inclusion of radiosensitizing chemotherapy.

Tumors rich in chronic inflammatory infiltrates may respond favorably to immunomodulatory strategies; these patients can be candidates for clinical trials of immune checkpoint inhibitors.

Role of Adjuvant Therapies

• In bone MFH, adjuvant chemotherapy paired with complete resection has shown exceptional survival in select series.
• In soft-tissue MFH, adjuvant radiotherapy is standard for high-grade or large tumors, while chemotherapy is reserved for metastatic or borderline resectable cases.

Integrated Decision Pathway

1. Present the case at a multidisciplinary tumor board, reviewing all prognostic factors.
2. Decide on neoadjuvant therapy when high-risk features (large size, high grade, deep location) are present.
3. Plan the extent of surgical resection with clear margin goals.
4. Tailor adjuvant radiotherapy and chemotherapy based on final pathology (margin status, grade, subtype).
5. Define surveillance intervals and modalities (MRI, PET-CT) according to risk stratification.

Beyond Treatment Planning

• Emerging molecular markers (TP53, RB1) will soon refine personalized therapy selection.
• Immunotherapy trials are exploring if inflammatory-rich MFH can be exploited by checkpoint inhibitors.

Rehabilitation and functional reconstruction are integral to maintaining quality of life post-treatment.