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Background

Sometimes benign tumors can have a very aggressive course. Fibromatosis is a soft tissue tumor that has a nasty habit of many local recurrences if not completely excised. These tumors can be very painful and disfiguring.

OUTLINE

Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

DISEASE ASSOCIATIONS CHARACTERIZATION
ORTHOPEDIC HIP REPLACEMENT  


Development of a desmoid tumor at the site of a total hip replacement.

Gebhart M, Fourmarier M, Heymans O, Alexiou J, Yengue P, De Saint-Aubain N.

Department of Orthopedics, Institut Bordet, Brussels, Belgium

Acta Orthop Belg 1999 Jun;65(2):230-4 Abstract quote

Extra-abdominal desmoid tumors are locally aggressive benign soft tissue tumors arising from the connective tissue of muscle and overlying fascia or aponeuroses. Location around the hip occurs in about 10% of all desmoid tumors.

The authors report the development of a desmoid tumor around the hip 45 months after implantation of a total hip prosthesis. Endocrine and physical factors seem to play an important role in the development of the disease. Moreover, an association has been reported between trauma and desmoid tumor. Desmoid tumors developing around silicon implants have also been described. However, no association between hip prostheses and desmoid tumors has been published in the world literature.

Although soft tissue tumors induced by metallic implants have been observed clinically, we still seek a coherent explanation for the exact pathogenesis.

 

PATHOGENESIS CHARACTERIZATION

Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology.

De Wever I, Dal Cin P, Fletcher CD, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, Van Den Berghe H, Vanni R, Willen H.

Department of Surgical Oncology, University of Leuven, Belgium.

Mod Pathol 2000 Oct;13(10):1080-5 Abstract quote

Whether fibromatoses are neoplastic or reactive lesions has long been controversial and the relationship, if any, between the superficial and deep forms (desmoid tumors) are poorly understood.

Clinical, pathologic, and cytogenetic data of 78 cases of fibromatosis were analyzed and correlated with each other. The results demonstrate that clonal chromosome aberrations are a common feature of this entity, being present in 46% of desmoid tumors, although less frequent in the superficial types (10%). In the deep-seated extra-abdominal fibromatoses, trisomies 8 and 20 and loss of 5q material were the only recurrent features. No correlation between +8 and local recurrence was found.

Our findings provide additional evidence for the neoplastic nature of fibromatoses.

Superficial Fibromatoses are Genetically Distinct from Deep Fibromatoses

Elizabeth Montgomery, M.D., Jae-Hyuk Lee, M.D., Ph.D., Susan C. Abraham, MD. and Tsung-Teh Wu, M.D., Ph.D.

Department of Pathology The Johns Hopkins University School of Medicine, Baltimore, Maryland

Mod Pathol 2001;14:695-701 Abstract quote

Whereas deep fibromatoses (abdominal, extra-abdominal, mesenteric) display locally aggressive behavior, superficial fibromatoses typically remain small and less likely to recur despite essentially identical morphology. Somatic ▀-catenin or APC gene mutations have been reported in [<=] 74% of sporadic deep fibromatoses and in virtually 100% of Gardner syndromeľassociated fibromatoses, whereas genetic events in superficial fibromatoses remain less well characterized.

We performed immunohistochemical staining for ▀-catenin on 29 superficial fibromatoses (22 palmar, 5 plantar, 1 penile, and 1 infantile digital fibromatosis) and 5 deep fibromatoses. Mutations of ▀-catenin and APC genes were analyzed in cases of superficial fibromatoses by direct DNA sequencing of the ▀-catenin gene on Exon 3 encompassing the GSK-3 36 phosphorylation region and of the APC gene on the mutation cluster region.

Nuclear accumulation of ▀-catenin was present in 86% (25/29) of superficial fibromatosis cases ranging from 5 to 100% of nuclei (mean, 13%; median, 10%), though in a minority of nuclei in most examples. Deep fibromatoses had 60 to 100% nuclear staining in all five cases. No somatic mutations of ▀-catenin or APC genes were identified in any of the superficial fibromatoses. In contrast to deep fibromatoses, superficial fibromatoses lack ▀-catenin and APC gene mutations; the significance of focal nuclear ▀-catenin accumulation is unclear.

This difference may account inpart for their divergent clinical manifestations despite their morphologic resemblance to deep fibromatoses.

BETA CATENIN MUTATIONS  
Detection of beta-Catenin Mutations in Paraffin-embedded Sporadic Desmoid-type Fibromatosis by Mutation-specific Restriction Enzyme Digestion (MSRED): an Ancillary Diagnostic Tool.

*Santa Casa School of Medical Sciences, Sao Paulo, Brazil Departments of †Histopathology ¶Radiology, Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP ∥Department of Histopathology, University College Hospital, Gower Street, London, WC1E 6BT ♯Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, UK ‡Department of Pathology, Universitair Ziekenhuis Gent, De Pintelaan 185, 900O Gent, Belgium §Hospital, Maastricht, The Netherlands.

Am J Surg Pathol. 2007 Sep;31(9):1299-1309. Abstract quote

Desmoid-type fibromatosis is a locally aggressive deep soft tissue tumor. Some cases are associated with adenosis polyposis coli germline mutations whereas others harbor somatic beta-catenin point mutations mainly in exon 3, codons 41 and 45. These mutations result in stabilization of beta-catenin, and activation of the Wnt signaling pathway.

The aim of this study was to determine the specificity and sensitivity of these 3 most common beta-catenin mutations in the diagnosis of desmoid-type fibromatosis using paraffin-embedded material. The results were compared with nuclear expression of beta-catenin. Mutation-specific restriction enzyme digestion methodology was employed to detect the 3 mutations.

One hundred and thirty-three cases were analyzed, including 76 desmoid-type, and 18 superficial fibromatosis, in addition to a further 39 fibromatosis mimics. A restriction site was present for analysis of the codon 41 mutation. Mismatch primers were designed for the codon 45 mutations. Mutations were detected in 66 cases (87%) of 76 desmoid-type fibromatosis (71 extra-abdominal). Of these, 34 (45%) were in codon 45 (TCT>TTT), 27 (35%) in codon 41 (ACC>GCC), and 5 (7%) in codon 45 (TCT>CCT). No mutations were detected in the other lesions studied. All desmoid-type fibromatosis cases and 72% of the mimics tested showed nuclear positivity for beta-catenin indicating immunohistochemistry is a sensitive but not a specific test for desmoid-type fibromatosis. In contrast, to date, beta-catenin mutations have not been detected in any lesions which mimic desmoid-type fibromatosis.

Mutation-specific restriction enzyme digestion, a simple and efficient means of detecting the common beta-catenin mutations in desmoid-type fibromatosis, complements light microscopy in reaching a diagnosis.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
Radiographs  
CT scan and MRI  

Imaging of musculoskeletal fibromatosis.

Robbin MR, Murphey MD, Temple HT, Kransdorf MJ, Choi JJ.

Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA.

Radiographics 2001 May-Jun;21(3):585-600 Abstract quote

The musculoskeletal fibromatoses comprise a wide range of lesions with a common histopathologic appearance.

They can be divided into two major groups: superficial and deep. The superficial fibromatoses are typically small, slow-growing lesions and include palmar fibromatosis, plantar fibromatosis, juvenile aponeurotic fibroma, and infantile digital fibroma.

The deep fibromatoses are commonly large, may grow rapidly, and are more aggressive. They include infantile myofibromatosis, fibromatosis colli, extraabdominal desmoid tumor, and aggressive infantile fibromatosis. Radiographs typically reveal a nonspecific soft-tissue mass, and calcification is common only in juvenile aponeurotic fibroma.

Advanced imaging (ultrasonography, computed tomography, and magnetic resonance [MR] imaging) demonstrates lesion extent. Involvement of adjacent structures is common, reflecting the infiltrative growth pattern often seen in these lesions.

MR imaging may show characteristic features of prominent low to intermediate signal intensity and bands of low signal intensity representing highly collagenized tissue. However, fibromatoses with less collagen and more cellularity may have nonspecific high signal intensity on T2-weighted images. Local recurrence is frequent after surgical resection due to the aggressive lesion growth.

It is important for radiologists to recognize the imaging characteristics of musculoskeletal fibromatoses to help guide the often difficult and protracted therapy and management of these lesions.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL Classically divided into superficial and deep seated lesions
GINGIVAL
 
INFANTILE DIGITAL
 
INTRA-ABDOMINAL
May arise de novo, secondary to trauma, hormonal stimulation, or in association with familial polyposis coli or Gardner's syndrome
JUVENILE HYALINE FIBROMATOSIS  
Juvenile hyaline fibromatosis: a case report.

Karacal N, Gulcelik N, Yildiz K, Mungan S, Kutlu N.

Department of Plastic and Reconstructive Surgery, Karadeniz Technical University, Trabzon, Turkey.

J Cutan Pathol. 2005 Jul;32(6):438-40. Abstract quote  

Juvenile hyaline fibromatosis ( JHF ) is a rare autosomal recessive disease characterized by papulonodular skin lesions, gingival hyperplasia, joint contractures, and bone lesions. The skin lesions may consist of multiple large tumors, commonly on the scalp and around the neck, and small pearly, pink papules and plaques on the trunk, chin, ears, and around the nostrils.

Here, we report a 2-year-old boy with characteristic stiffness of the knees and elbows and pink confluent papules on the paranasal folds, and periauricular and perianal regions. He also had hard nodules all over the scalp and around the mouth, and severe gingival hyperplasia. The lesions were totally excised and clinicopathological diagnosis was JHF
PALMAR (Dupytren's contracture)
 
PENILE (Peyronie's disease)
 
PLANTAR
 
VARIANTS  
BREAST  

Fibromatosis of the breast and mutations involving the APC/-catenin pathway

Susan C. Abraham, MD
Carol Reynolds, MD
Jae-Hyuk Lee, MD, PhD
Elizabeth A. Montgomery, MD
Blaire L. Baisden, MD
Alyssa M. Krasinskas, MD
Tsung-Teh Wu, MD, PhD

Hum Pathol 2002;33:39-46. Abstract quote

Fibromatoses of the breast are nonmetastasizing tumors, but can be infiltrative and locally recurrent. Breast fibromatoses are rare, and their specific genetic alterations have not been elucidated. However, their occasional occurrence in patients with familial adenomatous polyposis (FAP) and their morphologic identification with other deep fibromatoses (desmoid tumors) suggest that alterations of the APC/-catenin pathway might be involved in the pathogenesis of sporadic and FAP-associated breast fibromatoses.

We analyzed somatic -catenin and APC gene mutations in 33 breast fibromatoses (32 sporadic and 1 FAP-associated) using immunohistochemistry for -catenin, 5q allelic loss assays, and direct DNA sequencing for exon 3 of the -catenin gene and the mutation cluster region of the APC gene. Nuclear accumulation of -catenin was present in the stromal tumor cells in most (82%) cases but not in normal stroma or mammary epithelial cells. Somatic alterations of the APC/-catenin pathway were detected in 79% of breast fibromatoses, including activating -catenin gene mutations in 15 cases and somatic APC alterations (mutation or 5q allelic loss or both) in 11.

These findings indicate that alterations of the APC/-catenin pathway with resultant nuclear translocation of -catenin are important in the pathogenesis of both sporadic and FAP-associated breast fibromatosis. The spectrum of -catenin and APC alterations is similar to that described for desmoid tumors of the abdomen, paraspinal region, and extremities.

EXTREMITIES  

Fibromatoses of the extremities: clinicopathologic study of 36 cases.

Mehrotra AK, Sheikh S, Aaron AD, Montgomery E, Goldblum JR.

Department of Anatomic Pathology, Georgetown University, Washington DC, USA.

J Surg Oncol 2000 Aug;74(4):291-6 Abstract quote

BACKGROUND AND OBJECTIVES: Fibromatoses of the extremities are rare and often recalcitrant to treatment. We evaluated the clinical and pathologic features of a group of extremity fibromatoses treated by surgical excision with or without adjuvant therapy to determine if any clinical or pathologic parameters were predictive of clinical outcome.

METHODS: Thirty-six extremity fibromatoses were evaluated. A number of clinical and histologic features were correlated with risk of local recurrence.

RESULTS: The cohort included 19 females and 17 males with ages ranging from 11-72 years (mean: 35 years), with 12 tumors of the upper and 24 tumors of the lower extremity. Tumors ranged in size from 1.5-15.5 cm (mean: 7.5 cm). Histologically, 26 were infiltrative, 3 had pushing borders and 7 had both. Mitotic counts ranged from 0-5/50 high-power fields (mean: 0.74). Surgical margins were positive in 22 cases. Seventeen patients were treated with postoperative adjuvant therapy including radiation therapy and tamoxifen. Follow-up information was available in 34 cases (from 1-202 months; mean: 83 months). Nineteen patients (56%) had recurrences, including 11 with multiple recurrences (range to first recurrence: 5-61 months; mean 23 months). Seventy-one percent of patients with a positive surgical margin and clinical follow-up had a local recurrence, compared to 31%with a negative surgical margin (P < 0.05). None of the other clinical or histologic parameters correlated with the risk for local recurrence.

CONCLUSIONS: Local control in fibromatoses of the extremities remains problematic. Aside from positive surgical margins, none of the other clinical or histologic parameters evaluated in this study were useful in predicting the risk of local recurrence.

MESENTERIC FIBROMATOSIS  
Mesenteric Fibromatosis With Involvement of the Gastrointestinal Tract A GIST Simulator: A Study of 25 Cases

Jaime A. Rodriguez, MD, Luis A. Guarda, MD, and Juan Rosai, MD
Am J Clin Pathol 2004;121:93-98 Abstract quote

Mesenteric fibromatosis (MF) and gastrointestinal stromal tumors (GISTs) are distinct lesions, but they often are confused with each other. Correct identification is essential because of their vastly different therapeutic and prognostic connotations.


We reviewed 25 cases of MF with involvement of the wall of the gastrointestinal tract and found that GIST was the most common misdiagnosis (13 [52%]). MF was characterized by a spatially homogeneous proliferation of wavy spindle cells without atypia, associated with collagen deposition (often of the keloidal type), and an infiltrative border. Most cases displayed prominent muscular arteries and dilated, thin-walled veins. The mitotic count was relatively low, and no atypical mitotic figures were identified.

These features are sufficiently characteristic of MF to permit distinction from GIST on the basis of routinely stained sections in the large majority of the cases, but immunohistochemical analysis provides a supporting role in the few equivocal cases.
PEDIATRIC  
Palmar-Plantar Fibromatosis in Children and Preadolescents: A Clinicopathologic Study of 56 Cases With Newly Recognized Demographics and Extended Follow-Up Information.

Fetsch JF, Laskin WB, Miettinen M.

From the *Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC; and the daggerDepartment of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Am J Surg Pathol. 2005 Aug;29(8):1095-1105. Abstract quote  

Palmar-plantar fibromatosis, the most common type of fibromatosis, is well recognized in the adult population, but many clinicians and pathologists are unfamiliar with the fact that children may also be affected by this process.

This report describes the clinicopathologic findings in 56 cases of palmar-plantar fibromatosis in children and preadolescents. Our study group included 19 males and 37 females, ranging from 2 to 12 years of age at the time of their first surgical procedure (median age, 9 years). The patients typically presented with solitary, lobular or multilobular masses in the 0.5- to 2.5-cm size range. The preoperative duration of the lesions ranged from 1 month to 6 years, with 1 patient purportedly having clinical evidence of disease since birth. All but two of the initial lesions occurred on the plantar aspect of the feet, typically in the region of the arch. Only 2 patients presented with palmar disease. The tumors were usually painless, except when pressure was applied. Seven patients had a history of trauma, sometimes involving a foreign body. One patient presented with concurrent disease involving both feet, and 12 additional patients subsequently developed palmar-plantar fibromatosis in another extremity, knuckle pads on the hands, or had other clinical findings linked to this disease. A family history was available for 25 patients, and 11 individuals had relatives with palmar-plantar fibromatosis, and 4 others had relatives with a history that was either suspicious for palmar-plantar disease or positive for other disorders associated with this disease.

Histologically, the tumors involved aponeurosis and commonly formed discontinuous, moderately cellular, nodular masses composed of spindled cells with intervening collagen. Mitotic counts for 79 separately submitted tumor specimens ranged from 0 to 31 mitotic figures per 25 wide-field high power fields (mean mitotic count, 3.4 mitotic figures per 25 wide-field high power fields). Eight tumor had >/=10 mitoses per 25 wide-field high power fields. All patients were initially managed by local excision, and in most of cases, histologic examination showed tumor extending to the tissue edge.

Thirty-two of 38 patients (84.2%) with clinical follow-up, ranging from 4 months to 33 years (mean, 14 years 9 months; median, 16 years 1 month), had one (n = 16) or more (n = 16) local recurrence of their fibromatosis.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General

Bland bipolar spindle cells arranged in parallel fascicles
Rare non-atypical mitotic figures
No necrosis or significant pleomorphism

Merges with surrounding soft tissue

VARIANTS  
GIANT CELLS  
Multinucleated Giant Cells in Plantar Fibromatosis

Harry L. Evans, M.D.

From the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, U.S.A.

Am J Surg Pathol 2002;26:244-248 Abstract quote

Specimens from 13 patients with plantar fibromatosis were reviewed with particular attention to the presence and number of multinucleated giant cells in the lesions.

These were found in all specimens but one and ranged from very few to many. The nuclei of the giant cells were uniform, rounded to somewhat elongated, and arranged in circles, semicircles, ovals, clusters, chains, and V's. Aside from the giant cells, the lesions were composed of the usual uniform fibroblastic spindle cells. The growth pattern was almost always multinodular, with nodules having moderate to high cellularity. Maximal mitotic rate varied up to more than 10 mitotic figures per 10 high-power fields but was most often between 1 and 4 mitotic figures per 10 high-power fields.

The patients were from 10 to 66 years of age; nine were male and four were female. Two had bilateral involvement. Five patients had recurrence, including three with multiple recurrences, and all but one of the remainder had only short follow-up.

Judging from the available data, recurrence did not appear to be related to any specific clinical or pathologic feature.

JUVENILE HYALINE FIBROMATOSIS  
Juvenile non-hyaline fibromatosis: juvenile hyaline fibromatosis without prominent hyaline changes.

Anadolu RY, Oskay T, Ozsoy N, Erdem C.

Department of Dermatology, Ankara University Medical School, Ankara, Turkey.

J Cutan Pathol. 2005 Mar;32(3):235-9. Abstract quote  

Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive disease of the connective tissue. It is characterized by papulonodular skin lesions, soft tissue masses, gingival hypertrophy, osteolytic bone lesions and flexion contractures of the large joints.

Here, we report a 14-year-old girl with characteristic clinical features of JHF with early fatal outcome. Dermatopathologic examination of the early lesions however constantly lacked the so-called hyalin changes in multiple skin biopsies.

According to our experience; dermatopathological features of this entitity is not often and always consists of classical hyalinisation. Only larger lesions with long duration should expected to be exhibiting those features.

Therefore we suggest that; JHF may often present itself as Juvenil Non-Hyaline Fibromatosis: JHF without prominent hyaline changes. And thus this fact should not change the actual diagnosis and prognostic implications.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
Immunoperoxidase Vimentin+
Variably positive for SMA, CD117, desmin
Negative CD34
BETA-CATENIN  
Nuclear beta-Catenin Expression Distinguishes Deep Fibromatosis From Other Benign and Malignant Fibroblastic and Myofibroblastic Lesions.

Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, Ricci F, Weber K, Furlong MA, Fisher C, Montgomery E.

From the *Johns Hopkins Medical Institutions, Baltimore, MD; daggerGeorgetown University, Washington, DC; and the double daggerRoyal Marsden Hospital, London, UK. Dr. Bhattacharya's current affiliation is Department of Pathology, APC-12, Rhode Island Hospital, Brown University School of Medicine, Providence, RI.

Am J Surg Pathol. 2005 May;29(5):653-659. Abstract quote  

Deep fibromatoses (desmoid tumors) are clonal myofibroblastic proliferations that are prone to aggressive local recurrences but that do not metastasize. They must be distinguished from a host of fibroblastic and myofibroblastic lesions as well as from smooth muscle neoplasms. Virtually all deep fibromatoses have somatic beta-catenin or adenomatous polyposis coli (APC) gene mutations leading to intranuclear accumulation of beta-catenin. Since low-grade sarcomas in general lack beta-catenin and since reactive proliferations would not be expected to have it, we predicted that nuclear beta-catenin expression would be detected in deep fibromatoses but absent in other entities in the differential diagnosis.

We evaluated the role of beta-catenin to help differentiate distinguish deep fibromatoses from congeners. Formalin-fixed, paraffin-embedded sections from 21 lesions from 20 patients with deep fibromatoses were stained with monoclonal beta-catenin antibody (Transduction Laboratories) and compared with low-grade fibromyxoid sarcoma (n = 12), leiomyosarcoma (n = 10), various other fibrosarcoma variants (n = 13, including 3 myofibrosarcomas, 3 sclerosing epithelioid fibrosarcomas, 5 low-grade fibrosarcomas, 1 classic fibrosarcoma arising in dermatofibrosarcoma protuberans, 1 inflammatory myxohyaline tumor/myxoinflammatory fibroblastic sarcoma), myofibroma/myofibromatosis (n = 12), nodular fasciitis (n = 11), and scars (n = 9). Nuclear and cytoplasmic staining was assessed.

All 21 examples of deep fibromatosis displayed nuclear beta-catenin (focal nuclear staining in one case to 90% staining). All other lesions tested (n = 67) lacked nuclear labeling for beta-catenin, showing only cytoplasmic accumulation.

beta-Catenin immunohistochemistry separates deep fibromatosis from entities in the differential diagnosis, a finding that can be exploited for diagnosis. Most fibromatoses have diffuse nuclear staining although occasional examples only focally label.


beta-Catenin Immunohistochemistry Separates Mesenteric Fibromatosis From Gastrointestinal Stromal Tumor and Sclerosing Mesenteritis.

Montgomery E, Torbenson MS, Kaushal M, Fisher C, Abraham SC.

Am J Surg Pathol 2002 Oct;26(10):1296-301 Abstract quote

Although separating gastrointestinal stromal tumor (GIST) from mesenteric fibromatosis and sclerosing mesenteritis is clinically important, this distinction sometimes poses problems for practicing pathologists. In the STI571 (Gleevec, Imatinib) era, the problem may be further compounded when protocol-driven staining for CD117 (c-kit) is performed on spindle cell proliferations presenting in the bowel wall and mesentery using an antibody known to react with the majority of mesenteric fibromatoses when other antibodies are more specific.

Because most mesenteric fibromatoses have mutations in the pathway and hence have abnormal nuclear accumulation of beta-catenin protein, we studied beta-catenin expression among a panel of other immunohistochemical stains to distinguish mesenteric fibromatosis, GIST, and sclerosing mesenteritis. Examples of gastrointestinal stromal tumors (GIST, 11), sclerosing mesenteritis (5), and mesenteric fibromatosis (10) were retrieved from the archives of our institutions.

Cases were studied with an immunohistochemical panel consisting of CD117, beta-catenin, CD34, smooth muscle actin, desmin, keratin, and S-100 protein. Cases were scored as "negative," "focally positive," or "diffusely positive." In evaluating beta-catenin, nuclear accumulation was required. GIST all had CD117 (11 of 11, diffuse) and CD34 (11 of 11, diffuse) with variable actin (5 of 11, focal) and negative desmin, keratin, S-100 protein. All GIST lacked beta-catenin (0 of 11). Mesenteric fibromatosis had CD117 (6 of 10, 3 focal, 3 diffuse), typically expressed more weakly than in GIST, actin (5 of 9, focal), and desmin (3 of 8, focal) in keeping with myofibroblastic differentiation but lacked CD34, S-100, and keratin. CD117 staining was not eliminated by use of a non-avidin-biotin technique. Nuclear beta-catenin was detected in 9 of 10 fibromatoses, including one case associated with familial adenomatous polyposis. Two of five sclerosing mesenteritis cases focally expressed CD117. None of the sclerosing mesenteritis cases had nuclear beta-catenin. Sclerosing mesenteritis cases were otherwise fibroblastic and myofibroblastic with focal actin in 5 of 5 and negative desmin, keratin, and S-100 protein but one had CD34 (1 of 5, focal).

With increasing protocol-driven interest in evaluating bowel wall and mesenteric spindle cell lesions using CD117 (c-kit) antibodies, it is important for practicing pathologists to be aware that lesions other than GISTs are likely to express this antigen using certain antibodies. beta-Catenin staining identifies lesions that are, instead, mesenteric fibromatoses.

CD117 (c-kit)  
c-Kit Expression in Desmoid Fibromatosis
Comparative Immunohistochemical Evaluation of Two Commercial Antibodies


David R. Lucas, MD
Mousa Al-Abbadi, MD
Pamela Tabaczka
Merlin R. Hamre, MD
Donald W. Weaver, MD
and Michael J. Mott, MD

 

Am J Clin Pathol 2003;119:339-345 Abstract quote

To determine the frequency of c-Kit staining in desmoids and optimize an assay for clinical use, we stained 19 desmoids from various sites at various dilutions with 2 commonly used rabbit polyclonal, anti-c-Kit antibodies (A4502, DAKO, Carpinteria, CA; C-19, Santa Cruz Biotechnology, Santa Cruz, CA), with and without heat-induced epitope retrieval (HIER) in citrate buffer.

Appropriate external and internal control samples were evaluated for each test condition. At dilutions of 1:50 both antibodies stained substantial numbers of desmoids: with/without HIER, A4502, 89%/63%; C-19, 37%/74%. The staining was cytoplasmic without cell membrane accentuation. However, background stromal staining and nonspecific staining of endothelium and smooth and striated muscle were problematic with both antibodies at 1:50. At higher dilutions, C-19 stained no desmoid; however, diminished staining of external and internal control samples made it unreliable. A4502 similarly stained many fewer desmoids at higher dilutions. However, it retained strong staining of both external and internal control samples and showed much less nonspecific staining. Best results were achieved at 1:250 without HIER; only weak focal staining was present in 1 desmoid.

With a simple immunohistochemical method optimized for clinical use, desmoid can be regarded as a c-Kit–negative tumor.

 

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION
GARDNER FIBROMA  
Gardner Fibroma: A Clinicopathologic and Immunohistochemical Analysis of 45 Patients With 57 Fibromas.

*Department of Pathology, Primary Children's Medical Center and University of Utah School of Medicine, Salt Lake City, Utah daggerDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Am J Surg Pathol. 2007 Mar;31(3):410-416. Abstract quote

Gardner fibroma (GAF) is a benign soft tissue lesion with a predilection for childhood and adolescence and an association with familial adenomatous polyposis (FAP) and desmoid type fibromatosis (desmoid).

We report 45 patients with GAF with clinicopathologic correlation and immunohistochemical analysis for beta-catenin and related proteins. Forty-five patients with 57 GAFs were identified from surgical pathology and consultation files. Immunohistochemistry for beta-catenin, cyclin-D1, and C-myc was performed on formalin-fixed, paraffin-embedded tissues using standard techniques in 25 GAFs from 24 patients. Information about family history, intestinal polyps, colon cancer, and soft tissue tumors was available in 23 patients. Sixty-nine percent had known FAP or adenomatous polyposis coli (APC), 22% had no history of familial polyps or soft tissue tumors, and 13% had an individual or family history of soft tissue masses and/or desmoids, with follow-up periods of 6 months to 26 years (median 3 y, mean 5 y).

The age range at initial diagnosis was 2 months to 36 years. Seventy-eight percent were diagnosed in the first decade, 15% in the second decade, and 7% in the third decade. Eight patients (18%) had documented desmoids concurrently or later; 4 of these had FAP and 1 had familial desmoids. Sites of GAF included the back and paraspinal region in 61%, the head and neck in 14%, the extremities in 14%, and the chest and abdomen in 11%. All displayed a bland hypocellular proliferation of haphazardly arranged coarse collagen fibers with a bland hypocellular proliferation of inconspicuous spindle cells, small blood vessels, and a sparse mast cell infiltrate. Immunohistochemically, 64% showed nuclear reactivity for beta-catenin (9 patients with known APC, 5 without definite information about FAP). One hundred percent showed nuclear reactivity for both cyclin-D1 and C-myc. beta-catenin reactivity had no correlation with age, site, or recurrence. Two beta-catenin-negative GAFs were from FAP patients.

In conclusion, GAF has a predilection for childhood and early adulthood, a strong association with FAP/APC, an association with concurrent or subsequent development of desmoids, and overexpression of beta-catenin and other proteins in the APC and Wnt pathways. The proportion of sporadic GAFs that have APC mutation remains to be determined.
GASTROINTESTINAL STROMAL TUMORS  

Gastrointestinal Stromal Tumor Versus Intra-abdominal Fibromatosis of the Bowel Wall A Clinically Important Differential Diagnosis

Rhonda K. Yantiss, M.D.; Ira J. Spiro, M.D.; Carolyn C. Compton, M.D.; Andrew E. Rosenberg, M.D.

From the Department of Pathology, Harvard Medical School; and the James Homer-Wright Pathology Laboratories and the Department of Radiation Oncology of Massachusetts General Hospital, Boston, Massachusetts, U.S.A.

Am J Surg Pathol 2000;24:947-957 Abstract quote

Intra-abdominal fibromatosis (IAF) is an uncommon benign neoplasm that usually occurs in the mesentery or retroperitoneum and may, on occasion, mimic a gastrointestinal stromal tumor (GIST). Differentiating between these two entities is important clinically because IAF is a benign tumor whereas GISTs frequently have malignant potential.

In this study, the authors identified 13 cases of IAF with prominent involvement of the bowel wall as well as 35 GISTs of the small intestine, colon, or mesentery and analyzed their clinical, gross, histologic, immunophenotypic, and ultrastructural characteristics to identify important distinguishing features. Patients with IAF were younger (mean, 34 yrs) than patients with GIST (mean, 54 yrs). Both types of tumors tended to be large, but GISTs were soft and lobulated with hemorrhage, necrosis, or cystification whereas IAFs were firm, tan, and homogeneous.

Histologic features characteristic of GIST included the presence of spindle or epithelioid cells with variable architecture, mitotic activity (range, <1ľ95 mitoses/50 high-power fields [hpf]; mean, 15 mitoses/50 hpf), nuclear atypia, and myxoid or hyalinized stroma. Necrosis and hemorrhage were seen in 16 and 25 tumors, respectively.

In contrast, IAFs were composed of broad, sweeping fascicles of monotonous spindle cells with mitotic activity (range, <3ľ11 mitoses/50 hpf; mean, 4 mitoses/50 hpf), bland nuclear features, and finely collagenous stroma. Necrosis, hemorrhage, and myxoid degeneration were not seen.

Immunohistochemical studies performed on a limited number of GISTs and IAFs demonstrated that cells expressed vimentin (100% GIST and IAF), CD117 (88% GIST and 75% IAF), CD34 (42% GIST and 0% IAF), smooth muscle actin (63% GIST and 75% IAF), muscle actin (75% GIST and 75% IAF), desmin (8% GIST and 50% IAF), and S-100 protein (16% GIST and 0% IAF). Ultrastructural analysis of 21 GISTs revealed incomplete smooth muscle differentiation in some tumors whereas IAFs were shown to have complete myofibroblastic/fibroblastic differentiation.

Information regarding clinical outcome was available on 29 patients and revealed that three patients with histologically benign GISTs were alive with no evidence of disease at 5 months to 6 years (mean, 3.5 yrs) and one patient with a histologically benign tumor died of disease after 7 years. Of patients with histologically malignant GIST, one died of surgical complications, 10 were alive without disease at 1 to 13 years (mean, 5.4 yrs), four were alive with disease at 4 months to 15 years (mean, 3.8 yrs), three had disseminated disease at operation, and seven were dead of disease at 10 months to 3 years (mean, 2.2 yrs). Follow up of eight patients with IAF demonstrated that five were alive without disease at 4 months to 15 years (mean, 5.3 yrs) and three had recurrences at 1 (two patients) and 2 years (one patient).

In summary, IAFs can have many features (large size, infiltration of adjacent structures, mitotic activity) that can cause diagnostic confusion with GISTs and, importantly, the degree of mitotic activity present in IAFs may overlap that seen in malignant GISTs. These entities can be distinguished primarily by their light microscopic and ultrastructural features but there is a notable overlap in their immunohistochemical profiles. The distinction between these neoplasms is important because there are important clinical implications for the patient.

REACTIVE NODULAR FIBROUS PSEUDOTUMOR OF THE GI TRACT AND MESENTERY  


Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases.

Yantiss RK, Nielsen GP, Lauwers GY, Rosenberg AE.

 

Am J Surg Pathol 2003 Apr;27(4):532-40 Abstract quote

Although the majority of mesenchymal lesions of the gastrointestinal tract are neoplastic in nature, nonneoplastic reactive processes may involve the gastrointestinal tract and mesentery, causing diagnostic confusion with more aggressive neoplasms, such as fibromatosis or gastrointestinal stromal tumors.

In this study, we report a series of fibroinflammatory lesions of the gastrointestinal tract that we think represent a relatively cohesive group of tumors and describe the clinical and pathologic features of this entity, which we have termed "reactive nodular fibrous pseudotumor." The tumors affected five patients (four male and one female patient) who ranged in age from 48 to 71 years (mean 56 years). Two patients presented with acute abdominal pain without a significant past medical history, two had incidental lesions discovered during evaluation for other medical conditions, and one was found to have an abdominal mass. Three patients had a history of abdominal surgery. The tumors were multiple in three patients and solitary in two patients. In four cases, at least one of the tumors involved the small intestine or colon, and the lesion was confined to the peripancreatic soft tissue in one case.

The tumors were firm, tan-white, ranged in size from 4.3 to 6.5 cm in greatest dimension, and were grossly well circumscribed. All of the lesions were of low to moderate cellularity and composed of stellate or spindled fibroblasts arranged haphazardly or in intersecting fascicles. Three cases had microscopically infiltrative borders. The stroma was rich in collagen, which was wire-like, keloidal, or hyalinized. Intralesional mononuclear cells were sparse but were more numerous peripherally and frequently arranged in lymphoid aggregates. Immunohistochemical stains demonstrated that all of the tumors stained for vimentin, 80% stained for CD117 or muscle specific actin, 60% stained for smooth muscle actin or desmin, and none of the tumors stained for CD34, S-100 protein, or anaplastic lymphoma kinase-1.

Follow-up information was available in all cases: four patients had no residual disease following surgical resection (mean follow-up 16.3 months) and one patient who had an incomplete surgical resection had stable disease at 26 months. In summary, we report a series of distinct intraabdominal fibroinflammatory pseudotumors that we have collectively termed "reactive nodular fibrous pseudotumors."

These lesions are uncommon and may infiltrate the bowel wall, thereby mimicking primary bowel neoplasms or intraabdominal fibromatosis. Recognition of these nonneoplastic lesions is important, as they pursue a benign clinical course, but may be confused with other mesenchymal neoplasms that require more aggressive treatment.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSIS Adequacy of surgical excision with negative margins has thought be key to good prognosis
Deep seated tumors worse prognosis

Extremity and trunk desmoid tumors: a multifactorial analysis of outcome.

Merchant NB, Lewis JJ, Woodruff JM, Leung DH, Brennan MF.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Cancer 1999 Nov 15;86(10):2045-52 Abstract quote

BACKGROUND: The natural history of desmoid tumors remains an enigma. Previous reports attempting to identify their biology have included recurrent and primary tumors as well as tumors from both intra- and extra-abdominal sites. The purpose of this study was to analyze patients with primary extremity and trunk desmoid tumors treated and followed at a single institution and to determine factors influencing disease free survival.

METHODS: Between July 1982 and June 1997, 189 patients with extremity and superficial trunk desmoid tumors were treated and followed prospectively. Of these, 105 presented with primary disease and formed the basis of this study.

RESULTS: The median follow-up for the entire group of patients was 49 months; it was 46 months for patients who did not develop a local recurrence. During this time, 24 patients (23%) had a local recurrence. No patients died of disease. The 2-year and 5-year local recurrence free survival rates were 80% and 75%, respectively. None of the prognostic factors analyzed, including age, gender, depth of tumor, size of tumor, or tumor site, were significant for predicting local recurrence. Moreover, positive resection margins were not predictive of recurrence. The selective use of adjuvant radiation therapy did not influence the rate of local recurrence regardless of the margin status.

CONCLUSIONS: Attempts to achieve negative resection margins may result in unnecessary morbidity and may not prevent local recurrence. Operations that preserve function and structure should be the primary goal, because the presence of residual disease cannot be clearly shown to impact adversely on 5-year disease free or overall survival.

Recurrence Common
Metastasis Benign but locally aggressive and destructive
TREATMENT Complete excision

Surgery versus radiation therapy for patients with aggressive fibromatosis or desmoid tumors: A comparative review of 22 articles.

Nuyttens JJ, Rust PF, Thomas CR Jr, Turrisi AT 3rd.

Department of Radiation Oncology, Medical University of South Carolina, Charleston

Cancer 2000 Apr 1;88(7):1517-23 Abstract quote

BACKGROUND: Desmoid tumors (aggressive fibromatoses) are benign neoplasms with high rates of recurrence after surgery. Radiotherapy is sometimes reported to prevent recurrences, but not in all studies. In order to evaluate the effect of radiation, comparative analysis was performed.

METHODS: The authors conducted a MEDLINE search and collected all articles in the English language on the treatment of "desmoid tumor" or "aggressive fibromatosis" from the years 1983-1998. They categorized treatment into three groups: surgery alone (S), surgery with radiotherapy (S + RT), or radiotherapy alone (RT). The S and S + RT groups were each subdivided according to whether margins were free (-), positive (+), or unknown. Each subgroup was divided into cases with primary, recurrent, or unknown tumor.

RESULTS: The local control rates after treatment for cases in the S group with (-) margins, (+) margins, and overall were 72%, 41%, and 61%, respectively. For the S + RT group the local control results were 94%, 75%, and 75%, respectively, significantly different when compared with the results for the S group. For the RT group, the local control was 78%, significantly superior to that of the S group (61%). Cases with primary and recurrent tumors had significantly superior local control rates with S + RT or RT versus S. Radiotherapy complications noted were fibrosis, paresthesias, edema, and fracture.

CONCLUSIONS: RT or S + RT results in significantly better local control than S. Even after dividing the groups into cases with free and positive margins and cases with primary and recurrent tumors, the best local control is achieved with RT or S + RT.

Radiation
If used alone may not be effective in controlling primary and recurrent lesions

Long-term results with radiation therapy for pediatric desmoid tumors.

Merchant TE, Nguyen D, Walter AW, Pappo AS, Kun LE, Rao BN.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN

Int J Radiat Oncol Biol Phys 2000 Jul 15;47(5):1267-71

PURPOSE: To retrospectively review the treatment and outcome of pediatric patients with desmoid tumor who received radiation therapy at a single institution.

MATERIALS AND METHODS: Thirteen pediatric patients received radiation therapy for desmoid tumor at St. Jude Children's Research Hospital between 1962 and 1998. Only 2 of the patients reviewed received treatment prior to 1976. The median dose of external beam irradiation was 50 Gy.

RESULTS: At the time of this report, 10 of 13 patients have had tumors that recurred after radiation therapy and 3 have died from their disease. One additional patient was harboring a recurrence, and 1 had not been followed long enough to suggest that the patient had achieved disease control. One patient remained locally controlled after radiation therapy with long-term follow-up (196 months). The median time to recurrence following radiation therapy was 19 months (range, 3-135 months). Eight of the 13 patients suffered substantial tumor and treatment-related morbidity.

CONCLUSIONS: Desmoid tumors in pediatric patients are locally aggressive tumors that are likely to recur after radiation therapy. Alternatives to radiation therapy should be sought for the treatment of these tumors, and efforts should focus on low-morbidity therapies aimed at inhibiting the growth of these unique tumors.

Chemotherapy
Estrogens, colchicine, vinblastine, methotrexate, doxorubicin, and dacarbazine

Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

Lev-Chelouche D, Abu-Abeid S, Nakache R, Issakov J, Kollander Y, Merimsky O, Meller I, Klausner JM, Gutman M.

Department of Surgery B, Tel Aviv Sourasky Medical Center, Israel.

Surgery 1999 Nov;126(5):963-7 Abstract quote

BACKGROUND: The management of extensive, recurrent limb desmoid tumors is extremely difficult. The failure of multimodality treatments, such as repeated resections, radiotherapy, systemic chemotherapy, or endocrine manipulations, can end up with multilating surgery or even amputation, similar problems sometimes encountered in soft tissue sarcoma of the limbs. The high rate of limb salvage achieved by isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan for extensive, high-grade soft tissue sarcoma led us to implement this modality in difficult cases of limb desmoids.

METHODS: During a 4-year period, 6 patients aged 14 to 52 years were treated. All were significantly symptomatic and candidates for amputation or mutilating surgery. Five had lower and one had upper limb lesions. Two had multifocal disease. At ILP, 3 to 4 mg TNF and 1 to 1.5 mg/kg melphalan were delivered during a 90-minute period. One patient had a double perfusion. All patients underwent definitive resective operation 6 to 8 weeks after perfusion.

RESULTS: No systemic complications were observed, and local complications included reversible skin redness and blisters. Response rate was 83% with 33% (2 of 6) complete response and 50% (3 of 6) partial response. In 1 patient less than 50% regression was observed. Limb salvage rate was 100%; even the patient with stabilization of disease could be locally resected. Local recurrence during a follow-up period of 7 to 55 months (median 45 months) occurred in 2 patients at 8 and 24 months, respectively; the first underwent amputation, whereas for the second a wide excision was possible.

CONCLUSIONS: ILP with TNF and melphalan can be used as a limb preservation modality in patients with recurrent desmoids and significant symptoms who would otherwise require multilating surgery to control their neoplasm.

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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


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