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Nuchal-Type Fibroma in Two Related Patients With Gardner's Syndrome

Diwan, A. Hafeez M.D., Ph.D.; Graves, Ernest D. M.D.; King, Judy A. C. M.D., Ph.D.; Horenstein, Marcelo G. M.D.

American Journal of Surgical Pathology: November 2000 - Volume 24 - Issue 11 - pp 1563-1567
Case Reports

Nuchal-type fibroma is a distinct subcutaneous and dermal fibrous tissue proliferation that has been previously definitely identified in one patient with Gardner's syndrome and has been possibly present in two others. Gardner's syndrome is an autosomal-dominant condition with variable expressivity that comprises epidermoid cysts, fibrous tumors, osteomas, intestinal polyposis, as well as other findings. We report two cases of nuchal-type fibroma presenting in a 13-year-old boy in the right upper back and in his 60-year-old grandfather in the upper chest at the posterior axillary line. Both individuals carried a diagnosis of Gardner's syndrome and neither of them had diabetes. Although the boy has as of now only presented with cutaneous manifestations of Gardner's syndrome, his grandfather has exhibited both cutaneous and intestinal evidence of this syndrome. In addition, the boy's mother and her sister have documented Gardner's syndrome. Light microscopic findings of nuchal-type fibroma from both patients include paucicellular, haphazardly arranged collagen bundles with entrapped adipose tissue. A marked diminution of elastic fibers was noted with Van-Gieson stains. The lesions were diffusely positive for CD34 and contained a few factor XIIIa-positive cells. Electron microscopic analysis revealed no differences between the collagen comprising the nuchal-type fibroma as compared with control dermal collagen obtained from skin away from the tumor. These cases strengthen the view that there is an association between nuchal-type fibroma and Gardner's syndrome.

From the Departments of Pathology (A.H.D., J.A.C.K., M.G.H.) and Surgery (E.D.G.), University of South Alabama Medical Center, Mobile, Alabama, U.S.A.

Address correspondence and reprint requests to Marcelo G. Horenstein, MD, Director of Dermatopathology, University of South Alabama Medical Center, 2451 Fillingim St., Mobile, AL 36617; e-mail[colon] horenstein[commat]

In 1988, the second edition of Enzinger and Weiss' textbook on soft tissue tumor pathology carried a description of a nuchal fibroma. 5 Since then, two major studies of this entity have appeared in the literature. The first of these, by Balachandran et al., described nine cases of nuchal fibroma of which eight were men. 1 The median age reported by these authors was 43 years (range, 19[ndash]53 yrs). The second and larger study, by Michal et al., was based on 52 cases ranging from 3 to 74 years of age with a predominance of males (93[percnt]). 12 Approximately 31[percnt] of the lesions were in extranuchal locations such as the back, extremities, face, and chest. In a letter to the editor, Shek et al. 16 had previously drawn attention to an extranuchal nuchal fibroma. Therefore, the designation nuchal-type fibroma seems better suited for this condition, emphasizing both the primacy of the nuchal location as well as accounting for those lesions that arise in other parts of the body. Macroscopically, nuchal-type fibroma is poorly circumscribed, subcutaneous or dermal in location. Microscopically, nuchal-type fibroma is composed of paucicellular bundles of collagen, often with trapped fat, vessels, and nerves. The lesion has a low recurrence following excision, and deep invasion has not been documented. Michal et al. reported concurrent diabetes mellitus in 44[percnt] of patients. In addition, Gardner's syndrome was definitely identified in one patient and has been possibly present in two others. 12 This finding led the authors to speculate an association between nuchal-type fibroma and Gardner's syndrome. In the present report, we describe two cases of nuchal-type fibroma present in two related patients with Gardner's syndrome.

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Formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin and Van Gieson stain was obtained on both cases from the University of South Alabama Medical Center archives. Immunohistochemistry on paraffin sections was performed in both cases. After quenching of endogenous peroxidase and performance of proteinase K digestion (for factor XIIIa), sections were incubated with rabbit polyclonal antibody against factor XIIIa (1[colon]800; Calbiochem-Novabiochem Corp, La Jolla, CA, USA), murine monoclonal antibody against CD34 (1[colon]20; anti-HPCA-1, Becton Dickinson, San Jose, CA, USA), or murine antibody against muscle common actin (undiluted; Dako Corp, Carpinteria, CA, USA). Rabbit and mouse immunoglobulins diluted to the same concentrations were used as negative controls. The bound primary antibodies were reacted with biotinylated secondary antibodies and labeled with horseradish-peroxidase-conjugated streptavidin. Visualization of the complexes was accomplished with 3,3` diaminobenzidine tetrahydrochloride as chromogen. Sections were lightly counterstained with Mayer's hematoxylin.

Representative portions of the lesion and normal dermal tissue from case no. 1 were placed in 3[percnt] glutaraldehyde in cacodylate buffer. The specimens were postfixed in 1[percnt] osmium tetroxide in cacodylate buffer, dehydrated in a graded ethanol series, and embedded using Poly/Bed 812 Resin (Polysciences, Inc, Warrington, PA, USA). Thick sections (1 [mgr]m) were cut, stained with toluidine blue, and examined by light microscopy. Two blocks, one from the lesion and one from the adjacent unaffected tissue, were selected for thin sectioning. Sections were cut using a Leica Ultracut UCT microtome (Leica, Austria). Thin sections were examined and photographed using a Philips CM 100 TEM (FEI Co, Hillsboro, OR, USA).

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Clinical Findings

Case No. 1

This is a 13-year-old white boy who in 1996 underwent excisions of epidermoid cysts on his right upper forehead and on either side of his head on the temporal-occipital region. More recently, in early 1999, the patient presented again with three epidermoid cysts on the right temporo-parietal scalp, mid-forehead, and right anterior lower leg. The patient's family had documented Gardner's syndrome in several family members. Based on the strong family history of Gardner's syndrome, an anorectal proctoscopy was performed, but no polyps were identified during this examination. The patient has been regularly followed for detection of intestinal polyps. He presented in late 1999 with a 5-cm mass on the right upper back off the midline, which was excised and diagnosed as a nuchal-type fibroma.

The patient's mother and her sister are also known to have Gardner's syndrome (Fig. 1). The 39-year-old mother has had multiple sessile to pendunculated polyps of the stomach, the bulb, first, second, and third parts of the duodenum, colon, and rectum. She underwent a total colectomy with mucosal proctectomy, ileal J-pouch with ileo-anal anastomosis, and a diverting ileostomy in 1992. Subsequent endoscopic evaluations have shown recurrent tubular adenomas of the upper gastrointestinal tract. In addition to the gastrointestinal manifestations of Gardner's syndrome, a right labial epidermoid cyst was excised in 1993. In 1999, she underwent a hysterectomy and a widespread mesenteric firmness was encountered during the procedure. A 1-cm biopsy was removed from a larger mesenteric tumor and diagnosed as mesenteric fibromatosis. We reviewed the microscopic slides of this lesion, which we obtained from an outside hospital, and concurred with the diagnosis. Her 31-year-old sister was found to have multiple small colonic polyps in 1992. Since then, she has been regularly followed and has manifested multiple epidermoid cysts (labial cyst excised in 1993; back cyst excised in 1995), as well as multiple polyps both in the colon and the duodenum. Extensive surgical intervention has not been necessary to date, however.

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Case No. 2

The 60-year-old maternal grandfather of case no. 1 was found on routine preoperative evaluation to have heme-positive stools in 1992. This finding prompted a colonoscopy that revealed multiple polyps. A total abdominal colectomy was performed. During the course of this procedure, a duodenal polyp was detected and found to be adenocarcinoma, necessitating a pancreaticoduodenectomy as well. Following this event, he has been followed with routine esophagogastroduodenoscopy and flexible proctoscopy with multiple polypectomies, all of which have been diagnosed as either tubular or tubulovillous adenomas. He had an episode of spontaneously resolving small bowel obstruction in 1993. He presented in 1994 with a 5-cm mass in the upper chest at the posterior axillary line, which was excised. This was misdiagnosed as a desmoid tumor at the time. We reviewed that lesion and diagnosed it as a nuchal-type fibroma. A tubular adenoma was detected in his jejunum in 1997. Other cutaneous manifestations of Gardner's syndrome in this patient were epidermoid cysts removed in 1998 from the right face and posterior head.

Apart from two daughters with Gardner's syndrome (see above), the other two male children of case no. 2 do not have Gardner's syndrome. Case no. 2's brother is known to have Gardner's syndrome, and their mother died at an early age reportedly of cancer (Fig. 1).

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Pathologic Findings

On gross examination, the right upper back lesion from case no. 1 was a 5-cm, poorly circumscribed, white, predominantly subcutaneous mass with focal deep dermal involvement (Fig. 2). The upper chest lesion from case no. 2 exhibited a similar size and gross appearance, and was predominantly subcutaneous. Examination of formalin-fixed, paraffin-embedded, hematoxylin and eosin-stained sections of the lesion from case no. 1 as well as the nuchal-type fibroma misdiagnosed as a desmoid tumor excised from case no. 2 were almost identical. Both lesions were paucicellular and made up predominantly of irregularly arranged bundles of collagen with scattered islands of trapped adipose tissue (Fig. 3). Van Gieson staining on both cases showed decreased elastic fibers in the lesion as compared with the adjacent normal dermis. Immunohistochemistry revealed diffuse positivity for CD34 (Fig. 4) and rare factor XIIIa-positive cells. Muscle common actin was negative. Electron microscopic examination of the nuchal-type fibroma from case no. 1 was undertaken to evaluate possible differences between the dermal collagen, away from the main tumor mass, and the tumoral collagen. Both the lesion and normal dermis exhibited collagen fibrils with a characteristic cross-striated pattern with a periodicity of approximately 60 nm. No fibrous long-spacing collagen or other abnormal collagen fibrils were identified. Elastic fibers were markedly decreased in the nuchal-type fibroma compared with the normal dermis.

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Grossly, nuchal-type fibroma is poorly circumscribed, off-white, subcutaneous or dermal in location, with size ranging from 1 to 8 cm. Its microscopic appearance is that of haphazardly arranged bundles of collagen with marked hypocellularity. It is not uncommon to find adipose tissue, nerves, or vessels trapped between the collagenous bundles. These features allow one to differentiate nuchal-type fibroma from other similar conditions. 12 Circumscribed storiform collagenoma (sclerotic fibroma, plywood fibroma) is generally dermal, sharply circumscribed, and lacks trapped adipose tissue. 9 Connective tissue nevus is a hamartomatous collection of collagen that is generally smaller than nuchal-type fibroma and more superficial. 18 Collagenous fibroma, which was originally named desmoplastic fibroblastoma, 6 can arise from a variety of sites in older males with involvement of the subcutaneous fat, fascia, and even muscle. These are more cellular than nuchal-type fibroma, and the collagen is less haphazard and more homogeneous, or even myxoid in appearance. More homogeneous collagen is also a feature of fibroma of tendon sheath, which is also distinguished by its usual location on the surface of a tendon, and the fact that it usually forms a distinct nodule as opposed to being poorly circumscribed. 3 Elastofibroma, which characteristically occurs in the infrascapular region of middle-aged to older individuals, contains characteristic fragmented elastic fibers. 5,11 Elastic fibers are scant in nuchal-type fibroma as we demonstrated with elastic stains and on electron microscopy. Keloid scar has denser, thicker collagen than nuchal-type fibroma. Aggressive fibromatosis (desmoid tumor), which is the typical soft tissue tumor associated with Gardner's syndrome, tends to be more cellular and infiltrative than nuchal-type fibroma.

Gardner's syndrome is an autosomal-dominant condition with variable expressivity that comprises epidermoid cysts, fibrous tissue tumors, osteomas, and intestinal polyposis. 4,7,10,19 Epidermoid cysts are found in nearly all the cases, usually occurring on the face, scalp, and extremities, generally occurring between 4 and 10 years of age. Osteomas are found in 50[percnt] of the cases, being found mostly in the mandible, maxilla, and sphenoid bones. Intestinal polyposis tends to develop after the first decade, being present in approximately half the affected individuals by 20 years of age; as noted above. Case no. 1 has not at the present time developed any intestinal polyps. The polyps are most frequently found in the colon and rectum, although other parts of the gastrointestinal tract may also be involved. In slightly less than half the cases the polyps undergo malignant transformation over a period of 15 to 20 years, as probably occurred with case no. 2 described above.

Aggressive fibromatoses occur in Gardner's syndrome patients, mostly in association with incisional scars of the abdomen. They may also arise in intraabdominal locations in the mesentery. Rarely, they may occur in extra-abdominal locations such as the chest wall. 13 We have reviewed the literature regarding fibrous tumors in association with Gardner's syndrome to evaluate for prior cases of nuchal-type fibromas. On examination of published light micrographs and microscopic descriptions, we failed to encounter nuchal-type fibromas labeled as fibromatoses or other fibrous tumors. 2,8,15

At the molecular level, Gardner's syndrome is caused by mutations in the adenomatous polyposis coli (APC) gene located on chromosome 5q15-q22. 14 APC is involved in the regulation of the cellular level of beta-catenin. Immunohistochemically, fibromatoses consistently have elevated beta-catenin protein levels. 17 A similar mechanism could possibly be related to fibrous proliferation in NTF. However, no such studies have been conducted to date.

Our finding of two cases of nuchal-type fibroma in two patients with Gardner's syndrome who are related to each other is significant. The occurrence of nuchal-type fibroma in the same Gardner's syndrome family makes a compelling case for an association between these two conditions, an hypothesis that has been advanced by Michal et al. These authors previously speculated that the association between Gardner's syndrome and nuchal-type fibroma might be more widespread than they were able to determine, because the cases they evaluated came with limited clinical information. 12 Diabetes was present in 44[percnt] of their patients with nuchal-type fibroma. However, neither of the two patients we report here is diabetic.

This report is, to our knowledge, the first demonstration of nuchal-type fibroma occurring in multiple affected members from a Gardner's syndrome family and the first description of CD34 reactivity and electron microscopic findings of this lesion. The case reports described here thus support the contention that nuchal-type fibroma is one of the cutaneous manifestations seen in Gardner's syndrome.

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The authors thank Freda K. McDonald, BS, HTL(ASCP), for expert technical assistance with electron microscopy; and Sandra F. Chapman, BS, HTL (ASCP), and Sarah C. Frazer, HT, for expert technical assistance with immunohistochemistry.

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Nuchal-type fibroma; Gardner's syndrome; Fibromatosis; Soft tissue; Immunohistochemistry; CD34; Factor XIIIa; Electron microscopy

[copy] 2000 Lippincott Williams [amp] Wilkins, Inc.