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Background
The Birt–Hogg–Dubé syndrome is characterized by multiple, skin-colored, cutaneous papules located mainly on the face, neck, and upper part of the thorax. The skin changes are hamartomas with folliculo-sebaceous differentiation, called fibrofolliculomas and trichodiscomas.
OUTLINE
PATHOGENESIS CHARACTERIZATION Autosomal dominant
CLINICAL VARIANTS CHARACTERIZATION GENERAL
CONTEXT: Birt-Hogg-Dube (BHD) syndrome is a rare clinicopathologic condition transmitted in an autosomal dominant fashion. This complex entity is characterized by cutaneous fibrofolliculomas, kidney tumors, pulmonary cysts, and spontaneous pneumothorax. Recently, the gene possibly responsible for the clinical manifestations of BHD syndrome has been cloned and characterized. The few reviews of BHD syndrome found in the English literature mostly focus on the skin lesions or genetics, with limited information on other pathologic changes, particularly the kidney lesions.
OBJECTIVE: To review the literature on this subject with a special emphasis on BHD syndrome-associated renal pathology as well as recent advances in molecular genetic discovery of the BHD syndrome.
DATA SOURCES: We used all data available after performing a literature search using MEDLINE and searching under the headings "Birt-Hogg-Dube," "hybrid oncocytic tumors," and "folliculin."
CONCLUSIONS: The presence of BHD syndrome should be investigated in any patient with multiple bilateral kidney tumors, especially if the predominant histologic type is chromophobe renal cell carcinoma or the so-called hybrid oncocytic tumor. The genetic alteration for BHD syndrome has been mapped to chromosome 17p12q11, and the gene in this region has been cloned and believed to be responsible for the BHD syndrome. The function of the BHD product, called folliculin, is still unknown, although it is speculated to be a tumor suppressor gene. Numerous mutations have been described in the BHD gene. Studies are ongoing to determine the relationship between the BHD gene and development of sporadic renal cell carcinoma and other lesions.PLEURA
- Pleuropulmonary Pathology of Birt-Hogg-Dube Syndrome.
Butnor KJ, Guinee DG Jr.
*Department of Pathology, University of Vermont, Burlington, VT daggerDepartment of Pathology, Virginia Mason Medical Center, Seattle, WA.
Am J Surg Pathol. 2006 Mar;30(3):395-399. Abstract quote
Birt-Hogg-Dube (BHD) syndrome is a rare inherited genodermatosis characterized by distinctive cutaneous lesions, an increased risk of renal and colonic neoplasia, and the development of pleuropulmonary blebs and cysts. Although the pathology of renal and cutaneous manifestations of BHD has been well described, few reports have detailed the pathologic features of pulmonary involvement.
Herein we present the pathologic findings from biopsies of 2 BHD patients with spontaneous pneumothorax: 1 with known BHD and another clinically suspected to have lymphangioleiomyomatosis. Histologic features included basilar cysts comprised of intraparenchymal collections of air surrounded by normal parenchyma or a thin fibrous wall and blebs consisting of collections of air within the pleura. Although these histologic findings are not specific to BHD, their predominantly basilar location contrasts with the apical distribution of other more well-recognized causes of spontaneous pneumothorax, such as emphysematous bullae and idiopathic blebs. It is important for pathologists to be aware of this rare cause of spontaneous pneumothorax because BHD can radiographically simulate other causes of pulmonary cysts and the lung and pleura may be the initial sites of involvement. Patients with BHD are at increased risk for renal neoplasia and may benefit from periodic surveillance.
Pathologists should raise the possibility of BHD in nonapical lung biopsies from young or middle-aged patients that show blebs or cysts.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Histomorphologic and immunophenotypic analysis of fibrofolliculomas and trichodiscomas in Birt-Hogg-Dube syndrome and sporadic disease.Collins GL, Somach S, Morgan MB.
Department of Pathology, University of South Florida College of Medicine, Tampa, FL, USA, Department of Dermatology and Pathology, Case Western Reserve University School of Medicine, Department of Dermatopathology, James A Haley Veterans' Administration Hospital, and Department of Pathology, University of South Florida College of Medicine, Tampa, FL, USA.
J Cutan Pathol 2002 Oct;29(9):529-533 Abstract quote BACKGROUND: Fibrofolliculomas and trichodiscomas are benign dermal neoplasms that likely derive from the mantle of the hair follicle and can occur sporadically or in association with Birt-Hogg-Dube syndrome (BHDS). Little is known about the pathogenesis and immunophenotypic properties of these entities.
\METHODS: We investigated the histomorphologic and immnophenotypic properties of 15 fibrofolliculomas and trichodiscomas in two patients with BHDS and eight with sporadic disease.
RESULTS: We found the following: (1) fibrofolliculomas and trichodiscomas occurring in the setting of BHDS show microscopically contiguous histomorphologic features as compared to those occurring sporadically; (2) the immunophenotypic characteristics of syndromic-associated and sporadic types are identical and consist of (3) perifollicular vimentin (+), CD34 (+) and Factor XIII (-) spindle cells.
CONCLUSIONS: Despite subtle histomorphologic differences, trichodiscomas and fibrofolliculomas are immunophenotypically similar, and are thus likely derived from a similar histogenic precursor. Given the previously reported CD34 (+) immunophenotype of the hair mantle, our findings would support an origin of these lesions from the mantle of the hair follicle. The proliferation of CD34 (+) spindle cells seen in conjunction with these lesions should not be confused with other CD34 (+) dermal entities.
VARIANTS KIDNEY TUMORS
Renal tumors in the birt-hogg-dube syndrome.Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ.
Am J Surg Pathol 2002 Dec;26(12):1542-52 Abstract quote Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant genodermatosis characterized by the development of small dome-shaped papules on the face, neck, and upper trunk (fibrofolliculomas). In addition to these benign hair follicle tumors, BHD confers an increased risk of renal neoplasia and spontaneous pneumothorax.
To date, there has been no systematic pathologic analysis of the renal tumors associated with this syndrome. We reviewed 130 solid renal tumors resected from 30 patients with BHD in 19 different families. Preoperative computed tomography scans demonstrated a mean of 5.3 tumors per patient (range 1-28 tumors), the largest tumors averaging 5.7 cm in diameter (+/- 3.4 cm, range 1.2-15 cm). Multiple and bilateral tumors were noted at an early age (mean 50.7 years). The resected tumors consisted predominantly of chromophobe renal cell carcinomas (44 of 130, 34%) or of hybrid oncocytic neoplasms that had areas reminiscent of chromophobe renal cell carcinoma and oncocytoma (65 of 130, 50%). Twelve clear cell (conventional) renal carcinomas (12 of 130, 9%) were diagnosed in nine patients. These tumors were on average larger (4.7 +/- 4.2 cm) than the chromophobe (3.0 +/- 2.5 cm) and hybrid tumors (2.2 +/- 2.4 cm). Microscopic oncocytosis was found in the renal parenchyma of most patients, including the parenchyma of five patients with evidence of clear cell renal cell carcinoma.
Our findings suggest that microscopic oncocytic lesions may be precursors of hybrid oncocytic tumors, chromophobe renal cell carcinomas, and perhaps clear cell renal cell carcinomas in patients with BHD syndrome. Recognition by the pathologist of the unusual renal tumors associated with BHD may assist in the clinical diagnosis of the syndrome.
SKIN TUMORS FIBROMAS Localized Birt-Hogg-Dubé Syndrome With Prominent Perivascular Fibromas
Tilman Schulz, etal.
Am J Dermatopathol 2001;23:149-153 Abstract quote
The autosomal dominant Birt-Hogg-Dubé syndrome is a cutaneo-intestinal condition that manifests on the skin in the form of multiple, skin-colored small papules that, histologically, prove to be mantleomas (fibrofolliculomas and trichodiscomas). These cutaneous lesions usually appear in the region of the head, neck, and upper part of the trunk.
To date, only a single report in the literature describes the localized occurrence of this syndrome. We now describe a localized form of the Birt-Hogg-Dubé syndrome in a man with multiple mantleomas that were confined to the left half of the face, and which, in part, were arranged in the form of plaques. Another striking finding in this patient was a conspicuous vascular component in the lesions, characterized by a pronounced, well-demarcated fibrosis in the region of cutaneous blood vessel proliferations.
Because perivascular fibromas have already been observed in other patients with Birt-Hogg-Dubé-syndrome, the perivascular fibroma, with fibrofolliculoma and trichodiscoma, must be included within this syndrome's spectrum of skin changes.
MANTLEOMAS Neoplasms with follicular differentiation. Philadelphia/ London: Lea & Febiger, 1993:244–79.
Neoplasms with sebaceous differentiation Philadelphia/ London: Lea & Febiger, 1994:203—37.
Both fibrofolliculoma and trichodiscoma may represent various stages in the natural history of a single hamartoma, the mantleoma, implying differentiation toward the mantle region of the hair follicle
A common feature of fibrofolliculomas and trichodiscomas is the perifollicular fibrosis, which often results in a pronounced ensheathing of the follicular epithelial elements.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Birt-Hogg-Dube syndrome: a review of the literature and the differential diagnosis of firm facial papules.
Vincent A, Farley M, Chan E, James WD.
Department of Sermatology, University of Pennsyvania, Schoool of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Am Acad Dermatol. 2003 Oct;49(4):698-705 Abstract quote.
Birt-Hogg-Dube syndrome (BHDS) was originally described in 1977 as the grouping of 3 skin tumors-the fibrofolliculoma, trichodiscoma, and acrochordon-in family members with an autosomal dominant inheritance pattern.
In recent years it has become clear that these 3 lesions likely represent only 1 of these tumors, the fibrofolliculoma. More important, evidence now supports a definite susceptibility to malignant renal tumors and pulmonary disease in patients with BHDS. Clinical recognition of this entity is possible in spite of the fact that several syndromes exist that are characterized by the presence of multiple firm facial papules.
We will discuss the evolution of BHDS from the original description to the recent discovery of the genetic susceptibility locus, illustrate the clinical differential diagnosis, and highlight the workup needed for newly diagnosed patients and their family members.Arch Dermatol 1977;113:1674–7.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
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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