Perifollicular fibromas (about 100) which had appeared 6 years earlier on the neck and the nape of the neck were reported in 1925 by R. Burnier and J. Rejsek in a 56 year old woman [4]. Multiple perifollicular fibromas of the face and neck which had appeared in a 53 year old man by the age of 32 years, the brother and a cousin of whom had the same dermatosis (at a lesser degree) were later reported by J. Civatte and J.P. Le Tréguilly [5]. A.R. Birt, G.R. Hogg, and J. Dubé reported in 1977 multiple fibrofolliculomas in a family with hereditary medullary carcinoma of the thyroid, a condition now recognized as a tumour suppressor gene syndrome caused by a germline RET mutation [6]. Thirty-seven members of the kindred of 70 were more than 25 years of age, and 15 of them had fibrofolliculomas (confirmed by biopsy in ten lesions taken from six patients). Trichodiscomas and acrochordons were also present.

It is an unusual event which revealed the probable first reported case of the syndrome with pulmonary manifestations in 1960 [7]. JRW, a 20 year-old man, was taught for submarine escape training at US Submarine Escape Training tanks. The technique for escape was as follows. The person escaping enters a special isolated compartment, which is then flooded from the sea to about chest level. With compressed air the pressure within the compartment is increased to equal the outside sea pressure. The escape hatch can then be opened, allowing access to the sea. With an inflated Mae West life jacket the man escaping then steps into the sea and rises to the surface at a rate of about 375 ft per minute. The compressed air within the life jacket is vented through special valves to prevent rupture of the jacket through expansion of its contained air as the surface is approached. The man escaping exhales continually during his ascent.

JRW had a normal chest X-ray. He followed the procedure and left the area. He was found lying on the grass in a stuporous condition 30 mn later, then improved. He did two consecutive other procedures and collapsed after the second. Recompression was done, resulting in improvement, then decompression could be done.

Chest X-ray showed several cystic areas in the left upper lobe, some of which with air levels. It was supposed that this was a case of air embolism associated with acute development of pulmonary cysts during decompression from depth.

Over the 50 following years JRW was admitted five times at hospital for pneumothorax. He further had a curative resection for clear cell-type renal carcinoma. An (astute) intern at hospital eventually considered the possibility of the syndrome. The patient had indeed removal of acrochordons several times. He further had a colorectal adenoma [8].

“Unilateral lung cysts” (not otherwise precised) were reported in 1975 by Hornstein and Knickenberg [9] in a man with further kidney cysts and solid nodules on his face, neck, and back. His daughter had innumerable perifollicular fibromas on the face, neck and trunk, a large goitre, and adenomatous colon polyps one of them transformed into carcinoma.

Perifollicular fibromas were further reported in 1986 in a man with colon polyposis who developed iterative spontaneous pneumothoraces. Spontaneous pneumothorax had occurred in seven people in the family, including four with perifollicular fibromas with further colon polyposis [10].

Chung et al. [11] later reported multiple spontaneous pneumothoraces starting at 15 years of age with bullous emphysema in his early twenties in a male patient with skin fibrofolliculomas.

Toro et al. [12] reported pulmonary cysts present in 4 of 28 patients from kindreds with familial renal tumors. Of these patients 3 had characteristic skin features, and one developed pneumothorax.

Bilateral chromophobe renal adenocarcinoma was reported in 1993 by Roth et al. [13] in a patient with characteristic fibrofolliculomas on the face, neck, and upper chest.

Toro et al. [12] in a study of kindreds with familial renal cancer found 13 patients with the syndrome. Of these 3 had lung cysts.

Pneumothorax is a characteristic feature [19–29] which has been reported as early as at age 7 years in the son of a patient [30]. In contrast patients may not develop pneumothorax throughout their lifetime as in a 85-year-old man with characteristic skin features present since young adulthood who had multiple pulmonary cysts detected by HRCT only once the diagnosis of FLCN-S was established in his son [31].

In a large series [22] of 98 patients affected with the FLCN-S, 13 carriers of FLCN haplotype, and 112 unaffected family members, the age-adjusted odds-ratio for pneumothorax in FLCN-S individuals was 50.3 times higher. In a larger cohort of 198 patients from the same institution, all 48 patients with a history of pneumothorax had multiple lung cysts identified by chest CT imaging [23]. The median age of occurrence of the first pneumothorax was 38 years (with a range from 22 to 71 years). Seventy five percent of patients had a second pneumothorax. There was no association between smoking and the risk of pneumothorax. Exon location of the BHD mutation was associated with the number of cysts, with individuals with mutations in exon 9 having more cysts. In a further study [24] of 51 families with FLCN-S, 88 % of the families and 84 % of the patients had lung cysts on CT imaging. Fifty-three percent of families and 38 % of individuals had a history of spontaneous pneumothorax. Most patients with a history of pneumothorax had lung cysts by CT imaging. Fifty-eight percent of patients with a family history of pneumothorax developed pneumothorax compared to 28 % without a family history (p = 0.01). A family history of pneumothorax was not associated with an increased risk of kidney tumours. Out of 34 individuals with a total of 92 spontaneous pneumothoraces, 19 had 2 pneumothoraces, and 7 had 3–7 pneumothoraces.

Interestingly, pneumothoraces without cysts on CT imaging have been reported [19]. A pneumothorax was reported in a 33 year-old-woman after a long airplane flight, leading to the diagnosis of MCLD and further FLCN-S [32]. Pneumomediastinum developed in a patient with FLCN mutation, without skin or renal manifestations, with pneumothoraces with or without detected lung cysts in four of family members [33].

In a series of 17 patients with FLCN-S established by genetic testing [34], MCLD was present in 15 cases (bilateral in 13, and unilateral in 2). The distribution of the cysts predominated in the lower part of the lungs (13/15). Five patients had more than 20 cysts and 7 fewer than 10 cysts, the size of which ranged from 0.2 to 7.8 cm. The shape of the cysts varied from round to oval with the large cysts usually having a lobulated multiseptal appearance. In another study of 12 patients [35] the number of cysts varied from 29 to 407, with 77 % of cysts being of irregular shape, and 40 % located along the pleura. Distribution of cysts predominated in the lower medial zone (i.e. below the level of the tracheal carina, and in the inner half of the lung field). Cysts abutting or including the proximal portions of lower arteries or veins were present in all patients. The same group further compared the pulmonary cysts in patients with FLCN-S and in patients with LAM [36]. Females with FLCN-S were older (46 vs 36 year old), with a prevalence of 6/14 with a family history of pneumothorax within the second degree relatives (vs none in LAM patients). The percentage of the ratio of pulmonary cysts’ areas in each lung field, the number of cysts and the mean circularity of cysts (roundness) was greater in LAM; the mean size of cysts was greater in FLCN-S. The number and size of cysts in the reported studies is quite variable: some patients had only few cysts (5 or less to 10) whereas they were innumerable in other patients, with a size varying from a few millimetres up to 10 cm (Fig. 16.1).

Exon location of the FLCN mutation is associated with the number of cysts, with individuals with mutation in exon 9 having more cysts than individuals with mutation in other exons.

Resected lung specimens of FLCN-S have often been diagnosed by pathologists as nonspecific blebs or bullae or emphysema [15]. The pathologic features mentioned in case reports usually did not identify specific lesions, however most often only specimen of subpleural lung tissue were taken at the time of pleurodesis after pneumothorax, with wedge lung biopsy further obtained in only a few cases. These reports mentioned possible associated inflammation attributed to chronic pneumothorax.

Histopathological study of two cases with basilar cysts found intraparenchymal collections of air surrounded by normal parenchyma or a thin fibrous wall, and blebs (consisting of collection of air within the pleura). Although these features were not specific to FLCN-S their predominantly basal location contrasted with the apical distribution of the other more common causes of spontaneous pneumothorax especially emphysematous bullae or idiopathic blebs [37]. The cysts in FLCN-S are typically punch out intraparenchymal cysts without inflammation [38]. A detailed analysis [39] was done on three wedge-resected tissues containing several cysts up to 1 cm in diameter, mostly in the pleural and subpleural regions. On microscopy these were found to be located in the vicinity of the interlobular septa, visceral pleura, and junctional regions between the interlobular septum and visceral pleura. Each cyst was incorporated with interstitial stroma of the interlobular septum and/or pleural in part, and with normal alveolar structures in the other part. Some cysts had protrusion of veins into the cystic space, a feature of an intimate spatial relationship of blood vessels and pulmonary cysts [28, 39, 40]. It was proposed that the pulmonary cysts in FLCN-S may represent an aberrant cystic alveolar formation with deranged interaction between alveolar epithelial structures and the surrounding mesenchyma in the peripheral lobular compartment that may give rise to the formation of abnormal cysts without stromal reaction. Pneumothorax might result from further growth of cysts [39]. Histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated FLCN-S and 117 cysts from 34 patients with primary spontaneous pneumothorax were compared [41]. FLCN-S cysts differed significantly from primary spontaneous pneumothorax cysts by abutting on interlobular septa (88 %), having intracystic septa (14 %) or protruding venules (39 %) without cell proliferation or inflammation. Although the intrapulmonary FLCN-S cysts were smaller than the subpleural ones there was no difference in size between them when there was no inflammation. The conclusion of this study was that FLCN-S cysts are likely to develop in the periacinar region, an anatomically weak site in a primary lobule, where alveoli attach to connective tissue septa. The authors hypothesized that the FLCN-S cysts possibly expend in size as the alveolar walls disappear at the alveolar-septal junction, and grow even larger when several cysts merge. A study of eight cases reported that pulmonary cysts have their inner surface lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells with the cells constituting the cysts staining positive for phospho-S6 ribosomal protein expression, thus suggesting activation of the mTOR pathway [42]. Activation of the mTOR pathway has been considered in both TSC and FLCN-S. Facial hair follicle tumours (angiofibromas) in TSC patients coincidentally responded to the oral mTOR inhibitor rapamycin administrated after renal transplantation, and to topical rapamycin. However a topical rapamycin double-blind placebo-controlled randomised split-face trial did not demonstrate cosmetic improvement of fibrofolliculomas in FLCN-S patients [43]. Folliculin in the lung cysts studied by immunochemistry [39] was present in macrophages and epithelial cells in the lungs of the patients and normal control lungs. In the cyst lesions the pneumocytes that lined the inner surface of cysts were also immunostained for folliculin. Wedge biopsy in a patient with FLCN-S and a history of ten pack-years of smoking reported widespread emphysematous changes, with further an interlobular septum replaced by interstitial air resulting in the displacement and compression of the venous wall on the side abutting the air-filled space [25].

Characteristic multiple, dome-shaped, whitish papules usually develop after the age of 20 years, especially on the face (nose and cheeks). These are common on the neck, and they are sometimes present on the trunk or the ears. Histologically they consist of benign hair follicle tumours called fibrofolliculomas (Fig. 16.2).

In their original description Birt et al. [6] described, in addition to fibrofolliculomas, trichodiscomas and acrochondromas. Whereas the first two belong to a morphological spectrum, acrochondromas are common in the general population. The diagnosis of the skin lesions relies on clinical examination by an experienced dermatologist with further histological examination if necessary.

Renal cancer is the most threatening manifestation of the FLCN-S, occurring in up to one fourth of patients at a mean age of 50 years, and at a minimal age of 20. The most common histological types are chromophobe renal cancer, and a mixed pattern of chromophobe and oncocytic renal tumours. Renal cancer is multifocal and/or bilateral in more than half of patients with FLCN-S.

Most of these tumours are in the low-risk oncocytic renal neoplasia spectrum including chromophobe renal cell carcinoma, oncocytoma, and hydrid oncocytic tumours; clear cell and papillary renal cell carcinoma have also been reported [44, 45].

Renal (small size) angiomyolipoma [46] and renal cysts [12] has been reported in FLCN-S. Surveillance for renal tumours by annual magnetic resonance imaging starting by the age of 20 may be proposed.

Surveillance for renal tumours by annual magnetic resonance imaging starting by the age of 20 may be proposed.

MCLD in isolated pulmonary lymphoma may be associated with amyloidosis [81]. The cystic lesions were found to correspond to dilated bronchioles infiltrated by amyloidosis. Multiple cysts associated with nodular amyloidosis (of the AL type) especially in Sjögren syndrome without systemic amyloidosis [82–85], and isolated multiple cystic pulmonary amyloidosis have been reported [86].

Diffuse alveolar septal amyloidosis with multiple cysts and calcification has only rarely been reported [87].

Whereas light-chains of monotypic immunoglobulins may deposit in the tissues as fibrillar amyloidosis resulting from a β-pleated sheet configuration consequently binding Congo red, less commonly, light-chains may deposit in the tissues (especially the kidney) as an amorphous (non fibrillar) material [88].

Light chain deposition has been described in patients with MCLD referred for lung transplantation with a presumptive diagnosis of either PLCH or LAM. The disease was histologically characterised by non-amyloid deposits in the alveolar walls, the small-airways and the vessels (with further emphysematous-like changes and small airway dilation). Electron microscopy revealed coarsely granular deposits. Monotypic kappa light-chain fixation was demonstrated on the abnormal deposits and along the basement membranes [89]. Further using polymerase chain reaction a dominant lymphoid B-cell clone was identified in the lung with biological features suggesting antigen-driven primary pulmonary lymphoproliferative disorder [90]. A monoclonal immunoglobulin component may be identified in the blood and/or urine in a proportion of patients. The diagnosis of light-chain deposition disease may be obtained by pulmonary biopsy but also by bronchial biopsy in non-amyloid immunoglobulin deposition disease presenting as MCLD [91]. Mass spectrometry on formalin fixed paraffin-embedded tissue may confidently diagnose kappa light chain deposition disease [92]. Cysts in non-amyloid monoclonal immunoglobulin deposition disease are presented above (Fig. 16.5)