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Turkish Journal of CancerVol.32/ No. 1/ 2002

Primary adenocarcinoma of the lung in a case ofvon Recklinghausen neurofibromatosis

ÖNER DİKENSOY1, BÜLENT TUNÇÖZGÜR1, ZÜLAL ERBAĞCI2,AYTEN FİLİZ1

Departments of 1Thoracic Surgery and 2Dermatology, Gaziantep University,School of Medicine Sahinbey Hospital, Gaziantep-Turkey

Von Recklinghausen disease (neurofibromatosis, NF-1) is themost common inherited syndrome predisposing to neoplasia,particularly neural crest-derived tumors. However, occurrence ofprimary lung adenocarcinoma in association with NF-1 is notcommon. We present a 42-year old man with NF-1 and primaryadenocarcinoma of the lung to discuss the linkage betweenthese two entities. [Turk J Cancer 2002;32(1):32-36]

Key words: Neurofibromatosis, von Recklinghausen�sdisease, lung adenocarcinoma

Von Recklinghausen neurofibromatosis is an autosomal dominant diseasewhich features hyperplasia and neoplasia of neuroectodermal tissues largelyderived from the neural crest (1,2). The classic or peripheral form of thedisease, described by von Recklinghausen in 1882, is also known asneurofibromatosis type 1 (NF-1) and accounts for 85% of all cases. Its cardinalfeatures are cafe-au-lait macules and multiple neurofibromas. The presence ofat least six café-au-lait spots of more than 1.5 cm in diameter is diagnostic ofNF-1. Other features include hamartomas of the iris (Lisch nodules), axillaryfreckling and pseudoarthrosis of the tibia (3).

Mutation of NF-1 gene causes von Recklinghausen�s disease. The NF-1gene on chromosome 17 encodes a protein, neurofibromin, which is a GTPasethat modulates signal transduction through the ras pathway. NF-1 is a tumor-suppressor gene. Patients with NF-1 are at increased risk of developingnervous system neoplasms (4). Even though it is known as the most commoninherited syndrome in man predisposing to neoplasia, occurrence of malignanttumors other than neurogenic tumors is not common (4-7). Therefore, wepresent this case to discuss the risk factors for the development of lungcarcinoma in a patient with NF-1.

Case Report

A 42-year old male was admitted to our hospital with a history of left-sidedchest pain and progressive dyspnea on exertion for 1 month. He was a life-timenonsmoker, and he had no previous diagnosis for a specific disease. There

DİKENSOY et al. 33

were no remarkable data in his medical and family histories, and he denied anyenvironmental or occupational asbest exposure. Physical examination revealeda number of cafe-au-lait spots, and multiple cutaneous neurofibromassuggesting a diagnosis of NF-1. His chest X-ray revealed pleural effusion on theleft side. Computed tomography of the chest showed bilateral multiple bullaepredominantly in the upper zones (Figure 1) and a minimal left sided pleuraleffusion associated with obstruction of the left lower lobe bronchi by asurrounding mass, sized 4x5 cm (Figure 2).

Fig 1. Bullae formation in the upper lung regions

Repeated biochemical and cytological examinations of the pleural fluidyielded an exudate without malignant cells. Biochemical and cellular features ofthe pleural fluid were as follows; hematocrit, 23%; white blood cells,0.92x103/µL (differentiation of 70% lymphocytes); protein, 5.2 gr/dL; lacticdehydrogenase, 740 IU/L (normal range, 240-480 IU/L); glucose, 85 mg/dL.Pleural biopsy by Abrams� needle yielded chronic inflammation. Fiberopticbronchoscopic examination confirmed obstruction of the left lower lobe bronchiby a tumoral lesion, and bronchial biopsies revealed adenocarcinoma. Ametastatic survey including CT scan of the abdomen, cranium and total bodybone scan revealed no evidence of metastatic disease. He underwent left lowerlobectomy along with the partial resection of the diaphragm which was invadedby tumor, and regional lymph nodes were resected. Histopathologically, thetumor was staged as T3,N0,M0 (Stage IIIa). The pleural effusion wascompletely disappeared on the chest X-ray obtained 3 months after the surgery.No evidence for recurrence of the tumor or pleurisy was observed during thenine months of follow up.

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Fig 2. Obstruction of the left lower lobe bronchi by a surrounding mass andassociated pleural effusion

Discussion

Pulmonary involvement in NF-1 occurs in up to 20% of the cases, andfibrosis and thin-walled bullae formation, predominantly in upper zones are themost common pulmonary manifestations (2,3).

It has been suggested that the genetic abnormality responsible for NF-1increases a patient�s risk of various kinds of malignancies, and therefore,individuals with NF-1 have a significantly higher incidence of malignantschwannoma, neurofibrosarcoma, intracranial glioma, and pheochromacytoma(8). However, association of primary lung carcinoma with NF-1 is not common(7). A Japanese review reported only 11 cases of NF-1 with primary lungcarcinoma until 1992 (6). Adenocarcinoma was the most frequent histologicdiagnosis (72.9%) in this report as well as in most of the recent surveys of lungcancer in Japanese population (9). We found a few more cases in the medicalliterature presenting this association, and interestingly, those were also fromJapanese researchers (5,6,10-13). The questions raising from these reportsare; whether that occurrence of primary lung adenocarcinoma in these patientswith NF-1 is coincidental, or there is an increased risk for the development oflung adenocarcinoma in patients with NF-1. Since NF-1 is not a very raredisease and adenocarcinoma is the most frequent histologic type amongreported primary lung carcinomas, coincidental association of lungadenocarcinoma with NF-1 might be possible. On the other hand, thehypothesis of the increased risk for primary lung adenocarcinoma in NF-1 canbe explained by two different mechanisms: 1) most of these reports addressed

DİKENSOY et al. 35

the possibility that adenocarcinoma might be originating from previous scartissue or bullae wall because the tumor was usually in the upper lobes wherebullae and scar tissues were predominant in NF-1 (13-15); 2) NF-1 is the mostcommon inherited syndrome predisposing to neoplasia, and individuals withNF-1 have a significantly higher incidence of neural crest derived-tumors,particularly benign neurofibromas, malignant schwannoma, neurofibrosarcoma,intracranial glioma, and pheochromocytoma, so there might be also anincreased risk for the development of primary lung carcinoma in NF-1 (8). Latterhas been investigated in some genetic based studies which were not able toshow a strong relation but some evidences to support this hypothesis. NF-1gene has been mapped to a small region of chromosome 17q (4). Therefore,many surveys were conducted to show any genetic linkage between theabnormalities on chromosome 17 and the malignant transformation in NF-1(5,6,16). In a study by Menon et al (16) deletions of chromosome 17 in NF-1-derived tumor specimens were searched. While no loss of markers onchromosome 17 was observed in any of the benign tumors from NF-1 patients,17p but not 17q deletions were observed in neurofibrosarcomas. This region isknown to contain a candidate gene, P53, which has been implicated in theprogression of a broad spectrum of human cancers including lung carcinomas(5). Most recently, a highly significant association between P53 mutations anddeletions on 17p was found in the pathogenesis of non-small cell lungcarcinomas (17). In accordance with these findings, a loss of heterozygosity onchromosome arm 17p, but not 17q, in small cell lung carcinoma from a patientwith NF-1 was detected in a subsequent study by Shimuzi et al (5). And it wassuggested that inactivation of tumor suppressor gene on chromosome 17p,most likely P53, might be responsible for the development of small cell lungcarcinoma in their patient with NF-1.

On the basis of these findings, one can speculate that the risk for thedevelopment of primary lung carcinoma in NF-1 might be increased at least insome patients due to increased prevalence of deletions on chromosome arm17p.

In our case, the tumor was originated from the left lower lobe bronchi andthere was no association with scar tissue or bullae formation excluding thepossibility of a scar carcinoma. Since, our patient was a non-smoker young manand there was no family history of a previous cancer, whether this was acoincidental association, or development of the lung adenocarcinoma wasassociated with the increased genetic susceptibility of NF-1 is not certain.

We specifically presented this case because of the rare association of NF-1and primary adenocarcinoma of the lung. We suggest that the lungadenocarcinoma in our case was not originated from a scar tissue, and thelinkage between these two entities should be further investigated in geneticbased studies.

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