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Year : 2020  |  Volume : 63  |  Issue : 1  |  Page : 112-115
First case report of tongue squamous cell carcinoma in a neurofibromatosis type 1 patient and review of pathogenesis of carcinoma in neurofibromatosis type 1

Department of Oral Pathology, Dr. R. Ahmed Dental College and Hospital, 114, A.J.C. Bose Road, Kolkata, West Bengal, India

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Date of Web Publication31-Jan-2020


Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is a type of genodermatoses having an autosomal dominant inheritance pattern and is recently considered as a RASopathy. Such patients are very much prone to develop mesenchymal tumors. However, carcinomas are quite rare in NF1 patients. This case study is the first case of oral squamous cell carcinoma (SCC) in tongue of an NF1 patient. A 35-year-old male reported to the Department of Oral Pathology in a tertiary care center with a chief complain of a painful ulcer on tongue for last 1 month. For confirmation of diagnosis of NF1, the “Diagnostic Criteria for Neurofibromatosis Type 1” was followed. Biopsied specimen of the tongue lesion was examined under microscope and histopathological features were suggestive of infiltrating SCC. Immunohistochemistry with Pan CK and beta-catenin was positive. RASopathy, WNT–beta-catenin pathway alteration, heat shock factor 1 production, and miRNA activity are investigated to explain the pathogenesis of malignancies in NF1 patients. In this first case of tongue SCC, we have found out the altered WNT–beta-catenin pathway.

Keywords: Case report and review of carcinoma in neurofibromatosis 1, pathogenesis of carcinoma in neurofibromatosis type 1, tongue squamous cell carcinoma in neurofibromatosis 1

How to cite this article:
Ghose S, Pramanick D, Mazumdar A. First case report of tongue squamous cell carcinoma in a neurofibromatosis type 1 patient and review of pathogenesis of carcinoma in neurofibromatosis type 1. Indian J Pathol Microbiol 2020;63:112-5

How to cite this URL:
Ghose S, Pramanick D, Mazumdar A. First case report of tongue squamous cell carcinoma in a neurofibromatosis type 1 patient and review of pathogenesis of carcinoma in neurofibromatosis type 1. Indian J Pathol Microbiol [serial online] 2020 [cited 2022 Nov 28];63:112-5. Available from:

   Introduction Top

Neurofibromatosis type 1 (NF1), an autosomal dominant genodermatoses associated with RASopathy and having cancer predisposition, is caused by germline mutation of a long tumor suppressor gene NF1(~60 exons), which encodes a protein neurofibromin. Among the eight clinical types of neurofibromatosis, NF1 is the most common. Epidemiological data suggest that one person in every 3000 births suffer from NF1.[1] Clinically, NF1 patients exhibit features of numerous neurofibromas, Lisch nodules, axillary freckling, café-au-lait spots, and optic gliomas.[2]

NF1 patients mostly develop mesenchymal malignancies, such as malignant peripheral nerve sheath tumors.[3],[4] However, carcinomas are quite rare in them. Squamous cell carcinoma (SCC) is even rarer. Till date, only two cases of cutaneous SCC – one in the sole of the foot[5] and the other in the forehead,[6] have been reported in NF1 patients. This case is the first case of SCC of oral cavity affecting tongue in an NF1 patient.

   Case History Top


Study protocol was approved by Ethics Committee. A 35-year-old male, without any oral deleterious habit, reported to the Department of Oral Pathology of the tertiary care center with a chief complain of a painful ulcer on tongue [Figure 1]c and associated difficulty in speech and deglutition for last 1 month. While conducting general survey, he was found to be of average built with all the vital signs within normal limits.
Figure 1: Intra- and extraoral examination: (a) multiple neurofibromas over the back; (b) Café-au-lait spots in axillary region; and (c) ulceroproliferative lesion on posterior one-third of tongue dorsum

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Clinical examination revealed multiple cutaneous non-ulcerated nodules of varying size all along the body [Figure 1]a, numerous café-au-lait spots over the trunks, limbs and axillary freckling [Figure 1]b. Based on the above findings, he was provisionally clinically diagnosed as NF1.

On intraoral examination, a tender ulceroproliferative lesion measuring 2.5 cm × 3.0 cm in greatest dimension with rolled out margins, indurated borders, and surface granularity was noted at posterior one-third of tongue. Clinically, the tongue lesion was diagnosed as a malignant ulcer.


For confirmation of diagnosis of NF1, the “Diagnostic Criteria for Neurofibromatosis Type 1”[2] was followed.

For confirmation of the diagnosis of tongue ulcer, incisional biopsy followed by histopathological examination was planned. Before collection of biopsy specimen, informed consent of the patient was taken, followed by routine hematological, serological, and coagulation profile evaluation. The biopsied specimen was processed and hematoxylin and eosin staining was done. Immunohistochemistry (IHC) for cytokeratin (Pan CK) and beta-catenin was also performed.

   Results Top

Clinical diagnosis of NF1 was confirmed as patient met the “Diagnostic Criteria for Neurofibromatosis Type 1” [Table 1].
Table 1: Clinical findings of neurofibromatosis type 1 patient according to the “Diagnostic Criteria for Neurofibromatosis Type 1”

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Histopathological examination of the biopsied specimen revealed the features of infiltrating SCC [Figure 2]a. Diagnosis of SCC was confirmed by strong positivity for Pan CK [Figure 2]b. Beta-catenin IHC staining shows moderate to weak diffuse cytoplasmic positivity [Figure 2]c.
Figure 2: Histopathological study (both hematoxylin and eosin [H and E] and immunohistochemistry [IHC]) of tongue ulcer: (a) H and E-stained section of biopsied specimen showing features of infiltrating squamous cell carcinoma; (b) IHC showing positive Pan CK staining; and (c) IHC showing positive beta-catenin staining

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From the above results, it can be concluded that the NF1 patient was suffering from tongue SCC.

   Discussion Top

NF1, a complex syndrome caused by loss of function mutation in NF1 gene leading to haploinsufficiency is still an enigmatic disease from the pathophysiological point of view. The large size of the gene, comparative lack of mutational hotspots, and a panoply of pathogenic mutations can be held responsible for this biological complexities regarding pathogenesis of NF1 and its predisposition to cancer.

Since the mapping of the NF1 gene in the year 1987, many scientific papers depicting the association of various oncogenic pathways with this gene have been published.

Among them, the most cited explanation is centered around the interaction between neurofibromin and RAS/mitogen-activated protein kinase (MAPK) pathway. The protein neurofibromin, encoded by NF1 gene, acts as an inhibitor of the RAS/MAPK pathway, which is responsible for transmission of mitogenic signals to the nucleus.[7] Growth factors, after binding with their cell surface receptors, cause activation of RAS, which, in turn, activates the Raf-MAK (mitogen-activated kinase)/MEK pathway and stimulate extracellular signal-related kinase (ERK). ERK enters the nucleus of the cell and initiates transcription. Now, neurofibromin downregulates RAS by conversion of guanosine triphosphate to guanosine diphosphate. When there is a lack of expression of neurofibromin protein due to mutated NF1 gene, the inhibitory signal over the RAS/MAPK pathway is lost resulting in uninterrupted transmission of mitogenic signals to the nucleus, thereby resulting in uncontrolled proliferation.

WNT signaling pathway activation has also been investigated in the context of carcinogenesis in NF1.[8] The study conducted by Armelle Luscan et al. (2014) revealed autonomous activation of WNT pathway in NF1 gene knocked down Schwann cells. The study also showed that there was increased expression of active beta-catenin protein when NF1 was silenced. So, they concluded and tried to establish that NF1 alters WNT pathway and favors tumorigenesis.[9]

Another protein, heat shock factor 1 (HSF1), is overexpressed in NF1, which helps in combating the intrinsic stresses produced within the tumor cells, there by favoring their survival.

MicroRNA (miR) has important role in pathogenesis of cancer by post-transcriptional inactivation of messenger RNA of neurofibromin protein in NF1 patients. miR-193a, miR-365-2, and miR-10b are the important miRNAs reported to be dysregulated in NF1-associated cancer.

In this study, we have tried to explore the probable carcinogenesis pathway in NF1 syndrome [Figure 3]. In doing so, it was found that beta-catenin antibody showed a diffuse cytoplasmic positivity in the neoplastic epithelial cells in IHC staining. Overexpression of beta-catenin in the neoplastic cells of tongue SCC is in tune with previously explained WNT pathway activation in NF1 syndrome. However, this does not indicate that other pathways remained silent. Considering the age and absence of oral deleterious habits in this patient, it can be inferred that NF1 loss might be a principal factor in oral carcinogenesis.
Figure 3: Carcinogenesis pathways in neurofibromatosis type 1. Different carcinogenesis pathways showing RASopathy, WNT pathway, heat shock factor 1 (HSF1) production, and miRNA activity

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As far as our study is concerned, till date, this is the first reported case of tongue SCC in a NF1 patient. So, to conclude, NF1 patients must be followed up at regular intervals to diagnose not only sarcomatous lesions at an early stage but also SCC including OSCC.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


Authors thank patient for agreeing to use his biological materials for this investigation.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Brems H, Beert E, de Ravel T, Legius E. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol 2009;10:508-15.  Back to cited text no. 1
National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Arch Neurol Chicago 1988;45:575-8.  Back to cited text no. 2
Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: Population-based record-linkage study. Br J Cancer 2012;108:193-8.  Back to cited text no. 3
Zöller ME, Rembeck B, Odén A, Samuelsson M, Angervall L. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 1997;79:2125-31.  Back to cited text no. 4
Friedrich RE, Al-Dam A, Hagel C. Squamous cell carcinoma of the sole of the foot in neurofibromatosis type 1. Anticancer Res 2012;32:2165-8.  Back to cited text no. 5
Ishida M, Okabe H. Cutaneous squamous cell carcinoma in a patient with neurofibromatosis type 1: A case report. Oncol Lett 2013;6:878-880.  Back to cited text no. 6
Seizinger BR. NF1: A prevalent cause of tumorigenesis in human cancers? Nat Genet 1993;3:97-9.  Back to cited text no. 7
Behrens J, Lustig B. The Wnt connection to tumorigenesis. Int J Dev Biol 2004;48:477-87.  Back to cited text no. 8
Luscan A, Masliah-Planchon J, Laurendeau I, Ortonne N, Varin J, Lallemand F, et al. The activation of the WNT signaling pathway is a Hallmark in neurofibromatosis type 1 tumorigenesis. Clin Cancer Res 2014;20:358-71.  Back to cited text no. 9

Correspondence Address:
Debasish Pramanick
Department of Oral Pathology, Dr R Ahmed Dental College and Hospital, 114, A. J. C. Bose Road, Kolkata - 700 014, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_61_19

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  [Figure 1], [Figure 2], [Figure 3]

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