Dyskeratosis congenita and squamous cell carcinoma of the mandibular alveolar ridge

Abstract

Dyskeratosis congenita is a rare disease caused by telomerase dysfunction classically characterised by the triad: skin pigmentation, nail dystrophy and mucosal leukoplakia. Few cases are described in literature regarding patients with head and neck squamous cell carcinoma affected by dyskeratosis congenita, and the therapeutic decisions are not yet well defined. A review of the literature of the last 20 years (2001–2021) was performed, and it was analysed the case of a 38-year-old male patient affected by dyskeratosis congenita diagnosed with a squamous cell carcinoma of the inferior alveolar ridge, treated with surgery. The absence of complications and the good postoperative recovery of the patient comfort in saying that resection and reconstructive surgery can be safely performed. The occurrence of disseminated disease 6 months after the treatment warns about the extreme aggressiveness of the pathology, its often systemic nature and the necessity of a multidisciplinary approach as well as further studies.

Background

Dyskeratosis congenita (DC), also called Zinsser-Cole-Engman syndrome, is a rare disease caused by telomerase dysfunction with an annual incidence of less than one case out of 1 million, and classically characterised by the triad: skin pigmentation, nail dystrophy and mucosal leukoplakia.^1–3 It may have different transmission patterns (X-linked, autosomal dominant or recessive).¹ Often the disease manifests with disorders involving the bone marrow and the pulmonary system and it’s characterised by an increased incidence of malignant tumours, which are the main causes of mortality.^1–4 In the head and neck district, the patients suffering from DC develop with high-frequency benign lesions of the oral cavity, which may evolve into malignancies.^{2 3} Despite this, few cases have been described in literature concerning patients with head and neck squamous cell carcinoma (HNSCC) affected by DC, and the therapeutic decisions are not yet well defined, in particular as regards the surgical and reconstructive options.

Case presentation

In August 2017 referred to the Operative Unit of Maxillo-Facial Surgery of the Hospital Casa Solllievo della Sofferenza a 38-year-old male patient, who reported problem of a painless ulcerated swelling of the left lower alveolar ridge that appeared several weeks before. When DC was diagnosed in 2012 with genetic tests, the patient was affected by bone-marrow failure, skin discolouration (figure 1), dyskeratotic tongue lesions, alterations in the nail bed, horseshoe kidney and premature ageing. In 2013, he underwent bone marrow transplantation (allo-Haematopoietic stem cell transplantation (HSCT)) to treat a severe bone marrow failure. In the same year, he had also undergone the removal of a carcinoma in situ of the lower lip and subsequently, in 2015, the resection of a SCC involving the same site. He had periodic reactivations of cytomegalovirus (CMV) infections treated with antiviral therapy. Clinical examination showed an ulcerated mass of the left edentulous mandible of 3×2 cm (figure 2). No lymphadenomegalies were appreciable at palpation of the neck. The patient underwent a CT scan that evidenced a 2 cm lytic area of the left mandibular body (figure 3). A biopsy of the lesion was performed, with the diagnosis of poorly differentiated SCC.

Figure 1.

Frontal view of a 38-year-old male patient affected by dyskeratosis congenita.

Figure 2.

Endo-oral view of the swelling involving the inferior alveolar ridge.

Figure 3.

Preoperative CT scan showing bone erosion.

Treatment

A multidisciplinary team composed of haematologists, head and neck surgeons, oncologists and radiotherapists discussed the case. Haematological contraindications were excluded, and surgical management was indicated. The patient underwent mandibular resection, ipsilateral modified radical neck dissection and reconstruction with a free fibular osteomuscular flap (figure 4). Neither local nor systemic complications were observed in the postoperative period. He resumed oral nutrition on the ninth day and was discharged on the 16th post-operative day. The pathological staging was pT4a N0 M0 V0 L0 Pn1 R0 G3 (UICC 2017). The multidisciplinary team again evaluated the patient postoperatively and decided not to proceed with an adjuvant radiotherapic or chemotherapic treatment because of the high risk of a further neoplasm occurrence.

Figure 4.

Preoperative (A) and postoperative (B) Orthopantomography (OPG).

Outcome and follow-up

Six months after the discharge, the patient returned to follow-up with several not ulcerated swellings involving the left supraclavicular area, the anterior floor of the mouth and the right zygomatic skin. All the lesions were biopsied with a diagnosis of SCC. According to oncologists, haematologists and radiotherapists, because of the dissemination of the disease, the patient underwent only supportive care. One month later, he died of respiratory complications.

Discussion

DC is an inherited disorder described for the first time in 1906,^{1 3} caused by an early loss of normal telomere length, with variable expressivity, and a wide set of signs and symptoms that may occur at a different time in the same patient. As well as the classic triad consisting of dystrophic nails, mucosal leukoplakia and abnormal reticular skin pigmentation, DC can be characterised by the presence of endocrine and skeletal disorders, pulmonary fibrosis, gastrointestinal disease and genitourinary complication.^{1 3}

Patients with DC have a very high risk of developing malignant neoplasms, with an observed/expected tumours (O/E) ratio 11 times higher than the general population; the 40% of neoplasms are HNSCC with a 1000-fold increase in the O/E ratio for tongue cancer.¹

To date, more than 10 genes involved in the transmission of the disease have been studied, the 50% of patients developing solid tumours had almost a mutation of the TERC gene.^{1 3}

Genetic instability and cellular senescence are the main mechanisms involved in the malignant transformation of cells with telomere dysfunction.¹

HNSCC in DC occur more frequently on a precancerous lesion, and their treatment is still not well coded due to the rarity of the disease. Primary or adjuvant radiotherapic/chemotherapic treatments can increase the risk of a second neoplasm occurrence due to DNA-related damage. Hartman et al⁵ described a case of a 16-year-old patient affected by a hard palate carcinoma treated with adjuvant proton therapy to decrease radiation-related side effects. Surgical treatment depends on the stage of the disease and the patient’s general condition.

A review of the literature of the last 20 years (2001–2021) performed by the Authors about Oral Squamous Cell Carcinoma (OSCC) in DC showed only eight cases reported (table 1—cases of HNSCC on DC reported in the literature)^5–12: six male and two female (mean age: 26 years; range: 5–45 years). The sites involved were: tongue (n=6), cheek (n=1) and hard palate (n=1). The T stage ranged from T2 to T4. Six of the eight cases were surgically managed, in two cases (tongue) the defect was reconstructed with a free flap; in four patients adjuvant radiotherapy (n=3) or proton therapy (n=1) were performed. In one case, the surgical treatment was followed by a therapy with immunosuppressant and steroids, with a good control of the disease after 15 months of follow-up.

Table 1.

Cases of oral squamous cell carcinoma (OSCC) on dyskeratosis congenita (DC) reported in literature

Case	Author	Year	Gender (M/F)	Age	Site	TNM	Surgical treatment	RT	CT	Recurrence	Follow-up (months)	Status
1	Trott et al6	2019	M	10	Tongue	T4N2cM0	No	No	No	NA	20 days	DWD
2	Kim et al7	2019	F	5	Tongue	T1N0M0	Excision	No	Immunosuppressant and steroid	Yes	34	NED
3	Fatehi et al8	2018	M	41	Tongue	T3N0	Excision, neck dissection and forearm free flap reconstruction	Adjuvant	No	NA	NA	NA
4	Bongiorno et al9	2017	F	22	Tongue	NA	Excision	No	No	No	24	NED
5	Hartman et al5	2014	M	16	Hard palate	NA	Hemimaxillectomy right supraomohyoid neck dissection	Proton therapy (54 Gy)	No	No	18	NED
6	Gopal Ray et al10	2010	M	38	Tongue	NA (N+)	Excision, neck dissection	Adjuvant	No	NA	NA	NA
7	Cengiz et al11	2004	M	32	Tongue	T3 N0 M0	Left supraomohyoid neck dissection and left partial tongue resection	Adjuvant RT (55 Gy)	No	NA	NA	NA
8	Baykal et al12	2003	M	45	Cheek	NA	No	Yes	No	Second tumour (stomach)	6	DWD

CT, chemiotherapy; DWD, dead with disease; F, female; M, male; NA, not available; NED, not evidence of disease; RT, radiotherapy.

In the case described, the authors considered it appropriate to treat the patient with surgical resection of the alveolar ridge SCC and subsequent reconstruction with a free flap, which allowed the restoration of the mandibular function and the aesthetic appearance. With this case report, the authors want to describe what has been their experience in the treatment of a patient with DC affected by an oral cavity SCC. Given the very few cases described in literature, each case report adds a small piece to the decision process and to the knowledge of such rare disease, helping colleagues in the future. After a review of the literature, the case described turns out to be the first report of a SCC of the jaw in a patient with DC, treated with respective surgery and reconstructed with a free bone flap. The absence of complications and the good postoperative recovery of the patient comfort in saying that resection and reconstructive surgery can be safely performed also in patients with DC. The poor prognosis must warn about the extreme aggressiveness of SCCs in patients with DC, their often-systemic nature and the absolute necessity of a multidisciplinary approach as well as further studies.

Learning points.

• Dyskeratosis congenita is a rare disease caused by telomerase dysfunction classically characterised by the triad: skin pigmentation, nail dystrophy and mucosal leukoplakia.

• Few cases have been described in literature concerning patients with head and neck squamous cell carcinoma affected by dyskeratosis congenita and the therapeutic decisions are not yet well defined.

• Radiotherapic or chemiotherapic treatments are associated to a high risk of a further neoplasm occurrence.

• The absence of complications and the good postoperative recovery of the patient comfort in saying that resective and reconstructive surgery can be safely performed.