CASE REPORT

https://doi.org/10.5005/jp-journals-10015-2055
World Journal of Dentistry
Volume 13 | Issue 3 | Year 2022

Need for Panel of Immunohistochemical Markers in Primary Intraosseous Squamous Cell Carcinoma Ex Odontogenic Keratocyst

Aravind S Kapali1, Lizbeth Raju2, Vanishri C Haragannavar3, Satish C4, Roopa S Rao5, Vineeth K6, Rajanikanth Rajaram7, Kavitha Prasad8, Dominic Augustine9, Sowmya SV10, Shankargouda Patil11

1,4Department of Surgical Oncology, M Ramaiah Medical College and Hospital, MSR Nagar, Bengaluru, Karnataka, India

2,3,5,9,10Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, M Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, Karnataka, India

6-8Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, M Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, Karnataka, India

11Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Kingdom of Saudi Arabia

Corresponding Author: Lizbeth Raju, Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, M Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, Karnataka, India, Phone: +91 9482394971, e-mail: lizbethraju17@gmail.com

ABSTRACT

Aim: A unique case of primary intraosseous squamous cell carcinoma (PIOSCC) arising from the lining of odontogenic keratocyst (OKC) in a 49-year-old female patient, quite aggressive in nature is presented here.

Background: The occurrence of (PIOSCC) from an odontogenic cyst is rare with the incidence being 0.3–3%.

Case description: In the present case histopathology was deceptive owing to the presence of spindle-shaped cells. This prompted us to use a panel of immunohistochemical markers such as CD34, Pan-cytokeratin, CK5/6, SMA, S100, and p63 to differentiate from sarcoma.

Conclusion: The probable pathogenesis for such a transformation into malignancy could be attributed to the hypothesis of chronic inflammation. According to the English literature review, 34 cases have been reported until now, with the present case being the 35th case.

Clinical significance: This report emphasizes the use of immunohistochemistry to arrive at a definitive diagnosis in scenarios of overlapping histological features.

How to cite this article: Kapali AS, Raju L, Haragannavar VC, et al. Need for Panel of Immunohistochemical Markers in Primary Intraosseous Squamous Cell Carcinoma Ex Odontogenic Keratocyst. World J Dent 2022;13(3):283-288.

Source of support: Nil

Conflict of interest: None

Keywords: Immunohistochemistry, Malignant transformation, Odontogenic cyst, Odontogenic keratocyst, Oral squamous cell carcinoma

INTRODUCTION

Neoplastic transformation of odontogenic cyst is a definitive entity that could be encountered in clinical practice despite its rarity in occurrence. The lining of odontogenic cysts has the potential to transform into various tumors such as odontoma, ameloblastoma, ameloblastic fibroma, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor, squamous cell carcinoma (SCC), and mucoepidermoid carcinoma.1 Among these, the lining of odontogenic keratocyst (OKC) and dentigerous cyst have an increased tendency for neoplastic transformation. OKC has been widely known for its aggressiveness and increased rate of recurrence. Studies at the molecular level have validated this unique nature owing to the increased expression of proliferative and anti-apoptotic markers such as Ki67, p53, PCNA, and Bcl-2 in the keratocystic lining.2

Primary Intraosseous carcinoma (PIOSCC) was defined by WHO (2005) as “Squamous cell carcinoma arising within the jaws having no initial connection with the oral mucosa, and presumably developing from residues of odontogenic epithelium."3 PIOSCC is further classified into three subtypes:

PIOSCC ex OKC falls in the second subtype. This report puts forward a rare case of PIOSCC ex OKC in a 49-year-old female patient with unique histologic features consistent with its aggressive behavior. This report also aims at updating the literature review with an added note on pathogenesis in regard to the same.

CASE DESCRIPTION

A 49-year-old female patient reported to RUAS institute, with a chief complaint of a rapidly growing swelling in the front teeth region of the lower jaw that was clinically apparent for about two months. The patient gave a past dental history of pain and swelling 11 months back in the lower left jaw. The previous radiograph showed a multilocular radiolucency in the lower left mandible with perforation of the lower cortical bone (Fig. 1A). Histopathological biopsy report revealed a cystic lining composed of parakeratinized stratified squamous epithelium of 6–8 layer cell thickness with surface corrugations and palisading arrangement of basal cell layer along with the transition of cystic lining into malignancy. Tumor cells were arranged in islands showing dysplastic features like altered nuclear-cytoplasmic ratio, cellular and nuclear pleomorphism, hyperchromatism, and 1–2 mitotic figures per high power field (Fig. 1B). Surgically, Hemi-mandibulectomy of the left side was done (Fig. 1C).

Figs 1A to D: (A and B) CBCT image demonstrating an ill-defined multilocular radiolucency involving the left body of the mandible with perforation of the cortical plate. (C) The H&E stained section(10x) showing OKC lining with foci of transition of cystic lining into malignancy. (D) Postoperative radiograph after hemimandibulectomy

The patient had a recurrence after a period of 2 months with similar symptoms in the lower anterior region of the mandible. Extraoral examination showed facial asymmetry with swelling on the lower left side of the face in association with the previous surgery (Fig. 2A). Intraoral examination revealed an ovoid-shaped swelling obliterating the lower vestibule of the mandibular anterior teeth region with respect to 43, 42, 41, 31, 32, and 33 (Fig. 2B). Mucosa overlying the swelling appeared normal. On palpation, the swelling was soft in consistency. Radiographic investigations showed an ill-defined radiolucency extending from the distal part of 43 continuing toward the resected part of the mandible along with partial loss of interdental bone. There was no evidence of tooth resorption.

Figs 2A and B: (A) Intraoral view showing vestibular obliteration of the lower labial sulcus. (B) CBCT image demonstrating an ill-defined radiolucency involving the mandible extending from 43 to the resected part

An incisional biopsy was performed, the gross specimen received was reddish-brown in color, irregular in shape, and measured about 1 × 0.7 × 0.4 cm. Histopathologically, the biopsied specimen showed sheets of squamous cells in the connective tissue. The squamous cells showed dysplastic features like cellular and nuclear pleomorphism, hyperchromatism, increased nuclear/cytoplasmic ratio, loss of cohesion, numerous bizarre cells, and 4–5 abnormal mitotic figures per high power field. The stroma also consisted of sparse chronic inflammatory infiltrate comprising of lymphocytes, a few endothelial lined blood vessels engorged with RBCs, and a few hemorrhagic areas (Fig. 3). A diagnosis of recurrent intraosseous carcinoma of the poorly differentiated grade was given.

Figs 3A to C: Histopathological findings of Incisional Biopsy. (A) Shows sheets of tumor cells (4x). (B) Illustrates tumor cells showing dysplastic features like cellular and nuclear pleomorphism, hyperchromatism, increased nuclear/cytoplasmic ratio, loss of cohesion, numerous bizarre cells (black arrow) (10x). (C) Shows 4–5 abnormal mitotic figures (yellow arrows) and bizarre cells with increased nuclear-cytoplasmic ratio(black arrow) (40x)

Central arch resection of the mandible was done and the margins of the tumor were ensured to be free from the tumor. Histopathology of the excisional biopsy specimen showed sheets of noncohesive bizarre cells with cellular and nuclear pleomorphism, hyperchromatism and increased nuclear/cytoplasmic ratio, and presence of numerous mitotic figures, along with a foci of pleomorphic spindle-shaped cells with vesicular nuclei and multiple nucleoli. The connective tissue stroma showed diffuse inflammatory component predominantly consisting of lymphocytes and plasma cells with occasional giant cells (Fig. 4). Decalcified section of teeth also showed tumor tissue associated with the adjacent attached soft tissue However, the presence of pleomorphic spindle-shaped tumor cells posed a diagnostic dilemma of sarcoma or carcinosarcoma that had to be ruled out. Hence, the representative tumor tissue was later subjected to a panel of immunohistochemical markers to determine the cell of origin. The panel of markers included CD34, Pancytokeratin [AE1/AE3], CK5/6, SMA, S100, and p63. Immunohistochemistry showed negativity for CD34, S100 and strong positivity for pan cytokeratin, and weakly positive for p63 and SMA (Fig. 5). These results suggested that the tumor was of squamous origin of the poorly differentiated variant.

Figs 4A to F: Histopathological findings of excisional biopsy. (A) Shows sheets of tumor cells (10x). (B and C) illustrates tumor cells showing dysplastic features like hyperchromatism, increased nuclear/cytoplasmic ratio, loss of cohesion, abnormal mitotic figure (black arrow) (40x). (D) Shows decalcified section of tooth showing tumor cells associated with the soft tissue attached to it (4x). (E) Demonstrating areas of spindle-shaped cells (black arrows) (10x). (F) Photomicrograph showing spindle shaped cell (black arrow) with vesicular nuclei and multiple nucleoli (40x)

Figs 5A to F: Photomicrographs showing immunohistochemical findings (10x). (A) CD34. (B) AE1/AE3. (C) CK5/6. (D) p63. (E) S100. (F) H&E stained section showing sheets of tumor cells

DISCUSSION

The incidence of PIOSCC arising from an odontogenic cyst is 0.3–3%.4 The incidence and prevalence of PIOSCC ex OKC are unavailable due to less number of reported cases. It has been suggested that there is an increased risk for an OKC to transform into malignancy but evidence supporting the same seems to be lacking. The other probable reason for this could be the lack of definitive criteria which defines these group of lesions.

However, the following criteria were proposed by Gardner in the year 1975 in order to diagnose PIOSCC ex odontogenic cyst:5

A literature search was conducted by Acharya et al.7 where-in 25 cases of OOC/OKC transforming into malignancy were reported in English literature. After which, 10 more cases have been reported till 2016 including the present case (Table 1).

Table 1: Cases of PIOSCC ex OKC reported in English literature from 2013 to 2016
Sl Author No. Year Age/ Sex Site Symptoms Radiographic features Lining Grade of SCC Treatment Follow-up
1. Tan B et al.10 2013 45/Male Maxilla Swelling Radiolucency - WDSCC Maxillectomy, Radiotherapy Not stated
2. Tan B et al.10 2013 49/Male Mandible Pain, Swelling, Fever Radiolucency - MDSCC Bloc-resection, Chemotherapy, Radiotherapy Not stated
3. Tamgadge et al.11 2013 20/Female Mandible Pain, Swelling Multilocular radiolucency with Radiolucency with sclerotic margins - WDSCC Hemi-mandibulectomy, Neck Dissection Not stated
4. Jain et al.12 2013 70/Male Mandible Pain, Swelling Unilocular radiolucency Parakeratinized WDSCC Resection of Mandible 3 years, Free of disease
5. Park et al.13 2015 36/Male Mandible Pain, Limited mouth opening Multilocular radiolucency – SCC Segmental Mandibulectomy, Neck Dissection 24 months
6. Lukanda et al.14 2015 32/Female Mandible Pain, Swelling Multilocular radiolucency Parakeratinized and Orthokeratinized Infiltrative SCC Hemi-mandibulectomy Not stated
7. Bai et al.15 2015 59/Male Mandible Swelling Multilocular radiolucency – WDSCC Mandibular excision Not stated
8. Saxena et al.5 2015 60/Male Mandible Pain, Swelling, Paraesthesia Multilocular radiolucency Parakeratinized MDSCC to PDSCC – Not stated
9. Ramya et al.16 2015 35/Male Mandible Swelling Multilocular radiolucency Parakeratinized SCC Hemi-mandibulectomy Not stated
10. Present case 2016 40/Female Mandible Pain, Swelling Multilocular radiolucency Parakeratinized PDSCC Hemi-mandibulectomy Follow up being continued

The mean age of the 34 cases reported along with the present case, was 45 years (range 18–81 years), and the male: female ratio was 2:1. The most commonly involved site was the mandible as was seen in the present case. It has been suggested that this increased incidence of the OKC in the mandible could be attributed to the presence of dental lamina of high activity, which is more often seen in the posterior mandible.8 Pain and swelling are the most common clinical symptoms presented by the affected patients. Orthopantomograph most commonly reveals a multilocular radiolucency with the expansion of buccal and lingual cortices. Perforation of the cortices was observed in 25 cases including the present case.

Histopathologically, for a lesion to be diagnosed as PIOSCC ex Odontogenic Keratocyst, the above-mentioned criteria must be fulfilled. In the present case, there was evidence of OKC lining transforming into squamous cell carcinoma. Clinically, the overlying mucosa appeared normal and did not show any malignant changes thus suggesting that the lesion was a separate entity without any connection to the overlying epithelium. Since the PET scan revealed the absence of any primary tumor elsewhere in the body, the diagnosis of PIOSCC was favored. Similar to most of the other cases that have been reported in the literature, the present case showed a parakeratinized OKC lining. Squamous cell carcinoma seen in most of the cases belonged to the well-differentiated type, but in the present case, the poorly differentiated variant was observed, which could explain the aggressiveness of the lesion and the reason for its recurrence.

In the present case, the presence of spindle-shaped tumor cells leads to the addition of spindle cells lesions in the list of histopathologic differential diagnoses. Sarcomas, as well as carcinosarcomas, were ruled by a panel of Immunohistochemical markers which included a few epithelial markers such as pan cytokeratin and CK5/6 along with a few mesenchymal markers such as CD34, SMA, and S100. p63 was also included to confirm the poorly differentiated grade as most poorly differentiated squamous cell carcinomas stain positive for it. As the tumor cells exhibited negativity for mesenchymal markers and strong positivity for pan cytokeratin, its origin as a squamous cell was thereby confirmed. Negative staining for CK5/6 and weak positivity for p63 favored the poorly differentiated grade. This case scenario also signifies the importance of immunohistochemistry that could be utilized for a definitive diagnosis in the presence of such overlapping histopathological features.

The exact molecular pathogenesis of PIOSCC ex OKC is not clear and still needs further exploration. Whatsoever, hypotheses have been put forward by Bodner et al.9 that could give a possible explanation.

There has been a known correlation between chronic inflammation and carcinogenesis. It has been observed that the presence of inflammation in connective tissue is frequently associated with the malignant transformation of cystic epithelium. Chronic inflammation-induced carcinogenesis has been accepted even in other cancers such as oral squamous cell carcinoma. Though the underlying molecular mechanisms are not clearly understood, three main hypotheses by which inflammation can cause cancer have been proposed9 (Fig. 6):

Fig. 6: Pathogenesis of malignant transformation of odontogenic cysts

In the present case, the most probable reason for such transformation of OKC lining into malignancy could be the presence of chronic inflammation. Hence, patients presenting with odontogenic cysts must be monitored thoroughly from both clinical and pathological points of view.

CONCLUSION

Though the incidence of Primary Intraosseous Carcinoma ex OKC is rare, its possibility of occurrence should not be neglected in clinical scenarios. As these cases can present as a highly aggressive lesion, all cases of OKC must be thoroughly scrutinized for any malignant changes. Moreover, in cases posing a diagnostic dilemma, immunohistochemistry must be utilized to rule out the presence of any factors that could affect the treatment outcome. In case of any evidence of malignant changes, appropriate surgical treatment and follow-up must be carried out for improving the prognosis of such patients.

REFERENCES

1. Masthan KMK, Rajkumari S, Deepasree M, et al. Neoplasms associated with odontogenic cysts. J Dent Oral Hyg 2011;3(10):123–130. http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0718-381X2011000300004&lng=en&nrm=iso&tlng=en.

2. Leite TC, Meirelles V Jr, Janini MER. Odontogenic keratocystic tumor: a clinical and histopathologic retrospective study based on the new WHO classification. Int J Odontostomatol 2011;5(3):227–234. DOI: 10.4067/S0718–381X2011000300004

3. Barnes L, Eveson JW, Reichart P, et al. World Health Organization Classification of Tumours: Pathology & Genetics of Head and Neck Tumours Edited. Lyon: IARC press 2005.

4. Fanibunda K, Soames JV. Malignant and premalignant change in odontogenic cysts. J Oral Maxillofac Surg 1995;53(12):1469–1472. http://www.ncbi.nlm.nih.gov/pubmed/7490661. DOI: 10.1016/0278-2391(95)90680-0

5. Saxena C, Aggarwal P, Wadhwan V, et al. Primary intraosseous squamous cell carcinoma in odontogenic keratocyst: a rare entity. J Oral Maxillofac Pathol 2015;19(3):406. DOI: 10.4103/0973-029X.174615

6. Slootweg PJ, Müller H. Malignant ameloblastoma or ameloblastic carcinoma. Oral Surg Oral Med Oral Pathol 1984;57(2):168–176. http://www.ncbi.nlm.nih.gov/pubmed/6366686. DOI: 10.1016/0030-4220(84)90207-x

7. Acharya S, Tayaar AS, Hallkeri K, et al. Squamous cell carcinoma emerging in an orthokeratinized odontogenic cyst: a case report and brief review. J Oral Maxillofac Surg Med Pathol 2014;26(4):563–568. DOI: 10.1016/j.ajoms.2013.06.011

8. Li TJ, Kitano M, Chen XM, et al. Orthokeratinized odontogenic cyst: a clinicopathological and immunocytochemical study of 15 cases. Histopathology 1998;32(3):242–251. DOI: 10.1046/j.1365-2559.1998.00380.x

9. Bodner L, Manor E, Shear M, et al. Primary intraosseous squamous cell carcinoma arising in an odontogenic cyst: a clinicopathologic analysis of 116 reported cases. J Oral Pathol Med 2011;40(10):733–738. DOI: 10.1111/j.16000714.2011.01058.x

10. Tan B, Yan TS, Shermin L, et al. Malignant transformation of keratocystic odontogenic tumor: two case reports. Am J Otolaryngol 2013;34(4):357–361. DOI: 10.1016/j.amjoto.2013.01.002

11. Tamgadge S, Tamgadge A, Modak N, et al. Primary intraosseous squamous cell carcinoma arising from an odontogenic keratocyst: a case report and literature review. Ecancermedicalscience 2013;7:316. DOI: 10.3332/ecancer.2013.316

12. Jain M, Mittal S, Gupta DK. Primary intraosseous squamous cell carcinoma arising in odontogenic cysts: an insight in pathogenesis. J Oral Maxillofac Surg 2013;71(1):e7–e14. DOI: 10.1016/j.joms.2012.08.031

13. Park H, Kim T-S, Geum D, et al. Mandibular intraosseous squamous cell carcinoma lesion associated with odontogenic keratocyst: a case report. J Korean Assoc Oral Maxillofac Surg 2015;41(2):78–83. DOI: 10.5125/jkaoms.2015.41.2.78

14. Lukandu OM, Micha CS. Primary intraosseous squamous cell carcinoma arising from keratocystic odontogenic tumor. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120(5):e204–e209. DOI: 10.1016/j.oooo.2015.03.006

15. Bai M, Shen T, Chen Y, et al. Primary intraosseous squamous cell carcinoma in pre-existing keratocystic odontogenic tumor: a case report and literature review. Mol Clin Oncol 2016;4(2):187–190. DOI: 10.3892/mco.2015.678

16. Ramya S, Divya Uppala SM. Primary intraosseous squamous cell carcinoma arising from keratocystic odontogenic tumor. J Nucl Med Radiat Ther 2015;6120(5):5–7. DOI: 10.4172/2155–9619.1000253

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