Metastatic oncocytic adrenocortical carcinoma of mandible: an extraordinarily rare occurrence &
Vivek Nayyar, MDS,a Ajoy Roychoudhury, MDS,b Ashu Seith Bhalla, MD, and Deepika Mishra, MDSª
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Adrenocortical carcinoma (ACC) is an uncommon primary cancer in the adrenal gland. Its incidence of showing metastasis in the head and neck region is very rare. Herein, we present a case of a 46-year-old man who presented with complaints of pain and numbness on the left side of the lower face for 4 months. Radiographic examination revealed an osteolytic lesion with an ill- defined border in the left body region of the mandible. Histopathologic examination revealed a tumor composed of sheets of oval to polygon-shaped tumor cells predominantly displaying abundant eosinophilic granular cytoplasm. These tumor cells showed features of a high degree of anaplasia. On immunohistochemical examination, tumor cells were focally positive for synaptophy- sin, inhibin, vimentin, pancytokeratin (pan-CK), cytokeratin (CK)5/6, CD68, and CK8/18 and immunonegative for CK7, chromog- ranin, melan-A, S100, SMA, and SATB2. The Ki-67 proliferation index was approximately 20%. To the best of our knowledge, this is the first case of metastatic oncocytic ACC to the oral cavity region. (Oral Surg Oral Med Oral Pathol Oral Radiol 2022;134: e277-e280)
Metastasis to the oral cavity region is unusual and is mostly associated with widespread disease. The jaws, particularly the mandible, are the most affected site, followed by soft tissues, frequently gingiva.1 Meta- static tumors can present with a varied range of clinical signs and symptoms, which may create a diagnostic dilemma and may result in delayed diagnosis. Patients presenting with paresthesia of the mandible in the absence of any specific etiology should raise the possi- bility of metastatic signs, because this implies invasion into the bone and involvement of the inferior alveolar nerve.2 The aim of this report is to discuss a very rare case of metastatic oncocytic adrenocortical carcinoma (ACC) in the jaw.
CASE REPORT
A 46-year-old man presented with a chief complaint of pain and numbness on the left side of the lower face for 4 months. He had undergone an open transabdominal adrenalectomy (left) for ACC (stage II, pT2N0M0). On extraoral examination, a diffuse swelling was visible over the region corresponding to the body of the left hemimandible. The left submandibular lymph nodes were enlarged, hard, fixed to the deep tissues, and ten- der on palpation. Intraorally, a dome-shaped swelling was present in the left floor of the mouth, lingual to the left first and second mandibular molars. The swelling was soft to firm in consistency and compressible. The
ªDepartment of Oral Pathology and Microbiology, CDER, All India Institute of Medical Sciences, New Delhi, India.
bDepartment of Oral and Maxillofacial Surgery, CDER, All India Institute of Medical Sciences, New Delhi, India.
“Department of Radiodiagnosis, All India Institute of Medical Scien- ces, New Delhi, India.
Corresponding author. E-mail address: deepika1904@gmail.com
Received for publication Aug 6, 2021; returned for revision Nov 23, 2021; accepted for publication Jan 30, 2022.
@ 2022 Elsevier Inc. All rights reserved.
2212-4403/$-see front matter
https://doi.org/10.1016/j.oooo.2022.01.022
left first and second mandibular molars demonstrated grade 2 mobility. The lower lip opposite to the left mandibular incisors was numb.
An orthopantomogram showed an irregular osteo- lytic lesion with cortical destruction in the left body region of the mandible. Contrast-enhanced computed tomography was suggestive of an enhancing soft tissue in the left body of the mandible measuring approxi- mately 2.5 x 1.2 cm, causing erosion of mandibular cortices with extension into the floor of the mouth as a small soft tissue mass (Figure 1). Whole-body fluoro- deoxyglucose positron emission tomography and non- diagnostic computed tomography demonstrated a mildly metabolically active osteolytic lesion with a large soft tissue component involving the left mandibu- lar body and sacrum, as well as an isometabolic hypo- dense lesion in left lobe of the liver (Figure 2). Based on the patient’s past medical history and clinical and radiologic findings, metastatic disease was suspected. Intraosseous carcinoma, osteosarcoma, chondrosar- coma, and odontogenic malignancies were also included in the clinical differential diagnosis.
The histopathologic examination of the incisional biopsy from the left body region of the mandible revealed highly cellular connective tissue composed of sheets of oval to polygon-shaped tumor cells predomi- nantly displaying abundant eosinophilic granular cyto- plasm. These tumor cells showed features of anaplasia, namely hyperchromatism, increased nuclear/cyto- plasmic ratio, nuclear and cellular pleomorphism, prominent nucleoli, and 2-3 mitotic figures per high- power field. Numerous tumor giant cells were seen with bizarre nuclei. At places, tumor cells showed clear to faint eosinophilic cytoplasm (<20% of tumor cells). On immunohistochemical examination (using mouse antihuman monoclonal antibodies, all from Thermo Fisher Scientific Inc., Waltham, MA, USA), tumor cells showed focal cytoplasmic immunopositivity for synaptophysin, inhibin, vimentin, pan-CK, cytokeratin
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(CK)5/6, CD68, and CK8/18 and were immunonega- tive for CK7, chromogranin, melan-A, S100, SMA, and SATB2. The Ki-67 proliferation index was approx- imately 20% (Figure 3). Based on histologic and immunohistochemical findings, the diagnosis of meta- static oncocytic ACC of mandible was reached. No sur- gical intervention was undertaken for the metastatic lesion. The patient is currently undergoing chemora- diotherapy.
The previous histopathologic records were accessed. The gross examination of the adrenalectomy specimen
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showed no capsular invasion. Serial sectioning further revealed a variegated tumor (16 x 10.5 x 10 cm) with its closest margin reaching up to 3 mm from the capsule. A normal adrenal gland was identified at the periphery. Lesional tissue showed oncocytic cells arranged in a dif- fuse pattern. The tumor cells were large, round to polyg- onal in shape, with abundant eosinophilic cytoplasm and rounded nuclei, with few showing multiple nucleoli. Few neoplastic giant mononuclear and binucleate cells were also seen. A mitotic count of 7-8/10 high-power fields and areas of necrosis were noted. No capsular or vascular invasion was detected. Tumor cells were immunopositive for pan-CK and synaptophysin, whereas they were immunonegative for chromogranin, inhibin, melan-A, and calretinin. The Ki-67 proliferation index was approximately 25%.
DISCUSSION
Metastatic deposits from ACC are very rare in the oral region. A literature search revealed only 3 cases of metastases from ACC: 2 to the tongue and 1 other case to the mandible.3-5 ACC is uncommon; yet, it is the most well-known primary cancer in the adrenal gland, with an incidence of 0.5-2 cases per 1 million popula- tion.6 In addition to the conventional type, 3 histologic variants (oncocytic, myxoid, and sarcomatoid) are noted in the recent World Health Organization classifi- cation of ACC.7 Oncocytic ACC is the most common variant, composed of predominantly round to polygo- nal tumor cells with abundant granular eosinophilic cytoplasm, similar to our case. Patients with oncocytic ACC have a better prognosis than patients with con- ventional, myxoid, and sarcomatoid ACC.8 To the best of our knowledge, 56 cases of oncocytic ACC in the
adrenal gland are reported in the English-language literature.”
A review by Kanitra et al.9 stated that oncocytic ACC does not show any sex predilection, that the mean age of presentation was determined to be 48, and that most cases arose in the left adrenal gland. Distant metastasis was documented in only 13% of cases. The 5-year overall survival rate for patients with oncocytic ACC was found to be 47%. The tumor could metasta- size to the liver, lung, bone, and ovary.9 To the best of our knowledge, this is the first case of metastatic onco- cytic ACC in the oral cavity.
Metastatic lesions resemble the primary tumor but may pose diagnostic difficulties when appearing as intraosseous anaplastic carcinoma and sarcomas. In the present case, the metastatic lesion of ACC, undifferen- tiated pleomorphic sarcoma, oncocytic variant of cen- tral mucoepidermoid carcinoma, and osteosarcoma were considered in the histopathologic differential diagnosis. Immunostaining for pan-CK, CK5/6, CK8/ 18, and vimentin was done to investigate the line of dif- ferentiation. In our case, lesional cells showed focal positivity for all these markers. Variable immunoreac- tivity for vimentin and generally weak CK immunore- activity is a typical intermediate filament profile for ACC.10,11 Immunostaining for SMA and CD68 was done to rule out a myogenic and histiocytic origin of the tumor, respectively. Tumor cells showed immuno- negativity for SMA and focal positivity for CD68, sug- gestive of tumor-infiltrating histiocytes.
Negative immunostaining for SATB2, S100, and CK7 markers was helpful in excluding intraosseous malignancies such as osteosarcoma, chondrosarcoma, and intraosseous salivary gland malignancy, respec- tively. Both metastatic melanoma and adrenal cortical carcinoma can be positive for melan-A. However, posi- tive staining for synaptophysin and inhibin, and immu- nonegativity for S100 and melan-A, in our case helped to confirm the diagnosis of adrenal cortical carcinoma.
A Ki-67 labeling index >10% suggests the high-risk nature of the disease (i.e., associated with shortened disease-free survival).12,13 Vargas et al.14 stated that the mean proliferation index (evaluated through per- centage of MIB-1-positive cells) was 20.8% in pri- mary tumors and 16.6% in recurrent or metastatic tumors. In the present case, the Ki-67 labeling index was approximately 25% in the primary lesion and 20% in the metastatic lesion, indicating an unfavorable prognosis. The immunohistochemical features of pri- mary tumor and jaw metastasis are compared in Table 1.
CONCLUSION
Metastatic jaw lesions are associated with a poor prog- nosis primarily because they are suggestive of
| Immunohistochemical marker | Primary tumor | Jaw metastasis |
|---|---|---|
| Synaptophysin | Diffuse positive | Focal positive |
| Inhibin | Negative | Focal positive |
| Pan-CK | Diffuse positive | Focal positive |
| Melan-A | Negative | Negative |
| Chromogranin | Negative | Negative |
| Ki-67 proliferative index | 25% | 20% |
CK, cytokeratin.
widespread disease. This is an important clinical con- sideration, and, in 25% of cases, it is the first warning sign of an unknown malignancy at a remote site. 1 Knowledge of these rare entities and their unique histo- pathologic profile can help narrow the differential diag- nosis quickly for oral pathologists.
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can be found in the online version at doi:10.1016/j. oooo.2022.01.022.
REFERENCES
1. Hirshberg A, Shnaiderman-Shapiro A, Kaplan I, Berger R. Meta- static tumours to the oral cavity - pathogenesis and analysis of 673 cases. Oral Oncol. 2008;44:743-752.
2. Akinbami BO. Metastatic carcinoma of the jaws: a review of lit- erature. Niger J Med. 2009;18:139-142.
3. Dominici A, Rizzo M, Travaglini F, Nesi G, Franchi A. Non- functioning adrenal cortical carcinoma presenting with metasta- sis to the tongue. J Oral Pathol Med. 2003;32:185-187.
4. Nakata M, Yamashita T, Watanabe Y, Ono H, Kirimoto K. Non- functioning adrenocortical carcinoma revealed by metastasis to
the base of the tongue. Gan No Rinsho. 1986;32:1855-1859. [in Japanese].
5. Rachapalli V, Blanco-Guzman M, Jones GM, Oriolowo A. Inter- esting case: metastatic adrenal adenocarcinoma of the mandible. Br J Oral Maxillofac Surg. 2006;44:239.
6. Nakamura Y, Yamazaki Y, Felizola SJ, et al. Adrenocortical car- cinoma: review of the pathologic features, production of adrenal steroids, and molecular pathogenesis. Endocrinol Metab Clin North Am. 2015;44:399-410.
7. Lam AK. Adrenocortical carcinoma: updates of clinical and pathological features after renewed World Health Organisation classification and pathology staging. Biomedicines. 2021;9:175.
8. Renaudin K, Smati S, Wargny M, et al. Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation. Mod Pathol. 2018;31:1708-1716.
9. Kanitra JJ, Hardaway JC, Soleimani T, Koehler TJ, McLeod MK, Kavuturu S. Adrenocortical oncocytic neoplasm: a system- atic review. Surgery. 2018;164:1351-1359.
10. Wick MR, Cherwitz DL, McGlennen RC, Dehner LP. Adreno- cortical carcinoma. An immunohistochemical comparison with renal cell carcinoma. Am J Pathol. 1986;122:343-352.
11. Cote RJ, Cordon-Cardo C, Reuter VE, Rosen PP. Immunopa- thology of adrenal and renal cortical tumors. Coordinated change in antigen expression is associated with neoplastic conversion in the adrenal cortex. Am J Pathol. 1990;136:1077-1084.
12. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179:G1-G46.
13. Morimoto R, Satoh F, Murakami O, et al. Immunohis- tochemistry of a proliferation marker Ki67/MIB1 in adreno- cortical carcinomas: Ki67/MIB1 labeling index is a predictor for recurrence of adrenocortical carcinomas. Endocr J. 2008;55:49-55.
14. Vargas MP, Vargas HI, Kleiner DE, Merino MJ. Adrenocortical neoplasms: role of prognostic markers MIB-1, P53, and RB. Am J Surg Pathol. 1997;21:556-562.