Clinical Pathologic Conference Case 3: A WELL-DEFINED OSTEOLYTIC LESION IN THE BODY OF THE MANDIBLE WITH SPECIAL EMPHASIS ON DIAGNOSTIC ALGORITHM USING IMMUNOHISTOCHEMICAL AND HORMONAL PROFILING

Case Presentation

A 56-year-old North Indian woman presented with heaviness in her right lower back teeth region for 3 months. On intraoral examination, root stumps were present in #18 and #25 regions (FDI numbering system). No visible soft tissue lesions were found in the oral cavity, but an orthopantomogram revealed an ill-defined unilocular osteolytic radiolucency in the right body of the mandible, corresponding to the periapical regions of #43, #44, and #45, with blunting of root apices (Fig. 1). The patient had a history of fine-needle aspiration biopsy from the left breast, which was suggestive of invasive breast carcinoma of no special type. The hormonal profile of the tumor was as follows: estrogen receptor (ER)–positive (Allred score = 8/8), progesterone receptor (PR)–positive (Allred score = 7/8), and Her2Neu–negative (0/8). The tumor cells retained E-cadherin expression, with a Ki67 labeling index of 10% in proliferating areas. Following histopathological diagnosis, the patient underwent neoadjuvant chemotherapy (6 cycles of doxorubicin at 84 mg, cyclophosphamide at 840 mg, and G-CSF at 300 mg) and radiotherapy (15 cycles of 2.67 gray whole breast irradiation). A follow-up positron emission tomography (PET) scan revealed metabolically active soft tissue enhancement in the upper outer quadrant of the left breast. Thus, a mastectomy was performed to excise the residual tumor, which showed similar histopathological and immunohistochemical features as the incisional biopsy, with ypT3ypN3ayMx staging; Miller Payne grade 3, residual cancer burden (RCB) score of 4.536, and RCB class III.

Differential Diagnosis

The clinical presentation of the lesion favored a range from a benign cystic lesion to a malignant neoplasm. The differential diagnosis included central giant cell granuloma, odontogenic keratocyst, odontogenic fibroma, unicystic ameloblastoma, osteosarcoma, solitary plasmacytoma, non-Hodgkin's lymphoma, Langerhans cell histiocytosis (LCH), intraosseous mucoepidermoid carcinoma, and metastatic disease.¹

Central giant cell granulomas are more common in the anterior portions of the jaw that frequently cross the midline and, radiographically, may appear as a unilocular radiolucency with well-delineated borders. In the case of an odontogenic keratocyst, the lesion shows anteroposterior growth within the medullary cavity without causing expansion of the medullary cavity.¹ Odontogenic fibromas are rare lesions, and more than half of the tumors are located posterior to the first molar of the mandible. Solitary plasmacytoma of bone shows a preponderance in males and is most common in the spine, with the least occurrence in the mandible. It may also produce a well-delineated radiolucency.² LCH most commonly occurs in children younger than 15 years old as multiple or solitary, sharply punched-out radiolucencies, with a characteristic “scooped-out” appearance that may be evident in most cases. Unicystic ameloblastoma is seen most often in younger patients, with about 50% of all tumors diagnosed during the second decade of life.² In many patients, this lesion typically appears as a well-circumscribed radiolucency that surrounds the crown of an unerupted third molar, resembling a dentigerous cyst.² Osteosarcoma exhibits a male predominance and, radiographically, appears as a mixed radiolucent-radiopaque lesion with evidence of cortical destructions and periosteal reaction.³ Intraosseous salivary gland neoplasms, especially mucoepidermoid carcinoma, are rare entities and could be differentiated by their histological characteristics.³ The provisional diagnosis of metastatic breast carcinoma was made, as the medical history of the patient substantiates our clinical findings.

Diagnosis and Treatment

An incisional biopsy was performed after obtaining consent, which showed small fragments of brownish soft tissue collectively measuring 1.0 × 0.5 × 0.3 cm. Microscopic examination revealed epithelial tumor cells dispersed in fibrous connective tissue stroma in the form of strands and cords arranged in Indian file appearance. The neoplastic cells were round to oval in shape, showing nuclear and cellular pleomorphism with hyperchromatic nuclei and clear cytoplasm (Fig. 2).

The tumor cells were immunopositive for CK7, CK19, mammaglobin, and GATA3 (Fig. 3), which further confirms the diagnosis of metastatic carcinoma from breast origin. In addition, the tumor cells were immunonegative for CK20 and p63, which excludes metastasis from the thyroid, lungs, and renal carcinoma. The hormonal panel showed immunopositivity for ER with immunonegativity for PR and Her2neu. A PET scan revealed metabolically active foci in the right breast and the right body of the mandible.

Management

The patient is currently under regular follow up, and the multidisciplinary board is planning for chemotherapy followed by targeted therapy.

Discussion

Breast carcinoma (BC) is a fatal tumor in women, accounting for 26% of all newly diagnosed cancers in female patients, and is responsible for 15% of cancer-related deaths in women.⁴ BC metastasizing to the mandible occurs three times more often (41% of metastatic cases to the mandible) than any other malignant tumor in women.⁴ These tumors spread to almost any region of the body but they commonly invade regional lymph nodes in nearly one-third of patients. In the oral cavity, the jawbone most commonly involved is the mandible (80-90%), mainly at the molar or retromolar sites followed by maxilla and soft tissues.⁵ These areas are more prone to the deposition of cancerous cells due to the presence of hematopoietic bone marrow, subdivision of local blood vessels, and reduced velocity of blood flow.⁶ Metastases to the oral cavity sometimes present with pain, paresthesia of the involved region, loosening of teeth, and pathological fracture of the affected bone or they may remain asymptomatic.⁶ Radiographic examination most frequently reveals an osteolytic lesion with ill-defined margins; mixed lesions may be seen rarely, however.⁶

The histologic features of metastatic jaw tumors are often poorly differentiated, making it challenging to determine the origin of the lesion, especially in cases with no history of a primary malignancy. However, a thorough histological evaluation with a panel of immunohistochemical markers could ease efforts in reaching a final diagnosis. The majority of metastatic breast carcinomas consistently show positivity for GATA3 (80%) and mammaglobin (56%), that could aid in delineating invasive breast carcinomas from other metastatic diseases.⁹ In addition to immunoprofiling, determining the hormonal status of breast cancer cells in metastatic foci is crucial. The status of hormone receptors such as ER and PR along with HER2 status, serves as predictive and prognostic factors for BC therapy decision making by international guidelines. Due to their critical role in prognosis, recently the World Health Organization (2022, 5th edition) has sub-divided BC as (1) ER-positive, HER2-negative; (2) ER-positive, HER2-positive; (3) ER-negative, HER2-positive, or (4) ER-negative, HER2-negative tumors.¹⁰ About 80% of all BCs are said to be ER-positive (better prognosis) and around 65% of these are also PR-positive. Targeted therapy is a novel technique that uses specific drugs to block cancer growth by interfering with the function of certain molecules responsible for tumor cell proliferation and survival.⁷ Targeted treatment for metastatic BC is determined by the presence or absence of hormone receptors, cancer recurrence, metastasis rate, and metastasis site. Thus, metastasis is an important factor in breast cancer treatment because it can guide for a therapeutic target and serve as detectable biomarker.⁷ Moreover, immune cells in the stroma of breast cancer play different roles in various microenvironmental signaling and have been proven to have a strong association with metastasis by increasing adhesion to the extracellular matrix. Therefore, evaluating inflammatory cells and secreted factors could be used as potential targets for the treatment of metastatic breast cancer.⁸ Combination of targeted therapeutic agents with tailored blocking substances could be used to manage aggressive metastatic lesions and improve prognosis.

The clinical as well as radiographic findings of a metastatic lesion can be deceiving due to the lack of pathognomonic signs and symptoms, leading to faulty diagnosis of a benign process. Therefore, in such cases, especially in patients with a history of malignant disease, biopsy is mandatory. Metastasis is a complex process through which a primary tumor develops into a distant secondary tumor. It is a hallmark of cancer and a major cause of treatment failure, often resulting in patient death. The 5-year relative survival rate of patients with metastatic disease is only 25%, and the management is primarily palliative and may include radiotherapy, chemotherapy, hormone therapy, and, rarely, surgical intervention. In some instances, surgical intervention is used for betterment of the patients.¹¹

Conclusions

This case presents the clinicopathological and immunohistochemical features of mandibular metastasis of breast cancer in a 56-year-old woman with special emphasis on hormonal therapy. Because the prognosis of these lesions is very poor, early diagnosis and timely interventions for oral cavity metastases play an important role in prolonged survival. It is mandatory to differentiate primary oral malignancies from metastatic lesions for proper treatment and better outcomes. Thus, it is of prime importance to take a detailed history with thorough clinical and radiographic examination in case of asymptomatic osteolytic lesions of the jaw(s). We believe that our results would guide in detecting the metastatic jaw tumors in an organized manner.