The existence of the adenoma-cancer sequence has always been a fascinating topic, similar to the pathogenesis of colorectal cancer caused by colonic polyps previously discussed(14, 15). Some experiments have also indirectly shown us the possibility of ACT transforming into ACC(16, 17). In recent years, the transition from ACA to ACC has also received some support from molecular biology. First, many adenomas and ACC share a common genetic pathway, such as Wnt/β-catenin(18, 19).
Our case shows an adrenal incidental tumor that developed extensive metastasis two years after surgery and was subsequently diagnosed with ACC and treated. We have several hypotheses for the development of ACC in this patient. (i) ACC of patients is evolved from ACA. The history of rapid tumor growth before ACA tumor resection and postoperative immunohistochemistry showed that the patient had a Ki-67 index of 5–10%, indicating potential malignancy. According to literature reports, Ki-67 > 10% in adrenal tumors represents the high-risk population for the future development of ACC, and also has a pointer for adjuvant chemotherapy(20). (ii) There were already some small ACC cells in the pathological specimen of adrenal cortical adenoma at that time, which our pathologist just missed. (iii) The initial adrenal lesion was a simple benign adenoma. Two years later, the adrenal tumor was found to contain ACA and ACC.Of course, we prefer the first perspective.
Ki-67, originally an antigen of monoclonal antibody detected in the nucleus of proliferating cells, has gradually become an important value-added marker widely used in pathology. Ki-67 is an important prognostic factor for localized ACCs. The Ki-67 index is reported to be about 1.9% in normal adrenal glands; In adenoma, 2.11%; For cancer, it was 11.94%(21). Ki-67 inde༞10% as a marker of high recurrence risk, the use of adjuvant chemotherapy is generally accepted by most people(20, 22). Some guidelines suggest that adjuvant therapy is not recommended for adrenal tumors with uncertain malignant potential. However, for patients at low/moderate risk of recurrence (stage I-II, R0 resection, and Ki67 ≤ 10%), experts do not recommend supporting or is supporting adjuvant therapy, and adjuvant therapy options should be discussed on an individual basis(23). In this case, the patient's Ki-67 index was 5–10%, which was in a critical state, and no postoperative adjuvant therapy was given.
In clinical practice, the diagnosis of most ACC (> 70%) cases is confirmed by the malignant biological behavior of invasive metastasis of adrenal tumors(24), including the patient in this paper. This is because ACC and ACA are sometimes difficult to distinguish in clinical practice, especially for small tumors (༜4cm tumor). This case suggests that there is a possibility of adenoma-to-cancer transformation in ACC. We should increase the frequency of follow-up for potential malignancies and inform patients of this concept so as to attract attention. Specific follow-up should be carried out for several years. According to previous reports on the transformation of AI to ACC, most of them experienced a malignant transformation period of more than 7 years. Therefore, we still recommend follow-up every 3 months, and after 2–3 years of follow-up, if ACA is asymptomatic and hormone expression is normal, the follow-up time can be appropriately extended. However, follow-up should not be abandoned as an important means for early detection of malignant tumors. With regular follow-up, tumor recurrence or metastasis can be detected earlier, so as to get a better chance of treatment.
According to the genetic reports of patients, we searched the literature to find the relationship between these mutated genes (BTK, MSH6, KMT2A, NCOR1, ASXL2) and ACC(Figure 8). Unfortunately, the mutated genes found in the above genetic tests are only somatic mutations, and there are currently no targeted therapies for these mutated genes. Combining our case with previously published ACC precision medicine studies, we concluded that no target genes of special significance for ACC have been found in genetic testing studies(19). This may be related to the limited availability of rare genetic reports of ACC incidence, as well as the complex molecular background and tumor heterogeneity of ACC(25). ACC has been reported to be associated with Lynch syndrome in some human germline mismatch repair gene (MMR) mutations (MLH1, MSH2, MSH6)(26). In general, MMR defects are thought to be associated with accelerated progression of adenomas, as many Lynch syndrome patients have less than 3 years of tumor progression, compared to an average of 15 years in the general population. Our patient reported a systemic mutation in the MSH6 gene. This may explain the rapid progression from adenoma to carcinoma in this patient(27). The transition from ACA to ACC was reported to have taken at least 7 years, while our case was less than 2 years. Paradoxically, however, our patient had only the MSH6 mutation, which was systemic, and subsequent immunohistochemistry showed no loss of MMR expression and no family history of cancer. Therefore, the role of the MSH6 gene in the development of the disease in this patient has not been determined.
Due to the benign pathological results after AI surgery, doctors and patients did not pay enough attention to it and did not carry out closer follow-up. This case reminds us that adrenal adenoma have the potential for rapid malignant transformation into carcinoma. If we can alert ACA patients to these symptoms earlier, we may be able to detect some malignant tendencies earlier, intervene earlier, and give patients more opportunities.