We presented an autopsy case of a patient with Cowden’s disease and multiple TTM, and these findings agreed with previous reports that TTM occurred more frequently in patients with hereditary cancer syndrome [
3]. To our knowledge, this is the first case report of a patient with Cowden’s disease having multiple TTM from a lung cancer to cavernous hemangiomas and cerebellar dysplastic gangliocytoma. Campbell et al. [
1] established the following criteria for the diagnosis of TTM: 1) The presence of two or more distinct tumors must exist; 2) The presence of extravascular metastasis; 3) Exclusion of tumor embolism and of “collision tumors”; and 4) Exclusion of tumors that have metastasized to lymphatic systems that were already involved by generalized lymphatic or hematological malignancy. Pamphlett established three criteria for the diagnosis of TTM [
5]: 1) The metastatic nidus must be at least partially enclosed by a rim of histologically distinct primary tumor tissue; 2) The existence of a primary carcinoma must be proven; 3) The metastatic tumor must be demonstrably compatible with primary carcinoma by morphological or immunohistochemical methods. Our case almost fully met both sets of criteria for TTM. The most frequent metastatic donor in TTM is lung cancer, followed by breast cancer [
2,
6‐
8], while renal cell carcinoma and meningioma have been reported as the most common recipient tumors [
2,
9]. Recipient tumors have been considered to have certain characteristics that make them favorable sites of metastasis, such as hypervascularity, high glycogen and lipid contents, the high expression of cell adhesion molecules, and a slow growth rate [
10‐
12]. However, it has also been reported that TTM cannot be induced by a vascular-rich environment alone [
13]. Thus, it remains to be clarified why certain tumors are more likely than others to be recipients of TTM. In turn, Cowden’s disease is a
PTEN hamartoma tumor syndrome caused by
PTEN gene mutation. It is an autosomal-dominant disease characterized by the development of multiple hamartomas in the skin, mucosa, digestive tract, breast, and central nervous system, and presents a high risk for malignant tumors in some organs. The pathological findings of the present case fully satisfied the criteria for Cowden’s disease [
14]. Breast cancer, thyroid cancer, and endometrial cancer are the most common malignant neoplasms in Cowden’s disease, and lung adenocarcinoma is rare [
15]. Although hemangioma was not included in the diagnostic criteria for Cowden’s disease [
14], the revised diagnostic criteria proposed by Pilarski et al. [
16] included vascular anomalies in the minor criteria. There have also been some reports of complicating hemangioma in patients with
PTEN mutation [
17‐
19]. Moreover, loss of PTEN function has been reported to result in enhanced angiogenesis, and it was suggested that patients with Cowden’s disease may experience accelerated growth of any incipient tumors due to enhanced angiogenesis [
20]. Thus, we speculated that the hemangiomas in our case may have been caused by Cowden’s disease. TTM is considered to occur more frequently in hereditary cancer syndrome because asymptomatic benign tumors are not treated in hereditary cancer syndrome, and thus are at risk of becoming recipient tumors in the long term. For example, hemangioblastoma is rarely excised in von Hippel-Lindau (VHL) disease because of its slow growth and absence of symptoms: therefore, hemangioblastomas have been considered to be a preferred site for metastasis in VHL disease [
3]. However, there has been no report describing TTM in Cowden’s disease, even though it is also a hereditary cancer syndrome. This phenomenon remains to be fully explained. In the present case, however, we speculated that there were three reasons for the multiple TTM. First, the patient had asymptomatic and long-standing neoplastic lesions such as multiple hemangiomas and cerebellar dysplastic gangliocytoma, which may have become preferred sites for metastasizing tumors. Second, lung cancer is the most common donor neoplasm in TTM. Third, it has been reported that TTM could occur as a results of metastasis from lung cancer with more aggressive behavior [
13], which is similar to the present case.