Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency

Eduard Yakubov1,2, Ali Ghoochani1, Rolf Buslei3, Michael Buchfelder1, Ilker Y. Eyüpoglu1, Nicolai Savaskan1,4

1Translational Neurooncology Laboratory, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
2Department of Neurosurgery, Klinikum Nürnberg, Paracelsus Medical University, Nürnberg, Germany
3Department of Neuropathology, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
4BiMECON Ent., Berlin, Germany

Correspondence to: Nicolai Savaskan, email: nic.savaskan@gmail.com; savaskan@gmx.net

Keywords: Cowden syndrome, PTEN gene, meningioma, multiple hamartoma syndrome, brain tumor

Received: February 29, 2016 Accepted: May 13, 2016 Published: June 30, 2016

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cowden syndrome (CS) is clinically presented by multiple hamartomas, often with mucocutaneous lesions, goiter, breast cancer and gastrointestinal polyps. CS is a genetic disorder of autosomal dominant inheritance and is one distinct syndrome of the phosphatase and tensin homolog on chromosome 10 (PTEN) hamartoma tumor spectrum. Noteworthy, PTEN germline mutations are related to a wide range of brain tumors. We performed a systematic analysis and review of the medical literature for Cowden syndrome and meningioma and additionally present the case of a 29-year-old CS patient diagnosed with multiple meningiomas. We found strong evidence for high incidence of brain tumors in CS patients. In particular meningiomas and gangliocytomas/Lhermitte-Duclos disease were often associated with 8% and 9% respectively in CS patients. Since aberrations in chromosome 10q are associated with meningiomas, it is likely that the underlying mutations in CS drive to a certain extent neoplastic meningioma growth. We propose to include meningiomas and brain tumors in the major criteria spectrum of CS-related disorders. This could warrant early diagnosis of brain lesions and close therapy, as well as better monitoring of patients with CS.


Cowden syndrome (CS) is a clinically complex disease that is characterized by multiple hamartomas of ectodermal, mesodermal, and endodermal origin [1]. CS is now well recognized as a highly variable, autosomal-dominant hereditary cancer susceptible syndrome with increased risk of developing benign and malignant transformations [1-3].

In 1997, CS has first been linked to pathogenic mutations in the phosphatase and tensin homologue deleted on chromosome ten (PTEN) gene, located on chromosome 10q23.31 [4-6]. It is estimated to affect one in 200,000 individuals with a strong female predominance [7]. However, the incidence of CS before the identification of the underlying PTEN gene mutation was estimated to be 1:1,000,000 [8]. Approximately two-thirds of the mutations in CS occur in exons 5, 7, and 8 of the PTEN gene. Exon 5, which encodes the PTEN phosphatase core motif, comprises merely 20% of the PTEN gene. This domaine is also associated with approximately 40% of the identified mutations in CS [9]. Furthermore, PTEN encodes a dual phosphatase protein that negatively regulates the PI3K-Akt-mTOR pathway.Given the importance of PTEN as tumor suppressor gene, mutations in the germline of PTEN have been linked to at least four distinct autosomal dominant syndromes including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndrome. In addition, PTEN has also been found in various sporadic human cancers affecting the brain, breast, colon, thyreoid and endometrium [10].

Due to its variable clinical presentation, the diagnosis of Cowden Syndrome is still a clinical challenge. In practice, CS comes along with complex phenotypes and various clinical diagnoses which do not necessarily adjunct to genetic testing. However, technical standards have been established in managing PTEN screenings in individuals, such as the Cleveland Clinic adult clinical scoring system. The International Cowden Consortium has also contributed with a list of criteria to assess the diagnosis of Cowden syndrome. These criteria are based on the most common arising clinical features of this disease [11]. In fact, meningiomas and brain tumors are not included in the CS consortium criteria, presumbly due to the lack of data regarding its association with Cowden syndrome. Further, the screening recommendations of the National Comprehensive Cancer Network (NCCN) add help to diagnosing CS. Nevertheless, currently no CS diagnosis criteria provide specific guidelines for cerebral magnetic resonance imaging [11].

In this paper, we addressed the question whether the PTEN-associated CS appears with increased brain tumor incidence. We found strong evidence for the association between CS and the occurance of meningiomas.


We performed a systematic meta-analysis of meningioma cases in patients suffering from CS (Table 1). Our study was based on 109 patients with CS and with confirmed PTEN mutation. We focused on cases of CS with PTEN mutation because, as mentioned above, PTEN is suspected to be a meningioma tumor suppressor gene due to its location on chromosome 10 [12-17]. According to the fact that CS is prevalent in females, the ratio of female to male in our study was 2.1 : 1 (n=107). The median age of the patients with CS was 43.5 years (n=101). Furthermore, 36 of the 109 patients did not have any malignant neoplasy or brain tumor. The most frequent cancers that we dealed with were breast, thyroid, endometrial, colorectal, and renal cancer as well as brain tumors, inter alia, gangliocytoma/Lhermitte-Duclos disease and meningiomas (Table 1). Our results showed the following incidences in CS: breast cancer (37.61%), brain tumor (20.18%), thyroid cancer (14.68%), endometrial cancer (10.09%), colorectal cancer (9.17%), and renal cancer (3.67%). One fifth of patients with CS suffered from brain tumors, making this the second most frequent among the other cancers. The most common tumor in CS patients is breast cancer with nearly 38% of all cases. Within brain tumors, specially meningiomas were highly frequent in CS as confirmed by an incidence of 8.25% of patients with CS.

Although gangliocytomas (9.17%) are the most frequent brain tumors, the incidence of meningiomas is close to the incidence of gangliocytomas making up the majority of brain tumors in CS (Table 1). Astonishingly, males were more often affected with meningiomas as females (ratio of female to male was 4 : 5). This sex distribution is inverted to the general incidence of meningiomas in females and males (2.1:1). Since the International Cowden Consortium diagnostic criteria were basically drafted two decades ago where diagnostic criteria and imaging techniques were not standardized or simply did not exist, we propose to revise the criteria including menigiomas (Table 2).


Further, we closely followed up the case of a 29-year-old female who was referred to our hospital for the evaluation of her cervical polyps. A diagnostic hysteroscopy with fractional curettage was performed revealing an endometrial carcinoma (grade II). The patient underwent a radical hysterectomy. Postoperative therapy included brachytherapy in afterload technique in the vagina. Approximately 12 months later after a routine clinical examination, she displayed a nodular goiter. The patient underwent a subtotal thyroidectomy. Due to unclear intestinal complaints, a colonoscopy was performed. In an endoscopic examination small polyps were found in the sigmoid colon and rectum from which a biopsy was taken (Figure 1). Histopathological investigations revealed the overall picture of a mucosal ganglioneuroma. The neurological examination showed significant dysdiadochokinesia on both sides, as well as an ataxic uncertain gait pattern. Cerebral magnetic resonance imaging (MRI) was performed for further evaluation. MRI scans revealed two infra-tentorial tumorous lesions on the left side (Figure 2). Due to tumor increase, a resection

Author’s contribution

NES and IYE conceived and designed the study. EY, AG and MB collected the data and EY analyzed the data. NES and EY wrote the manuscript with input from IYE, RB and MB. All authors contributed to the discussion of the content and editing of the final manuscript before submission.

Table 1
PTEN mutational frequency in patients with Cowden syndromeTumorTumor FrequencyCases count n=109
Table 1: PTEN mutational frequency in patients with Cowden syndromeTumorTumor FrequencyCases count n=109
Table 2
Revised Clinical Diagnostic Criteria for Cowden syndrome
Table 2: Revised Clinical Diagnostic Criteria for Cowden syndrome
Figure 1
Clinical aspects of intestinal polyps in a patient suffering from Cowden syndrome.
A. Endoscopic aspects of two rectal tumors next to multiple polyps. B. Numerous intestinal polyps at the recto-sigmoid transition.
Figure 1: Clinical aspects of intestinal polyps in a patient suffering from Cowden syndrome.
Figure 2
Meningioma in a patient with Cowden syndrome.
A. Coronal (left), sagittal (middle) and axial (right) gadolinium- enhanced T1-weighted MR images at pre-operative stage. B. contrast enhanced T1-weighted MRi images following neurosurgical intervention. Scale bar represents 4 cm.was performed, and the histopathological examination of the excised tumor tissue showed meningioma WHO° I (Figure 3). Physical examination revealed macrocephaly, multiple facial papules, gingival fibromas, trichilemmomas and acral keratoses. The family history was inconspicuous concerning CS and neurological syndromes.The patient presented clinical signs all indicative for the Cowden syndrome (Table 2). Subsequently, human genetic test detected a novel germline G132F mutation in PTEN gene. This mutation occurs within exon 5, which encodes a portion of the phosphatase domain. Interestingly, the G132F missense mutation has not previously been reported in association with Cowden syndrome.Finally, we summarized 109 cases of CS from the peer-reviewed literature featured in Supplementary Table S1. DISCUSSIONThe main purpose of this paper was to investigate the occurrence of meningiomas in patients with Cowden syndome. A particular attention is paid to the role of PTEN mutation in the complex syndrome-related diseases [10]. In fact follows a PTEN inactivation hyperactivation of the PI3K-Akt signaling pathway in many human tumors, including meningioma. Moreover, PTEN mutations predispose to Cowden syndrome. Our results verified for the first time the hidden association of Cowden syndrome with PTEN mutation and meningiomas.
Figure 2:  Meningioma in a patient with Cowden syndrome.
Figure 3
Histological features of meningioma in Cowden syndrome.
A. Histologic examination presented a meningioma characterized by onion bulb formations (→) and psamomma bodies (►) which both are characteristics for meningioma histopathology. B. Immunocytological confirmation of meningioma tumor by Mib1/Ki67 staining. Note the positive cells (brown dye) next to psamomma body. C. Immunopositivity was detected for EMA. D. Immunopositive Vimentin stained cells are detecable. Scale bar represents 20 μm.magnetic resonance imaging (MRI) can dramatically improve the diagnostic ability of this type of tumor. Early diagnosis and close monitoring of patients with Cowden syndrome is important in view of the malignancies associated with this rare disease. Considering that 20% of Cowden syndrome patients tend to develop brain tumors (Figure 4), further investigations on the relation between Cowden syndrome, PTEN mutation, and meningiomas is warranted. The presented data from our cohort investigation give good evidence to include brain tumor monitoring to the criteria of the International Cowden Consortium and screening recommendations of the National Comprehensive Cancer Network (Table 2). Thus we propose to consider meningiomas in patients with CS and other PTEN-related diseases such as PTEN Hamartoma tumor syndrome. MATERIALS AND METHODSA systematic review of published results was performed by the authors using PubMed (http://www.ncbi.nlm.nih.gov/pubmed). The search terms used were Cowden syndrome, Cowden disease, multiple hamartoma
Figure 3:  Histological features of meningioma in Cowden syndrome.
Figure 4
Lifetime risk of selected tumors in Cowden syndrome.
Summary of 109 reported cases diagnosed with Cowden syndrome. Patients suffering from Cowden syndrome, a rare inherited disease characterized in part by benign neoplasia growth throughout the body, are at high risk of several tumors, including breast cancer (37% lifetime risk), brain tumor (20% lifetime risk), thyroid cancer (14% lifetime risk), and endometrial cancer (10% lifetime risk).
Figure 4:  Lifetime risk of selected tumors in Cowden syndrome.
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