Monday, October 27, 2014

Peutz-Jeghers syndrome and thyroid problems - benign and malignant

I first posted this to the PJS Online Support Group in May 2001 and updated it in 2014. There are two addenda - first is my correspondence with Dr. Stratakis of the NIH, the second from 2014 is a list of five abstracts about PJS & thyroid cancer. - healing wishes, Stephanie

Dear PJS friends;

This report is on the PJS/thyroid connection. For our newcomers, I've written several pieces on PJS from a patient's view. Some topics include: sex cord tumors, bowel preparations, a review of the article Very High Risk of Cancer in Familial PJS, (7) , etc. Please remember these pieces are not medical
advice, but reviews of the literature that you can take to your doctor. Some of you may want to have your thyroids screened, others with thyroid troubles may be surprised by the PJS connection.

This topic was introduced in 2000 by two group members, who both visited Dr. Stratakis at the NIH in Bethesda, Maryland. Dr. Stratakis is an endocrinologist who works primarily on Carney Complex. His study (1) is open to people with PJS. One member wrote her thyroid tumors were found during her study participation. The other member wrote to us on September 4, 2000:
"The doctor gave me a couple of his articles.   His latest, from 'Frontiers in Bioscience', discusses the overlap between disorders associated with multiple tumors and pigmentation defects.   Among the non- GI neoplasms associated with PJ, endocrine tumors including thyroid cancer and ovarian and Sertoli cell tumors are the most frequent.   My surgeon at home was unaware of any thyroid association with PJ.   When I needed bloodwork for my surgery in May, I asked to get my thyroid level checked.   All came back normal.   But, Dr. Stratakis told me that it is not sufficient to just get bloodwork.   You also need a thyroid ultrasound.   He said that there is an especially aggressive form of thyroid cancer associated with PJ."

The full article from Frontiers in Bioscience is available online. (2)

The news of potential thyroid cancer & screening for people with PJS was particularly startling since none of the screening guidelines from other doctors include the thyroid. (3) I read Dr. Stratakis' article which included the following quote, "Among the nongastrointestinal neoplasms associated with
PJS, endocrine tumors including thyroid cancer and ovarian and Sertoli cell tumors are the most frequent." He referenced three articles (4-6), but when I read the articles, I found only one mention of thyroid cancer or tumors. My correspondence with Dr. Stratakis of the NIH follows in addendum I.

Dr. Giardiello in his article, Very High Risk of Cancer In Familial PJS, (7) showed no increased risk of thyroid cancer in PJS and doesn't even include it in his tables. I have to wonder what Dr. Stratakis knows that we don't know. If he sees an increased risk for thyroid cancer, it might be as a result of
his studies or one-to-one communications with other doctors. Now that I have a large collection of PJS articles, I combed them for reports of thyroid tumors, malignant & benign, in people with PJS. You will see from my table, that there are reports of thyroid tumors in PJS folks.

The most common type of thyroid cancer in PJS folks and the general population is papillary carcinoma. A search at Cancer Net revealed that thyroid papillary adenocarcinoma is a differentiated cancer that is highly treatable and curable. (14) So Dr. Stratakis' comment on an aggressive thyroid cancer associated with PJS isn't substantiated from my readings of the literature. (Please see the addenda below for more up-to-date details).

Though I did find cases of PJS folks with thyroid problems, but I have no idea if these findings are significant. Since thyroid problems are fairly common in the general population, there may not be a connection to PJS. Hopefully time and further investigations will tell whether there's a PJS/thyroid connection.

Warmest regards to all,
Stephanie Sugars
Peutz-Jeghers syndrome
Mailing list manager & contact


Author, publication date, reference patient gender & age     diagnosis

Spigelman, 1989 , (6)                    f30                      thyroid

Burdick & Prior, 1981, (8)               f61                      thyroid
colloid nodule & Hashimoto's thyroiditis

Yamamoto M, 1992, (9)                f29                      Thyroid

Reed MW, 1990, (10)                                          papillary
carcinoma of the thyroid.

Boardman LA, 1998 (11)               33                       Thryoid cancer

Srivatsa, PJ, 1994    (12)                f91                      Grade 1
metastatic papillary cystic adenocarcinoma of thyroid with squamous
2 months after first operation (patient was 91 years old and in good health
at time of article)

Srivatsa, PJ, 1994    (12)                f21                  Graves'
subtotal thyroidectomy

Srivatsa, PJ, 1994    (12)                f40                  Adenomatous

Srivatsa, PJ, 1994    (12)                f32                  Colloid
of thyroid with small area of papillary carcinoma

Dormandy, TL, 1957 (13)              f60                  nodular goiter

Dormandy, TL, 1957 (13)              m 52                 nodular goiter


(1) Definition of the Genotype and Clinical Phenotype of Primary Pigmented Nodular Adrenocortical Disease and its Associated Conditions (Carney Complex) Study # 95-CH-0059. The study includes a complete physical examination with genetic testing. Contact Meg Keil at 301-496-4686.

(2) From Genetics of Carney Complex and Related Familial Lentiginoses and Other Multiple Tumor Syndromes

By Contsantine A. Stratakis

(3) Please search our archives for screening guidelines.

(4) Giardiello, F. M.; Welsh, S. B.; Hamilton, S. R.; Offerhaus, G. J. A.; Gittelsohn, A. M.; Booker, S. V.; Krush, A. J.; Yardley, J. H.; Luk, G. D. : 
Increased risk of cancer in the Peutz-Jeghers syndrome. 
New Eng. J. Med. 316: 1511-1514, 1987. PubMed ID : 3587280

(5) Hizawa, K.Iida, M., Matsumoto, T., Kohrogi, N., H. Kinoshita & T. Yao: 
Cancer in Peutz-Jeghers Syndrome. 
Cancer November 1, 1993, Volume 72, No. 9.

(6)   Spigelman, A. D.; Murday, V.; Phillips, R. K. S. : 
Cancer and the Peutz-Jeghers syndrome. 
Gut 30: 1588-1590, 1989.
PubMed ID : 2599445

(7) Giardiello, Francis, et al.: 
Very High Risk of Cancer in Familial Peutz-Jeghers Syndrome. Gastroenterology 2000;119:1447-1453.

8)   Burdick, D.; Prior, J. T. : 
Peutz-Jeghers syndrome: a clinicopathologic study of a large family with a 27-year follow-up. 
Cancer 50: 2139-2146, 1982.
PubMed ID : 7127254

(9) Yamamoto M, Hoshino H, Onizuka T, Ichikawa M, Kawakubo A, Hayakawa S.:
Thyroid papillary adenocarcinoma in a woman with Peutz-Jeghers syndrome.
Intern Med 1992 Sep;31(9):1117-9
PMID: 1421720

(10) Reed MW, Harris SC, Quayle AR, Talbot CH.: 
The association between
thyroid neoplasia and intestinal polyps. 
Ann R Coll Surg Engl 1990 Nov;72(6):357-9
Department of Surgery, Royal Hallamshire Hospital, Sheffield.
PMID: 2241052

(11) Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart
LJ, Ahlquist DA, Podratz KC, Pittelkow M, Hartmann LC: 
Increased risk for cancer in patients with the Peutz-Jeghers syndrome. 
Ann Intern Med. 1998 Jun
PMID: 9634427

(12) Srivatsa, PJ et al.: 
Disseminated Cervical Adenoma Malignum and Bilateral Ovarian Sex Cord Tumors with Annular Tubules Associated with Peutz-Jeghers syndrome. 
Gynecological Oncology 53, 256-264 (1994).
(13) Dormandy, Thomas L.: G
astrointestinal Polyposis with Mucocutaneous Pigmentation (Peutz-Jeghers syndrome). New England Journal of Medicine, 1957 June 13; 1141-1146.

(14)   Cancernet for Thyroid Cancer,

Addendum I

2002 - from Dr. Stratakis of the NIH

Dear Ms. Sugars,

I might have missed your first e-mail on the subject.

The association of thyroid tumors with PJS is emerging in the literature - I agree with you that it is hard to substantiate it now with good studies, though. Neverthless, there is evidence out there and you have cited it (Dr. Boardman's paper and others). There is also a report that we have published
that is not available on line-not yet anyway (to a journal that my department edits):

-Pathomvanich A, Koch C, C.A. Stratakis.   Thyroid abnormalities in Peutz-Jeghers syndrome: Report of new observation and review of the literature. J Endocr Genet 1:47-49, 1999.

In any case, our observations are that at least 3 of our pediatric patients with PJS have multiple hypoechoic thyroid mini-nodules. This is interesting, because patients with CNC also get the same lesions at a pediatric age (although at a higher frequency). As you know, CNC and PJS share a  number of manifestations, which is why we started doing thyroid US on pediatric
patients with PJS.

Now the issue of aggressiveness; although you are right to say that, in general, thyroid tumors are not aggressive, those associated with hereditary conditions tend to be more aggressive than usual. I have confirmed this with discussion with thyroid pathologists but one nice paper talking about the aggressive features of thyroid cancer associated with a hereditary condition (in that case, it was FAP), is the following:

Harach HR et al. Histopathology 25:549-561, 1994.

Although clearly more studies need to be done, and this is why we continue our PJS study, my (final for now) word on the subject is that, from our (few) clinical observations on PJS and our experience on CNC, as well as the reports of thyroid cancer in patients with PJS, there seems to be a connection between the two: although thyroid cancer may not be a diagnostic component of PJS, patients with PJS may be predisposed to thyroid cancer, just like they are predisposed to get other cancers, which are not part of their original syndrome. We recommend that a thyroid US is performed at the initial diagnostic evaluation of a patient with PJS; f/up studies may be obtained as necessary. Biochemical studies (blood thyroid function tests) do not substitute US, because these small nodules are non-functional.

I hope I cleared the issue, a little bit, anyway.

Sincerely yours,

Constantine A. Stratakis, MD
Unit on Genetics & Endocrinology (UGEN)
Developmental Endocrinology Branch (DEB), NICHD, NIH
Building 10, Room 10N262, 10 Center Drive, MSC 1862
Bethesda, MD 20892-1862, USA

Tel. 301-4964686/402-1998, Fax 301-4020574


From: []
Sent: Wednesday, May 16, 2001 5:57 PM
To: Stratakis, Constantine (NICHD)
Subject: PJS and thryroid
Dear Dr. Stratakis;

Thank you for your quick and thorough response to my questions about PJS and thyroid problems. I've since read the abstract of Harach's article and several text book entries on the thyroid. Is it possible to have hypoechoic thyroid mini-nodules and be asymptomatic for thyroid problems? To have both
clear blood tests and a healthy functioning thyroid? Or do the mini-nodules cause either hypo or hyper thyroidism? Or perhaps other difficulties?

I noticed that in general females are more likely than males to have thyroid problems, it's thought because of hormones. Since PJS females are likely to have SCTAT of the ovaries, perhaps the thyroid problems come from this? Most of the PJS patients with thyroid problems that I read about were women, four with adenoma malignum of the uterine cervix.

I appreciate receiving your word on this subject and have passed the information on to our group members.

With Gratitude,
Stephanie Sugars
Peutz-Jeghers syndrome
Mailing list manager & contact
And his reply --


The thryoid nodules are not functional: almost all patients with PJS or CNC have normal thryoid function. No other clinical problems either -of course, with the exception of becoming cancerous about 10% of the time in CNC - I do not know the percentage in PJS. There is no relationship between ovarian and thyroid lesions in PJS or in CNC.


Constantine A. Stratakis, MD

Unit on Genetics & Endocrinology (UGEN)
Developmental Endocrinology Branch (DEB), NICHD, NIH
Building 10, Room 10N262, 10 Center Drive, MSC 1862
Bethesda, MD 20892-1862, USA
Tel. 301-4964686/402-1998, Fax 301-4020574



Addendum II
These are case reports of five people with PJS who had cancer in their thyroid. Their ages ranged from 16 months to 58 years. Case #5 didn't have thyroid cancer, but stomach cancer that travelled (metastasized) to his thyroid.

Remember, only odd and interesting case reports are published in medical it's difficult to know whether these are common or unusual manifestations of PJS.

healing hugs,

1. Eur J Gynaecol Oncol. 2011;32(4):452-4.

Endometrial carcinoma and ovarian sex cord tumor with annular tubules in a patient with history of Peutz-Jeghers syndrome and multiple malignancies.

Kondi-Pafiti A(1), Bakalianou K, Iavazzo C, Dastamani C, Hasiakos D, Liapis A.

Author information: 
(1) Pathology Department, University of Athens, Aretaieion Hospital, Athens, Greece.

Background: Peutz-Jeghers syndrome is a rare syndrome which is inherited in a dominant manner. It is characterized by hamartomatous polyps of the gastrointestinal tract, hyperpigmented macules of the oral mucosa and an increased risk of developing neoplasms in the gastrointestinal tract, pancreas,
breast and genital system. Women with Peutz-Jeughers syndrome often develop an ovarian sex cord tumor and cervical adenocarcinoma of minimal deviation adenoma malignum type. 

A case of a 58-year-old patient with Peutz-Jeghers syndrome and history of multiple malignancies (thyroid, breast and colon cancer) who presented with metrorrhagia is reported. 

The dilatation and curettage revealed endometrial  adenocarcinoma. The patient underwent total abdominal hysterectomy with bilateral oophorectomy. The histologic examination showed an endometrioid endometrial adenocarcinoma that developed in atypical endometrial hyperplasia. The histologic examination of the right ovary revealed a sex cord tumor with annular tubules,
measuring 3 cm. Sex cord tumors with annular tubules in patients with Peutz-Jeghers syndrome are usually small, bilateral tumors of the ovaries which have common characteristics with granulosa cell tumor and Sertoli cell tumor. Hyperestrogenism is a rather common finding with development of
estrogen-dependent lesions.

PMID: 21941977  [PubMed - indexed for MEDLINE]

2. Thyroid. 2011 Nov;21(11):1273-7. doi: 10.1089/thy.2011.0063. Epub 2011 Aug 30.

Papillary thyroid carcinoma in Peutz-Jeghers syndrome.

Triggiani V(1), Guastamacchia E, Renzulli G, Giagulli VA, Tafaro E, Licchelli B,  Resta F, Sabbà C, Bagnulo R, Lastella P, Stella A, Resta N.

Author information: 
(1)Endocrinology and Metabolic Diseases, Aldo Moro University of Bari, Bari, Italy.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare dominantly inherited disease characterized by the association of gastrointestinal hamartomatous polyposis, mucocutaneous hyperpigmentation, and increased risk of cancer at different target organs. Its occurrence with differentiated thyroid cancer, particularly papillary thyroid carcinoma (PTC), even if rare, has been described.

SUMMARY: We here present a case of PTC observed in a PJS patient and a review of  the literature aiming at discussing the utility of thyroid surveillance in the management of these patients. A 22-year-old woman presenting with hyperpigmented  lesions of the lips and hamartomatous polyps in the stomach, duodenum, jejunum, and ileum, leading to the suspicion of PJS, was submitted to genetic analysis. Mutation scanning of the Liver Kinase B1 (LKB1) gene identified the presence of
the truncating mutation E265X, thus confirming the clinical diagnosis. 

Beside the endoscopic, radiologic, and echographic evaluations required by the standard surveillance guidelines, the patient had a neck ultrasound (US), which showed a 5×4×6 mm hypoechoic nodule in the right thyroid lobe. The nodule contained microcalcifications and a perinodular vascular pattern. The cytological preparations derived from US-guided fine-needle aspiration biopsy of the nodule
demonstrated the presence of PTC. The patient underwent a video-assisted total thyroidectomy and the histological examination revealed a follicular variant of papillary microcarcinoma. 

Radioactive iodine therapy was not performed because of the small size of the lesion. The patient was started on levothyroxine therapy to keep the serum thyrotropin levels suppressed. Both the sequencing and the multiplex ligation-dependent probe amplification analysis could not identify any  LKB1 mutation in the tumor specimen, and the methylation-specific polymerase chain reaction assay excluded hypermethylation of the LKB1 promoter as the mechanism of inactivation for the remaining normal allele in the tumor.

CONCLUSIONS: Although other mechanisms of LKB1 silencing may be responsible for its inactivation in the thyroid cancer, we cannot rule out that the occurrence of thyroid carcinoma could be a coincidental finding in this patient. However, the case here presented suggests that US of the thyroid could possibly become an integral part of the evaluation and the follow-up program adopted for PJS

PMID: 21877933  [PubMed - indexed for MEDLINE]

3. J Pediatr Surg. 2011 Mar;46(3):570-3. doi: 10.1016/j.jpedsurg.2011.01.005.

The association of adrenocortical carcinoma and thyroid cancer in a child with Peutz-Jeghers syndrome.

Yalçin S(1), Kirli E, Ciftci AO, Karnak I, Resta N, Bagnulo R, Akçören Z, Orhan
D, Senocak ME.

Author information: 
(1 )Department of Pediatric Surgery, Hacettepe University Faculty of Medicine,
Ankara, Turkey.

Peutz-Jeghers syndrome (PJS) is a rare, dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps, mucocutaneous hyperpigmentation, and an increased risk of cancer. 

We present a 16-month-old child diagnosed with PJS, who had distinguishing features compared with the previously reported cases with respect to her clinical presentation, associated malignancies, and genetic analysis. To our knowledge, this is the first report of adrenocortical carcinoma in association with PJS, as well as the first instance of associated thyroid cancer in a child with PJS. 

We briefly review the relevant  literature and highlight the recent progress achieved in the investigation of the syndrome.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21376213  [PubMed - indexed for MEDLINE]

4. Exp Clin Endocrinol Diabetes. 2009 May;117(5):234-9. doi: 10.1055/s-0028-1102920.
Epub 2009 Feb 20.

Differentiated thyroid carcinoma (DTC) in a young woman with Peutz-Jeghers syndrome: are these two conditions associated?

Zirilli L(1), Benatti P, Romano S, Roncucci L, Rossi G, Diazzi C, Carani C, Ponz 
De Leon M, Rochira V.

Author information: 
(1)Integrated Department of Medicine, Endocrinology and Metabolism, and Geriatrics,  University of Modena and Reggio Emilia, Ospedale S. Agostino-Estense di Baggiovara, Via Giardini 1355, Baggiovara, Modena, Italy.

AIMS: Peutz-Jeghers Syndrome (PJS) is a rare dominantly inherited disease characterized by hamartomatous small bowel polyposis, mucocutaneous hyperpigmentation, and increased risk of cancer. Differentiated thyroid cancers (DTCs) present mainly as sporadic, but they may have also a familial component.

We present a case of PJS in a caucasian 25 years-old woman, who developed a DTC.

METHODS: The patient had a palpable nodule in the right side of the thyroid region and an endocrinological evaluation, including hormonal assays, neck ultrasound (US) and fine needle aspiration (FNAB) of the nodule was performed.

RESULTS: US confirmed a single nodular lesion in the right thyroid lobe (14 mm).  Cytological analysis at FNAB revealed a pattern compatible with papillary thyroid carcinoma. The histological analysis after total thyroidectomy confirmed the diagnosis of a Hurtle cell variant of papillary thyroid carcinoma, with
follicular architecture.

CONCLUSION: Even though rare, the association between PJS and DTC can be possible. In clinical practice it must be borne in mind that the wide spectrum of possible cancer diseases occurring in PJS could also include DTC, that the latter can occur earlier in life in PJS population and with a more aggressive histological pattern. Furthermore, in patients with PJS, US of the thyroid should be performed whenever thyroid disease is suspected at physical examination or based on patient's medical history. Due to lack of established data allowing for  a real esteem of the association between PJS and DTC, US of the thyroid, should not be recommended as a routine screening for all subjects with PJS.

PMID: 19235129  [PubMed - indexed for MEDLINE]

5. BMJ Case Rep. 2009;2009. pii: bcr12.2008.1392. doi: 10.1136/bcr.12.2008.1392.
Epub 2009 Apr 3.

Thyroid swelling in a 32-year-old male.

Pandey M(1), Kumar V, Shukla M, Kumar M.

Author information: 
(1)Institute of Medical Sciences, Surgical Oncology, Banaras Hindu University,
Varanasi, UP, 221005, India.

Patients with intrathyroidal metastasis may present with previous history of malignancy or they may present with a secondary neoplasm prompting us to search for the primary site.

 A 32-year-old male presented with a 4-month history of thyroid swelling and abdomen pain. Fine-needle aspiration cytology from the thyroid swelling revealed deposits from the mucinous  denocarcinoma. The further  diagnostic and metastatic work-up identified a diffuse carcinoma of the stomach as the primary site with liver as secondary and retroperitoneal lymph nodes having mucinous deposits with associated Peutz-Jeghers polyposis. 

This is the first report in the English literature of intrathyroidal metastasis from carcinoma of the stomach with Peutz-Jeghers polyposis presenting primarily as a thyroid swelling. Preoperative diagnosis, proper evaluation and high degree of suspicion may avoid unnecessary thyroidectomy and effective palliation can be achieved with chemotherapy in view of disseminated disease.

PMCID: PMC3028274
PMID: 21686341  [PubMed]

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