86 Letters to the Editor / Annales d’Endocrinologie 79 (2017) 82–90
FT4 > 7.77 ng/dL [0.93–1.7]; TT3 > 6.51 ng/mL [0.8–2]), in the
absence of L-thyroxine substitution., Finally, it was found that
the patient was taking biotin each morning (30 mg/day). After
24 hours discontinuation of biotin, thyroid function tests showed
a slightly elevated TSH level (6.48 mcUI/mL) and normal FT4,
in line with the initial diagnosis of subclinical hypothyroidism.
L-thyroxine treatment was resumed.
In our case, initial suspicion was not Graves’ disease due
to the negative result of TRAbs which directed the diagnostic
study to other causes of thyrotoxicosis. TRAbs were measured
by radioimmunoassay which does not interfere with the pres-
ence of biotin in the plasma sample. On the other hand, TSH
was measured by a one-step sandwich electrochemilumines-
cence assay (ECLIA) and FT4 and TT3 were measured by a
two-step competitive assay ECLIA in a Cobas e601 analyser
(Roche Diagnostics), in which biotin is interfering [3].
Tc99m pertechnetate uptake is relevant in the diagnostic pro-
cess of thyrotoxicosis, especially when the diagnosis is not
initially apparent [4]. In our patient, the almost total absence
of uptake was initially attributed to painless thyroiditis, but
according to the final diagnosis, it was found to be related to
L-thyroxine treatment in the context of subclinical autoimmune
hypothyroidism [5]. Therapeutic decisions and clinical outcome
are probably more relevant in some published cases than in ours
[6], although in all of them, the misdiagnosis can lead to unex-
pected hypothyroidism, unnecessary clinical explorations, and
finally to increase in health costs, as well as patient and doctor
burden.
In conclusion, clinicians should be aware that biotin inter-
ference could induce a misdiagnosis of painless thyroiditis in a
concrete clinical setting.
Disclosure of interest
The authors declare that they have no competing interest.
References
[1] Lim SK, Pilon A, Guéchot J. Biotin interferes with free thyroid hor-
mone and thyroglobulin, but not TSH measurements using Beckman-Access
immunoassays. Ann Endocrinol (Paris) 2017;78:186–7.
[2] Elston MS, Sehgal S, Du Toit S, Yarndley T, Conaglen JV. Factitious Graves’
disease due to biotin immunoassay interference—a case and review of the
literature. J Clin Endocrinol Metab 2016;101:3251–5.
[3] Wijeratne NG, Doery JC, Lu ZX. Positive and negative interference in
immunoassays following biotin ingestion: a pharmacokinetic study. Pathol-
ogy 2012;44:674–5.
[4] Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al.
2016 American Thyroid Association guidelines for diagnosis and mana-
gement of hyperthyroidism and other causes of thyrotoxicosis. Thyroid
2016;26:1343–421.
[5] Ramos CD, Zantut-Wittmann DE, Tambascia MA, Assumpção L, Etchebe-
here EC, Camargo EE. Thyroid suppression test with L-thyroxine and
[99mTc] pertechnetate. Clin Endocrinol (Oxf) 2000;52:471–7.
[6] Kummer S, Hermsen D, Distelmaier F. Biotin treatment mimicking Graves’
disease. N Engl J Med 2016;18:375 [704–6].
Camilo Silva Froján ∗
María Llavero Valero
Department of Endocrinology and Nutrition, Clinica
Universidad de Navarra, Avda. Pío XII 36, 31008 Pamplona,
Spain
Nerea Varo Cenarruzabeitia
Department of Clinical Chemistry, Clinica Universidad de
Navarra, Avda. Pío XII 36, 31008 Pamplona, Spain
Javier Salvador Rodríguez
Department of Endocrinology and Nutrition, Clinica
Universidad de Navarra, Avda. Pío XII 36, 31008 Pamplona,
Spain
∗ Corresponding
author.
E-mail address: csilvafr@unav.es (C. Silva Froján)
https://doi.org/10.1016/j.ando.2017.09.001
Prostate adenocarcinoma in a young patient with
multiple endocrine neoplasia 2B
Adénocarcinome de la prostate chez un jeune patient atteint de
néoplasie endocrine multiple 2B
Keywords: Prostate; Adenocarcinoma; Medullary thyroid carcinoma; Multiple
endocrine neoplasia; RET
Mots clés : Prostate ; Adénocarcinome ; Cancer médullaire de la thyroïde ;
Neoplasie endocrine multiple ; RET
1. Case presentation
A 20-year-old patient underwent total thyroidectomy with
lymph node dissection in 1989 for medullary thyroid carcinoma
(MTC) with lymph node metastases at diagnosis. Postoperative
calcitonin levels were persistently elevated (158 pg/mL). Four
years later, he was operated for bilateral pheochromocytoma
and abdominal paraganglioma. Genetic analysis confirmed an
activating point mutation on the codon 918 of the Rearranged
in Transfection (RET) proto-oncogene, affecting the tyrosine
kinase domain. In 2004, he suffered from a cutaneous neu-
rofibroma of the lower lip and from a megacolon. Periodic
workup with computed tomography, MRI, PET scan, bone scan
and Octreoscan identified no secondary localizations. Calcitonin
and carcinoembryonic antigen (CEA) levels increased progres-
sively until 2009, when the patient presented with persistent
dysuria and chronic abdomino pelvic pain irradiating to the
groin, and weight loss. Computed tomography detected a het-
erogeneously enlarged prostate. He was operated in 2009 by
radical prostatectomy with bilateral iliac LN dissection, and
removal of the bladder mass. The histopathological examina-
tion identified 3 lesions of prostate acinus adenocarcinoma with
Gleason score of 7 (3 + 4) (pT2aN0Mx). These lesions were
positive for P504S (AMACR) and PSA (Fig. 1 A/B/C), and
negative for the endocrine markers: anti-CD56, anti-calcitonin,
anti-synaptophysin and anti-chromogranin A on immunostain-
ing. A neuroendocrine mass was also identified with intense
positive immuno staining to calcitonin (Fig. 1 D/E), CD56, and
synaptophysin and negative for prostate specific antigen (PSA).
 Letters to the Editor / Annales d’Endocrinologie 79 (2017) 82–90 87

Fig. 1. Identification of the adenocarcinoma and the metastatic loci of medullary thyroid carcinoma in the prostate. A. Haematoxylin/eosin coloration of prostate section
showing multiple lesions of acinus prostate carcinoma (arrow heads), with its magnification (right side). B. P63-Racemase (AMACR) double immunostaining on the
prostate section. P63 (arrows) marked the normal basal epithelium, Racemase (arrow heads) marked the cytoplasm of multiple acinus adenocarcinoma without P63
staining, indicating the loss of the basal cells in the tumor acini. C. PSA positive immunostaining on the prostate adenocarcinoma. D. Haematoxylin/eosin coloration
of prostate sections showing lesions with neuroendocrine characteristics (arrow heads). E. Calcitonin positive immunostaining on the prostate neuroendocrine lesion.
Antibodies: PSA: DAKO Polyclonal Rabbit Antibody (ref. A 0562); P504S: DAKO Monoclonal Rabbitt anti Human AMACR, clone 13H4 – Ref. IR060; P63:
BIOCARE MEDICAL, Monoclonal antibody (Ref. PM 163 AA); Calcitonin Antibody: DAKO Polyclonal Rabbit antibody (Ref. IS 515).

The histopathology of the bladder lesion was identical to the 2. Discussion

neuroendocrine lesion of the prostate with the same immuno
staining profile. The intra-prostatic seminal vesicle and peripro-
static adipose tissue was also invaded by the neuroendocrine
tumor. Postoperatively, PSA levels were undetectable and serum
calcitonin declined from 233 to 65 pg/mL. No adjuvant treatment
was introduced for the prostate cancer.
Unfortunately, pelvic, lumbar and femoral metastases
appeared two years later, with calcitonin levels ele-
vated to 717 pg/mL, associated with humoral hypercalcemia
(2.97 mmol/L) secondary to the metastatic lesions, while PSA
was undetectable. Sunitinib, a tyrosine kinase inhibitor was
started, calcitonin levels reduced to 346 pg/mL with this treat-
ment.
Multiple Endocrine Neoplasia type 2 (MEN2A and B) are
rare multi-tumor syndromes arising from germline activating
mutations in Rearranged in Transfection (RET) proto-oncogene.
RET proto-oncogene encodes a protein belonging to the tyrosine
kinase receptor family. This gene has been mapped to chromo-
some 10q11.2 [1]. RET proto-oncogene (germline and somatic)
missense mutations are responsible for constitutive activation
(gain of function) of a tyrosine kinase protein resulting in cell
proliferation and tumorigenesis. It is transmitted in an auto-
somal dominant pattern. Multiple endocrine neoplasia 2B is
characterized by an association of MTC, pheochromocytoma,
marfanoid features, and ganglioneuroma. It is the most aggres-
88 Letters to the Editor / Annales d’Endocrinologie 79 (2017) 82–90
sive form of RET gene activation syndromes with earlier MTC
appearance with usually metastatic disease at diagnosis, affect-
ing the prognosis of these patients [2]. Distant metastases are
the major determinants of survival of patients with MTC with
10-year survival achieved only in 20% of patients [3].
The prostate gland contains epithelial and neuroendocrine
cells, and expresses RET [4]. In our patient, the early occur-
rence of an aggressive multifocal adenocarcinoma suggests an
involvement of RET mutation in prostate carcinogenesis.
Two literature evidences suggest prostate potential involve-
ment in multiple endocrine neoplasia type 2. Firstly, allelic
loss on chromosome 10 has been reported in prostate cancer,
but none has been directly associated with the RET locus [5].
Moreover, Dawson et al. confirmed RET proto-oncogene expres-
sion in benign prostatic epithelium, prostatic intraepithelial
neoplasia (PIN) and prostate adenocarcinoma samples. RET
appeared to be overexpressed in high-grade prostatic intraep-
ithelial neoplasia and prostate cancer when compared with its
expression levels in benign prostate epithelium [4]. In addi-
tion, there was an apparent increase in RET protein expression
with decreased cellular differentiation, i.e., increasing Gleason
pattern [4]. In one patient, a metastatic prostate cancer with
immunohistochemical positive staining for anti-RET antibody
was described in an autopsy, suggesting a potential link to multi-
ple endocrine neoplasia type 2 [6]. One of possible explanations
for RET mutation role in the prostate carcinogenesis is the con-
stitutive PI3K/AKT pathway activation; indeed, AKT activation
and/or PTEN (inhibitor of PI3K/AKT pathway) invalidation
were described to be associated with prostate carcinogenesis
by alteration of proliferation/apoptosis balance of the prostate
epithelium [7].
Secondly, the neuroendocrine differentiation of prostate car-
cinoma could be a supplementary argument for the potential
involvement of the prostate gland in the context of multi-
ple endocrine neoplasia. Neuroendocrine cells are present in
relatively large numbers in the prostate. Almost all adeno-
carcinomas of the prostate contain isolated neuroendocrine
cells. Neuroendocrine differentiation occurs commonly as focal
neuroendocrine differentiation in a conventional prostatic ade-
nocarcinoma, which is a frequent if not ubiquitous phenomenon,
particularly in patients with distant metastases [8]. The neu-
roendocrine cells in adenocarcinoma seem to develop from
atypical secretory tumor cells and are able to express the
endocrine markers (serotonin, calcitonin, somatostatin, chromo-
granin A, CD56) and PSA [9]. Furthermore, transdifferentiation
of prostate epithelial cancers to neuroendocrine prostate cancers
(NEPC) is also described in the literature, whether spon-
taneously or under influence of androgen receptor pathway
inhibitors (treatment-induced neuroendocrine prostate cancer or
t-NEPC) [10–13]. Such tumors will acquire small cell carcinoma
characteristics (aggressive variant prostate cancer or AVPC)
and become less dependent on androgens [14]. This differenti-
ation is usually associated with increased tumor aggressiveness
and poor prognosis; the tumors become castration- or andro-
gen deprivation- resistant and more prone for metastases
[15,16]. Indeed, PI3K/AKT pathway alterations are emerging
aberrations that are implicated in the neuroendocrine transdif-
ferentiation, explaining the role of RET proto-oncogene in this
process, and opening the way for tyrosine kinase inhibitors in
the treatment such tumors [17].
Despite these arguments supporting a close relationship of
prostate cancer to the RET mutations, to-date, no prostate can-
cers were described in patients with such mutations. Prostate
involvement would affect patients’ prognosis from one side
and opens new perspectives to understand the molecular phys-
iopathology of the prostate cancer on the other side. Shorter life
expectancy in multiple endocrine neoplasia type 2B may explain
the absence of cases reported in the literature.
The other particularity of this case is the discovery of a neu-
roendocrine tumor in the prostate. To date, two publications
described a neuroendocrine tumor of the prostate in patients
with multiple endocrine neoplasia type 2 [18,19]. In both pub-
lications, the diagnosis of a primitive neuroendocrine tumor of
the prostate was done in the first and second decades of life. On
the second report, Goulet-Salmon et al. described two cases of
genetically confirmed multiple endocrine neoplasia type 2B with
prostate neuroendocrine carcinoma [18]. Indeed, the dilemma is
in distinguishing between the primitive neuroendocrine tumor
of the prostate and a metastatic localisation of the MTC. Actu-
ally, metastases from MTC to the urinary tract have never been
documented. Immunostaining is supposed helpful to differenti-
ate a primitive prostate from a secondary lesion. PSA, PAP and
racemase (AMACR) or P504S proteins are expressed in both
adenocarcinoma and the primitive neuroendocrine tumor of the
prostate, but theoretically not in the metastatic lesion [20]. In
our case, the epithelial cancer and the neuroendocrine tumor are
quite distinct and well separated lesions in the prostate, and the
calcitonin and carcinoembryonic antigen levels fell after rad-
ical prostatectomy. Furthermore, concomitant invasion of the
prostate and the urinary bladder by the neuroendocrine lesion,
and the younger age of the patient are in favor of a metastatic
MTC rather than a primitive lesion.
In summary, this is the first prostate adenocarcinoma in a
20-year-old patient with multiple endocrine neoplasia type 2B.
This case highlights the potential role of RET proto-oncogene
activation in prostate carcinogenesis. Analysis of larger series
for the risk of prostate cancer in multiple endocrine neopla-
sia type 2 syndrome would confirm whether RET mutations
induce prostate epithelial carcinogenesis and/or aggressiveness.
On the other side, persistent urinary symptoms in patients with
RET mutations should alert the clinician for a possible neuroen-
docrine localization in the prostate (primary NET or metastatic
MTC) or in the juxta-vesical region (paraganglioma).
Disclosure of interest
The authors declare that they have no competing interest.
References
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tumors. Thyroid 2005;15:531–44.
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Cancer Res 1996;56:2143–7.
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[7] Pommier AJC, Alves G, Viennois E, Bernard S, Communal Y, Sion B,
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Salwan Maqdasy a,b,∗
Nicole Costes-Chalret c
Marie Batisse-Lignier a,b
Silvère Baron b
Igor Tauveron a,b
89
a
Service d’endocrinologie, diabétologie et maladies
métaboliques, CHU Clermont-Ferrand, 58, rue Montalembert,
63003 Clermont-Ferrand, France
b UMR CNRS 6293, Inserm U1103, département génétique
reproduction et développement, université Clermont-Auvergne,
BP 10448, 63177 Aubiere, France
c Service d’anatomopathologie, CHU Clermont-Ferrand,
63003 Clermont-Ferrand, France
∗ Corresponding author. Service d’endocrinologie, diabétologie
et maladies métaboliques, CHU Clermont-Ferrand, 58, rue
Montalembert, 63003 Clermont-Ferrand, France.
E-mail address: smaqdasy@chu-clermontferrand.fr
(S. Maqdasy)
https://doi.org/10.1016/j.ando.2017.09.002
J. Vouillarmet et al. in response to V. Aboyans et al.
concerning the article by M. Helfre et al.: Usefulness
of a systematic screening of carotid atherosclero-
sis in asymptomatic people with type 2 diabetes for
cardiovascular risk reclassification. Ann Endocrinol
(Paris). 2017;78:14–19
J. Vouillarmet et al. en réponse à V. Aboyans et al. concernant
l’article de M. Helfre et al. : utilité du dépistage systématique
de l’athérosclérose carotidienne chez les sujets diabétiques de
type 2 asymptomatiques pour le reclassement du risque cardio-
vasculaire. Ann Endocrinol (Paris). 2017;78:14–19
We thank Aboyans et al. for their interest in our work [1]
and for their important comment concerning what they call
the “aspirin reflex”. The usual prescription by physicians of
antiplatelet agents in primary cardiovascular (CV) prevention,
notably in patients with carotid atherosclerosis was supported
by most guidelines. Even nowadays, although the last European
guidelines no longer support the systematic use of antiplatelet
agents in primary CV prevention [2,3], some still consider
aspirin therapy (75–162 mg/day) not only for patients in sec-
ondary CV prevention but also as a primary prevention strategy
in type 1 or type 2 diabetic patients with an estimated 10-year
CV risk above 10% [4,5]. The evidence base is low (grade C)
and the indication must be balanced with the risk of bleeding.
A recent meta-analysis has concluded that for a 10-year risk
of CV events greater than 10%, the absolute CV benefit could
potentially outweigh the bleeding risks [6]. This meta-analysis
included two studies concerning only diabetic patients [7,8] in
which any benefits could be evidenced. However, two studies in
this specific population are ongoing (ASCEND, NCT00135226;
ACCEPT-D, ISRCTN48110081) and the question is still open.
Importantly, discontinuation of aspirin in chronically treated
patients could be harmful, as suggested by a recent Swedish
nationwide cohort study that found that in patients without major
bleeding this led to an increased risk of CV events [9]. For the
46% of patients who were on aspirin for primary CV prevention,
discontinuing aspirin was associated to a 28% higher rate of CV
events when compared with patients who were continuingaspirin
along a 3.0 years of follow-up.