Clinical and Experimental Medicine https://doi.org/10.1007/s10238-018-0512-7

REVIEW ARTICLE

Parathyroid carcinoma in multiple endocrine neoplasm type 1 syndrome: case report and systematic literature review Giovanna Di Meo1 · Lucia Ilaria Sgaramella1 · Valentina Ferraro1 · Francesco Paolo Prete2 · Angela Gurrado1 · Mario Testini1  Received: 15 March 2018 / Accepted: 10 June 2018 © Springer International Publishing AG, part of Springer Nature 2018

Abstract The aim of this report was to illustrate a case of parathyroid carcinoma (PC) in a patient with multiple endocrine neoplasia type 1 (MEN1) along with a comprehensive literature review. A 61-year-old man presented with 9-cm PC causing primary hyperparathyroidism (PHPT). His pre-operative corrected calcium and intact PTH serum levels were 2.92 mmol/L and 391.7 pg/mL, respectively. The neoplastic gland was removed in bloc with thyroid and central compartment lymph nodes. A literature review was run by searching PubMed MEDLINE from 1977 to 2018 for studies of all types, in the English language only, using the terms “Parathyroid, carcinoma, Multiple endocrine neoplasia, type 1, (MEN1).” Pathology confirmed PC. Post-operative calcium and PTH levels were normal. A diagnosis of MEN1 was established post-operatively. Seventeen cases of PC in patients with MEN1 have been reported in the literature. 59% of patients were men, and median age at diagnosis was 50 years, with median serum PTH of 379 pg/mL and median serum calcium level of 3.2 mmol/L. The occurrence of PC in the context of MEN1 is extremely rare. Diagnosis and treatment may represent a challenge, so opportune identification or suspicion of malignancy and adoption of correct surgical approach may offer affected patients the best outcome. Keywords  Parathyroid carcinoma · Multiple endocrine neoplasia type 1 · MEN1 · Primary hyperparathyroidism · Cancer · Surgery

* Mario Testini [email protected] Giovanna Di Meo [email protected] Lucia Ilaria Sgaramella [email protected] Valentina Ferraro [email protected] Francesco Paolo Prete [email protected] Angela Gurrado [email protected] 1

Department of Biomedical Sciences and Human Oncology – Unit of Endocrine, Digestive and Emergency Surgery, University “A. Moro” of Bari. Polyclinic of Bari, Piazza Giulio Cesare, 1, 70124 Bari, Italy



Department of Emergency and Organ Transplant, University “A. Moro” of Bari. Polyclinic of Bari, Piazza Giulio Cesare, 1, 70124 Bari, Italy

2



Abbreviations PC Parathyroid cancer PHPT Primary hyperparathyroidism NET Neuroendocrine tumours MEN1 Multiple endocrine neoplasia type 1

Introduction Parathyroid cancer (PC) is an uncommon clinical entity, which occurs equally in males and females at a median age of 45 years and accounts for 0.005% of all cancers and less than 1.0% of primary hyperparathyroidism (PHPT). Overall survival at 5 and 10 years has been 85.5 and 49.1%, respectively [1]. The aetiology of PC is unknown. In sporadic PC previous neck irradiation, evidence of hyperplasia or adenomas of the parathyroid glands, and hyperparathyroidism secondary to chronic renal insufficiency have been associated with increased incidence [1]. PC has also been associated with genetic syndromes as hereditary hyperparathyroidism—jaw tumour syndrome,

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multiple endocrine neoplasia type 2A (MEN 2A), and multiple endocrine neoplasia type 1 (MEN1). MEN1 is a rare autosomal dominant endocrine disorder with a high degree of penetrance and an estimate prevalence of 0.25%; the syndrome affects all age groups, but may also occur sporadically without a family history. PC was found in 0.28–1% of all cases undergoing surgical treatment for PHPT in the context of MEN1 [2]. We report a rare case of a large, partially retrosternal cystic mass adjacent to the left lobe of the thyroid gland that was unexpectedly diagnosed as PC. The patient was later diagnosed as having MEN1 syndrome.

Case description A 62-year-old man with a history of nephrolithiasis, constipation, thalassemia trait, and type 2 diabetes was admitted to our Department of General Surgery with a large asymptomatic, left-sided palpable neck mass. The patient has given written informed consent for his own treatment and for the present publication, according to the national and international ethical regulations. He had hypercalcemia (2.92 mmol/L), high levels of PTH (391.7 pg/mL), and polyuria. US colour Doppler showed a multinodular thyroid and a large, partially retrosternal cystic mass adjacent to the left lobe of the thyroid gland. CT scan confirmed the extension of the lesion, 9 cm in diameter, into the upper mediastinum (Fig. 1). FNA cytology clearly demonstrated a parathyroid neoplasm, and therefore, a PTH assay was not performed. The parathyroid mass was surgically excised en bloc with the thyroid gland and central lymph node compartment of the neck (Fig. 2). In our surgical team, the use of nerve-monitoring system is pre-operatively planned only for selected cases, as redo surgery, and hence it was not used during this surgical procedure. However, a careful dissection was performed by microsurgical technique (loupe magnification 3×) as strong adhesions between the mass, pre-thyroid muscles, left recurrent laryngeal nerve, and oesophagus were found. Intraoperative endoscopy showed

Fig. 2  Parathyroid gland surgically excised in bloc with the thyroid gland

integrity of the oesophagus without macroscopic infiltration. During bilateral neck exploration, the ipsilateral parathyroid gland appeared enlarged, and therefore, it was removed, while both the contralateral glands were macroscopically normal. Pathology confirmed PC without thyroid invasion or lymphatic metastases, while the other excised parathyroid gland showed nodular hyperplasia. No CDC73 gene mutation or deletion was detected, while positivity for parafibromin nuclear expression was found. Post-operative time was uneventful, unless the transient hypocalcemia the patient experienced during the first post-operative month treated with oral calcium and vitamin D supplements. In the meantime the patient’s brother, who had a history of kidney stones too, was found to have biochemical evidence of HPTH and was surgically treated in another hospital. The histology revealed PC, and an hereditary disease was suspected with the evidence of a germline mutation of the MEN1 gene (c.1252 G > A). Genetic test was suggested to patient’s relatives at risk, identifying the MEN1 mutation in two of them. The patient was evaluated for MEN1-related lesions. MRI of the head showed no pituitary lesions, while GI endoscopic US scan identified pancreatic lesions compatible with neuroendocrine tumours (NET), and CT scan with blood tests showed a non-functioning adrenal nodule. At 4-year follow-up, the patient is free from recurrence and shows normal calcaemia.

Methods Fig. 1  CT scan showed the extension of the lesion, 9 cm in diameter, into the upper mediastinum

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A systematic literature review was performed by searching PubMed MEDLINE from January 1977 to January 2018 for studies of all types reporting on PC in MEN1, using the

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terms “Parathyroid, carcinoma, Multiple Endocrine Neoplasia, type 1, (MEN1).” The search returned 592 publications in the English language only. A total of 581 publications were excluded as not relevant to search criteria (122 publications focused on parathyroid disease only, 118 were based on genetic features and 73 on general aspects of MEN, 112 on other diseases associated with MEN, 48 on hyperparathyroidism associated with MEN, 19 on treatment of MEN and 89 were not inherent to our research). A total of 11 publications were reviewed, and further 2 articles were found by manually searching references of retrieved articles. The full texts of 13 articles were assessed for eligibility. Table 1 summarizes all cases of PC occurring in MEN1 as reported in the retrieved literature. It categorized the details of review such as demographics data, symptomatology, aetiology, diagnosis, biochemical findings, tumour size, treatment, histopathologic features, genetic testing, and follow-up for each papers.

Results and discussion MEN1 is characterized by inactivating mutations of the MEN1 gene, which codes for the nuclear transcription factor MENIN. The originally described classical “P-triad” of MEN1 corresponds to parathyroid, pituitary, and pancreatic neuroendocrine tumours. PHPT is the main endocrinopathy associated with MEN1 (> 90%) and is typically the first endocrine manifestation, while the incidence of PC as the cause of PHPT in MEN1 is among the 0.28–1% [2]. We report herein a case of such uncommon association between PC and MEN1. The association between PC and MEN1 has been described in only 17 cases in the literature. All patients’ characteristics are summarized in Table 1 [3–14]. In this review, 59% of patients were men, with a median age of presentation of 50 years, almost as in sporadic cases. On the other hand, it is notable that PHPT diagnosis in MEN1 patients usually occurs by the age of 20 years, consequently arousing suspicion about long-lasting undiagnosed PHPT in MEN1 patients as a risk factor for PC. Meanwhile, an association of PHPT caused by either PA or hyperplastic PT glands and sporadic PC has been reported, occurring either synchronously or metachronously [15–17]. No evidence of sporadic PC arising from malignant transformation of pre-existing PT lesions, however, has been found [18], and, to the best of our knowledge, neither has been between PHPT in MEN1 patients and PC. As a matter of fact, because of its rarity, an actual correlation between them is not easy to establish. The Schantz and Castleman criteria, established in 1973, are the most commonly used and are based on the presence

of parenchymal mitoses, a lobular pattern of cell growth separated by thick fibrous bands and capsular or vascular invasion [18]. Even though capsular invasion remains the most specific marker of PC, it should be distinguished from “pseudoinvasion” (degeneration and subsequent fibrosis and “trapping” of tumour cells within the capsule) which may also occur in large PAs. Thus, different criteria of vascular invasion have been defined, according to whether capsular vessels or vessels in the surrounding tissues are involved and/or attachment of neoplastic cells to blood vessel wall or thrombosis are present [19, 20]. Ultimately, diagnostic accuracy is challenging even for the most experienced pathologists. In all cases we reviewed, authors stated that histological diagnosis had been made according to Schantz and Castleman criteria, confirming PC in all cases described. PC poses a diagnostic challenge also clinically due to the lack of features to definitely distinguish malignant from benign disease early in its clinical course. Symptoms such as lethargy, depression, anorexia, constipation, nausea, vomiting, weight loss, nephrolithiasis, kidney stones, hypercalciuria, dehydration, and hypertension are largely common to all causes of hypercalcaemia, while patients presenting with manifestations of parathyroid bone disease as osteitis fibrosacystica, subperiosteal bone resorption, “salt-and-pepper” skull, absence of lamina dura, diffuse osteopenia, osteoporosis, bone pain, and pathological fracture should arise suspicion of PC. Physical examination is commonly unrevealing, but the finding of a palpable cervical mass and laryngeal nerve palsy in the context of PHPT may lead to suspicion of PC. As reported in Table 1, in the cases reviewed, symptoms are largely attributable to hypercalcemia, and none of them reported neck swelling or voice changes. Moreover, PTH levels in PC are typically 5–10 times higher than the upper range of normal—while benign disease usually shows a more modest increase—such values should prompt the clinician to suspect the presence of PC. Similarly, it has been reported that calcium levels in carcinoma are typically above 3.49 mmol/L versus under 2.79 mmol/L in benign parathyroid disease [1]. Reported studies of PC in MEN1 patients demonstrate a median PTH of 379 pg/mL and a median serum calcium level of 3.2 mmol/L [2]. As a result, the malignant character of these tumours can be difficult to diagnose pre-operatively. Because of this, it is very important for every endocrine surgeon to be aware of the common intraoperative appearance of PC. It usually looks lobulated, grayish-white with occasional necrosis, stony-hard, often adherent to surrounding tissues, while adenomas are smaller, soft, round, and red-brown in colour [21]. However, PC is often not conclusively identified even during the operation. Indeed, the diagnosis of PC based upon morphologic criteria may be difficult at surgery too, unless gross local invasion and/or metastases are present. Among the PC cases of this reported series,

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Table 1  Published cases of PC in MEN1 Case No. References

Sex Age Symptoms/preop. diagnosis

Other MEN1Serum related diseases Calcium (mmol/L)

PTH (pg/mL) Tumour size (cm)

Surgery

1 2

Wu et al. [3] Sato et al. [4]

M F

52 51

PIT None

4.1 2.7

154.3 N/A

/ N/A

3

Dionisi et al. [5] M

35

PET SL

3.4

707

N/A

4

Agha et al. [6]

F

69

PIT PET

3.9

342.7

N/A

/ Total parathyroidectomy + autoplantation First surgery: ectopic PT excision Second surgery: subtotal parathyroidectomy First surgery: 3 PT excison Second surgery: last PT excision

M

32

PET

3.7

254.5

N/A

2 PT excision

PIT PET AD

3.4

1354

/

/

PIT PET

2.7

79.1

N/A

PET AD

3.1

204

1.7

First surgery: 1 PT excision Second surgery: subtotal parathyroidectomy 3 PT excision + Hemithyroidectomy

PIT PET AD SL

3.3

311.8

2.5 2.0

2 PT excision + Thyroidectomy + Neck lymphadenectomy

PIT AD

3.2

248.2

2.1

Hemithyroidectomy

PET AD CT

3.1

127.3

N/A

PET CT

2.6

42

1.8

First surgery: 1 PT excision Second surgery: 1 PT excision First surgery: Subtotal parathyroidectomy Second surgery: Completion parathyroidectomy

5 6

Shih et al. [7]

F

53

7

Kalavalapalli et al. [8]

F

44

8

Del Pozo et al. [9]

M

50

9

Joudele et al. [10]

F

39

10

Lee et al. [11]

F

59

11

Singh Ospina et al. [2]

M

62

12

Christakis et al. [12]

M

54

13

/ Suspicion of Thyroid tumour Suspicion of acute pancreatitis and hypercalcemia Symptomatic hypercalcemia Shortness of breath Dyspepsia Abdominal pain Polyuria Nausea Symptomatic hypercalcemia Neck pain Generalised aches Digestive symptoms Abdominal pain Diarrhoea General weakness Fatigue Weight loss Bilateral galactorrhoea Headache Symptomatic hypercalcemia Asymptomatic

Bone pain Fatigue

Clinical and Experimental Medicine Table 1  (continued) Case No. References

Sex Age Symptoms/preop. diagnosis

13

M

55

14

F

32

PTH (pg/mL) Tumour size (cm)

Surgery

3.4

673.1

3

Subtotal parathyroidectomy

2.99

N/A

0.7

Other MEN1Serum related diseases Calcium (mmol/L)

PIT PET AD Fatigue Symptomatic hypercalcemia Anorexia Weight loss Dyspepsia Palpable neck mass Fatigue PET CT

15

Omi et al. [13]

M

40

Renal stones

PIT PET

2.74

522

2.5 N/A

16

Cinque et al. [14]

M

61

N/A

7.3

55

AD PET AD

N/A

M

Nephrolithiasis Renal stones Renal stones Adrenal lesions

First surgery: 2.5-glands parathyroidectomy Second surgery: 1 PT excision First surgery: 3 PT excision (1 not found) + Hemithyroidectomy + autotransplantation Second surgery: Completion thyroidectomy + intrathyroidal PT 2 PT excision

1.48

286

4.6

1 PT excision

17

Case No. References

Metastasis/ Local invasion Post-op. recurrence calcium (mmol/L) after 6 months

1

Wu et al. [3]

/

2

Sato et al. [4]

Capsular invasion

3

Dionisi et al. [5]

Capsular invasion

4

Agha et al. [6] Adjacent bone invasion

5

Capsular invasion

Histology

Fibrous bands Local recurrence + Chest Mitoses wall metastasis N/A No Capsular invasion Nuclear polymorphism Mitoses Normalization Mediastinal Capsular invametastasis sion Vascular invasion Fibrous bands Kariokinesis Dense fibrous Hypocalcemia Mediastinal capsule recurrence Fibrous (ectopic bands Necroparathyroid sis Mitoses gland) Hypocalcemia No Capsular invasion Fibrous bands Mitoses /

Genetic testing

Post-op. therapy

Follow-up

/

/

/

842delC in exon 4

N/A

N/A

N/A

N/A

Died

N/A

N/A

N/A

N/A

No

N/A

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Table 1  (continued) Case No. References

6 7 8

9

Metastasis/ Local invasion Post-op. recurrence calcium (mmol/L) after 6 months

No Fibrous bands Nerve infiltra- / tion Vascular invasion Kalavalapalli N/A Normalization Lung metasN/A et al. [8] tasis Del Pozo et al. Capsular inva- Normalization Thyroid recur- Capsular [9] sion rence invasion Trabecular growth Mitoses Joudele et al. Capsular inva- Hypocalcemia Thyroid recur- Capsular inva[10] sion rence sion Shih et al. [7]

10

Lee et al. [11]

Capsular invasion

Normalization No

11

Singh Ospina et al. [2]

Normalization Oesophageal recurrence

12

Christakis et al. [12]

Oesophageal infiltration Nerve infiltration Capsular invasion Capsular invasion

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Histology

14

N/A

15

Omi et al. [13] Thyroid invasion

16

Cinque et al. [14]

17

Normalization No Recurrent hypercalcemia

No

Normalization No Normalization No

Normalization No Capsular invasion Oesophageal infiltration N/A No Capsular invasion Surrounding adipose tissue infiltration

Genetic testing

Follow-up

c.1406_13dup8 /

/

N/A

N/A

Remission

W183C in exon 3

No

Remission

No

Died

No

Remission

Radiation therapy

Remission

No

Remission

No

Under followup

N/A

No

Died

N/A

No

Remission

N/A

N/A

c.129insAcodon 43 in exon 2 Capsular inva- N/A sion Fibrous bands Necrosis Fibrous bands N/A Nuclear atypia

Lobular features Mitoses Capsular invasion Fibrosis Nuclear polymorphism Lobular features Fibrous bands Capsular invasion Vascular invasion N/A

Post-op. therapy

c.703 g > A (pE235 K) c.1378C > T (p.R460X)

c.1252G > A; p.D418 N in exon 9

Capsular inva- c.1252G > A; sion p.D418 N in exon 9

M male, F female, PIT pituitary, PET pancreatic endocrine tumour, AD adrenal disease, CT carcinoid tumour, SL subcutaneous lipoma, N/A not available

10 of 17 showed capsular invasion intraoperatively, and seven of 17 showed infiltration of surrounding structures (one thyroid involvement, one bone invasion, two nerve infiltrations, one surrounding tissue involvement, and two oesophageal infiltration), three were metastatic (lung, chest wall, and mediastinum), while five patients were

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readmitted for local, thyroid, oesophageal, or mediastinal recurrence. According to a National Cancer Database review in 2000, the average size of PC was 3.3 cm, although no clear prognostic role has been attributed to tumour size or to the presence or number of lymph node metastases [1]. While PC

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tumour size in the patient we treated was notable, the size of the PC in MEN1 in our review varied among 0.7 and 7.3 cm with an average size of 2.82 cm, as reported in nine of 17 cases. Surgical removal of the abnormally hyperactive parathyroid glands in patients with MEN1 is the definitive treatment, but it is controversial whether to perform subtotal (3 or 3½ glands) or total parathyroidectomy and whether surgery should be performed at a nearly or late stage of the disease. According to the review realized by Thakker et al. in order to establish Clinical Practice Guidelines for MEN1, subtotal parathyroidectomy has resulted in persistent or recurrent hypercalcemia within 10–12 years after surgery in 40–60% of patients with MEN1, and in hypocalcemia requiring longterm therapy with vitamin D or its active metabolite calcitriol in 10–30% [22]. Total parathyroidectomy has the lowest risk of persistent and recurrent PHPT instead, but inevitably comes with the highest risk of permanent hypoparathyroidism. In case of total parathyroidectomy with autotransplantation, both fresh and cryopreserved parathyroid tissue has been used [23]. Autotransplantation of parathyroid tissue to the forearm may be beneficial over subtotal parathyroidectomy because it avoids the necessity for vitamin D medication for the patient. If hypercalcemia recurs, the transplanted parathyroid tissue can be removed under local anaesthesia, and reoperation of the neck under general anaesthesia can be avoided. Indeed, recurrent hypercalcemia is present in more than 50% of patients with autotransplanted parathyroid tissue, and surgical removal of the transplanted grafts is not always successful [24, 25]. Subtotal parathyroidectomy may be suggested as the initial treatment of PHPT in MEN1; total parathyroidectomy with autotransplantation may also be reserved for those with extensive disease either at first or at repeat surgery. On the other hand, the treatment of choice for PC, since the pre-operative workups and the experience of the surgeon arise the suspicion of malignancy, should be the en bloc resection of the tumour, the ipsilateral thyroid lobe with gross clear margins, and the adjacent involved structures, paying particular attention to avoid the tumour spillage. If there is invasion of surrounding structures, such as the strap muscles, these should be incorporated into the resection. The recurrent laryngeal nerve should be resected if it is grossly infiltrated by the tumour. Tracheo-oesphageal, paratracheal, and upper mediastinal lymph nodes should be excised. There is no evidence that routine central neck dissection improves the survival rate [26, 27], but this approach has recently been recommended. According to Schulte et al., primary surgery for PC should include an oncological en bloc resection of the central compartment, together with the possibly involved surrounding tissues, in order to improve surgical outcomes [28].

Surgical approach in patients reviewed in Table 1 varied according to pre-operative suspicion. Patient admitted with a pre-operative diagnosis of MEN1 were submitted to total parathyroidectomy with autotrasplantation (one patient), as the current choice for parathyroid disease in patient with MEN1, or subtotal parathyroidectomy (3 or 3½ glands) as primary treatment of PHPT (5 patients). The remaining cases reviewed had no pre-operative diagnosis of MEN1 and were submitted to parathyroidectomy of the neoplastic gland with eventual concomitant excision of other macroscopically enlarged or suspect parathyroid glands. Only one patient out of 17 was managed with the pre-operative suspicion of PC, undergoing tumour excision with thyroidectomy and neck dissection. Considering the rarity of this condition and the diagnostic challenge, it is not surprising that 41% of the patients underwent a redo surgery, getting mostly a subtotal (3 cases) or total parathyroidectomy with autotrasplantation as a final result (3 cases). In all the reported cases of missed pre-operative diagnosis of PC or MEN1, the choice of redo surgery was subordinated to persistent/recurrent hyperparathyroidism and to symptomatic hypercalcemia. Christakis et al. emphasize the difficulties in the postoperative management in patient with histological diagnosis of MEN1 submitted to surgery for PC. They advocate limited resection and the use of minimally invasive approaches in the setting of redo surgery for PHPT in MEN1 patients (without suspect of parathyroid neoplasia), while, if there is sufficient evidence to suspect a local recurrence of malignancy, an open approach with adequate exposure is required to perform an oncological resection [12]. Nonsurgical treatment of PC is based on radiotherapy and chemotherapy generally with modest results. Nonetheless, recent reports suggest the use of irradiation as adjuvant therapy: a median disease-free survival of 60 months in four patients given post-operative adjuvant radiotherapy has been reported [29]. Furthermore, the MD Anderson Cancer Center experience suggests a benefit of adjuvant radiation given, independent of the type of operation and stage of the disease [30]. Among the PC cases here reviewed, only Sigh Ospina et al. reported radiation therapy in a patient submitted to left superior parathyroidectomy for a parathyroid tumour infiltrating the oesophagus with nerve involvement. After the restoration of the left vocal cord function, the patient underwent a second operation with the removal of the hyperplastic right superior parathyroid gland, and radiation therapy (60 Gy) to the surgical bed and to the regional lymph nodes (54 Gy) [2]. As it is well known, during follow-up, serum calcium and PTH should be closely monitored, bearing in mind that in case of PC associated with MEN1, the reappearance of hypercalcemia might not be due to cancer recurrence, but rather be secondary to adenomatous hyperplasia

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of other non-excised parathyroid glands—in patients first operated without a MEN1 diagnosis. Survival outcomes in this review were not reported in four of 17 cases; among the remaining were recorded three deaths and six remissions, while one patient is still in follow-up for recurrent hypercalcemia. Although rare, the presence of PC in MEN1 is noteworthy because it affects the extent and complexity of surgical approach. If hypercalcemia recurs, an open approach is suggested over minimally invasive techniques in the redo setting for benign disease. As suggested by Iacobone et  al., genetic testing in hereditary endocrine tumours should be preferably available before surgery because specific and targeted operative management is needed to achieve the best chance of cure. In fact, hereditary tumours need a targeted management that is very often different from sporadic variants, as in case of PC in MEN1 syndrome. Genetic testing may achieve an early diagnosis, with subsequent adequate follow-up and tailored therapy [31]. Pre-operative clues that may indicate the presence of PC should mandate operative management by an expert endocrine surgeon, who is able to tailor the operative plan on the suspect of a neoplasm and extend resection to achieve clear macroscopic margins where possible.

Conclusions In conclusion, surgery is the main treatment for PC, and of course of PC in MEN1. The extreme rarity of this condition represents a challenging in diagnosis, treatment and follow-up of those patients, and because of this the cooperation of experienced endocrine specialists is a key issue. Authors’ contributions  GDM contributed to conception and design of the study, case and literature review, draft writing, manuscript review, and intellectual input. LIS and VF contributed to case and literature review, draft writing, and manuscript review. FPP and AG contributed to draft writing, manuscript review, and intellectual input. MT helped in design and coordination of the study, draft writing, manuscript review, and intellectual input. All the authors read and approved the final manuscript. Funding  This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards  Conflict of interest  The authors declare that they have no conflicts of interest.

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Clinical and Experimental Medicine

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