A Case of Thyroid cancer in Ectopic thyroid tissue (Critical analysis)

Original case by Yanery’s Agosto-VargasMadeleine GutiérrezJosé Hernán MartínezMichelleMangual-GarciaCoromoto PalermoSharon Vélez-MaymiLuis Hernández-VázquezSamayra Miranda-RodríguezAlex González-BossoloErnesto Solá-Sánchez, and Marianne Hernández-Negrón

CRITICAL REVIEW BY DR. OM J LAKHANI (ENDOCRINOLOGIST)

This is the case of a 33-year-old man without significant medical history who was incidentally diagnosed with a right neck cystic mass by computer tomography (CT) after a motor vehicle accident. Patient denied diaphoresis, palpitations, diarrhea, constipation, mood changes, or any other symptoms. Physical exam revealed a right-sided tender neck mass, without any other remarkable findings. He did not have history of neck irradiation, thyroid disease, or family history of thyroid cancer. Thyroid function tests were within normal limits (TSH: 1.5 IU/mL). Excisional biopsy of the neck mass reported metastatic, well-differentiated, thyroid papillary carcinoma within lymph node tissue. Pathologic description consisted of a nodular segment, tannish, rubbery specimen with attached membranous cystic tissue. The pathological specimen (lymph node) was distorted and had a well-defined cystic structure within it. While the cystic structure measured 2 cm × 1.5 cm × 1 cm, the lymph node measured 1.5 cm × 1 cm (Figure 2). Due to previous findings, he underwent total thyroidectomy with right neck dissection in order to rule out occult primary carcinoma of the thyroid. Histopathological findings revealed a normal thyroid gland without evidence of papillary thyroid carcinoma and sixteen right neck lymph nodes without evidence of metastasis. Thyroid pathology was meticulously reviewed, without any evidence of papillary thyroid carcinoma identified.

Q What is your impression of this case ?

It seems there is PTC present in a rare ectopic tissue present in the cervical region since the Eutopic thyroid gland has no evidence of thyroid cancer.

Q So this is a case of Papillary thyroid cancer (PTC) post thyroidectomy. Would you give post operative radioactive iodine in this case ?

All patients with PTC donot require radioactive iodine therapy post operatively.  In all such cases a post-operative re-staging is done to classify the patient into Low risk,  Intermediate risk and high risk.

Radioactive iodine therapy is indicated in those considered to have high risk according to American thyroid association (ATA) guidelines. The following are considered to be high risk

  • Gross extrathyroidal extension
  • Incomplete surgery / gross residual disease
  • Distant metastasis
  • Post op Tg suggestive of distant metastasis

It is considered in those with ‘intermediate’ risk and not indicated in those with low risk.

Q In which risk category would you classify this patient ?

It is difficult to classify the patient according to ATA classification since there is presence of PTC in the ectopic thyroid gland but not in the eutopic thyroid gland. Also there is no evidence of lymph node metastasis. Hence it would be difficult to classify this patient and hence consider the patient as having intermediate risk and CONSIDER radioactive iodine therapy for this patient.

 

Q How will you follow up this patient ?

I would not start the patient on LT4 and follow the patient after 6-8 weeks with TSH. If TSH is >30 , patient sent for Radioactive iodine ablation with 30 mCi.

After surgery, thyroid hormone replacement was started. One month after procedure, thyroglobulin was 133.61 ng/ml (1.15–130.77 ng/ml) and thyroglobulin antibodies were 11.8 uU/ml (negative, less than 45 uU/ml).

Q What is interpretation of these reports ?
We donot know if the Tg is stimulated or unstimulated, however in either case Tg is very high and needs evaluation. This would be classified as ‘Biochemical incomplete response’ or ‘Structural incomplete response’ depending on the presence or absence of any remnant tissue in the neck. So I would order a neck ultrasound from an experienced radiologist as my first line of approach.

In retrospect it suggests that the authors should have considered Radioactive iodine ablation post operatively. However, we have an advantage of hind sight and as described above the post operative staging according to ATA was tricky to begin with.

Thyroid scintigraphy reported functional thyroid remnants at the right thyroid bed. Ultrasonography evaluation revealed hypoechoic foci within the thyroid beds bilaterally, likely secondary to postsurgical granulation tissue versus residual thyroid tissue.

A right, level 2A lymph node seen measured 2.1 × 1 cm with loss of normal lymph node morphology, without microcalcifications or internal increase in vascularity. Another lymph node at level 3 measured 2 cm × 0.7 cm × 8.7 cm, without worrisome features. Fine needle aspiration biopsy of the aforementioned nodules showed papillary thyroid carcinoma.

Q How will you restage this patient now ?

The patient now is re-staged as high risk.

Q What are the treatment options now ?

For residual disease in neck the options are close follow up, surgery and radioactive iodine ablation.

In Gross extensive residual disease surgery is the best option. For minimal residual disease surgery is indicated in cases where size of lateral nodes is >1.5 cm. In this case a repeat surgery for local disease would be a better option.

Final diagnosis was malignant transformation of heterotopic thyroid tissue. Whole-body scan showed functional thyroid tissue remnants in the thyroid bed with multiple enlarged neck lymph nodes. At that time, TSH was elevated (44.3 IU/mL) and free T4 was suppressed (0.58 ng/dl; normal value: 0.75–1.54 ng/dl). The patient was referred to nuclear medicine for radioiodine therapy. Radioiodine ablation 142.2 mCi was given. After appropriate cessation of hormone replacement therapy, whole-body scan showed no nodules uptake.

Q Why this approach is incorrect to an extent ?

Presence of considerable local disease it is difficult to judge and ablate distant metastasis. Hence ideally surgery would have been a better approach followed by Radioactive iodine ablation if needed. In the currently scenario there seems to be a false reassurance of absence of distant mets on a radioactive iodine pre-therapy scan. I would advice the authors for a close post operative follow up of this case.

Learning objective.

  1. This is a rare case where PTC in an ectopic thyroid tissue that too in lateral neck region without evidence of malignancy in the eutopic thyroid.
  2. In cases where post-operative ATA staging is ambiguous, it is better to consider a higher stage than a lower stage.

 

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A CASE OF MEDULLARY THYROID CARCINOMA WITH A TWIST !

Original case by I Huguet et al 

A 63-year-old woman was referred to our clinic following the incidental finding of a 1 cm thyroid nodule.

Q  What tests would you order on finding the thyroid nodule ?

  1. Review the ultrasound and physical examination findings
  2. A thyroid function test
  3. FNAC of the thyroid nodule if indicated

Q  What is the indication for FNAC according to new ATA 2015 guidelines ?

 

  1. High suspicion and intermediate suspicion- FNAC if nodule > 1 cm in size
  2. Low suspicion – FNAC if nodule > 1.5 cm in size
  3. Very low suspicion- FNAC if nodule > 2 cm in size
  4. Benign – avoid FNAC

 

Q  What are the high and intermediate risk features on ultrasound for which FNAC would be indicated in this case ?

Intermediate suspicion

  1. Hypoechoic with regular margins

High suspicion

  1. Hypoechoic + one of the following:
    1. Microcalcification
    2. Irregular margins
    3. Taller than wider
    4. Extrathyroidal extension
    5. Suspicious lymph nodes
    6. Interrupted calcification

Fine-needle aspiration cytology revealed a MTC.

Q  What are typical findings of MTC on FNAC ?

 

  1. Spindle shaped cells
  2. Cells have eccentric nuclei
  3. Amyloid like material in background

Q  How will you enhance the specificity of FNAC finding ?

Use of calcitonin staining in the FNAC smear- which will confirm the diagnosis of MTC.

Subsequently, plasma calcitonin levels were found to be elevated at 84 pg/ml (normal <11.5 pg/ml).

Q  What is the cutoff used for calcitonin in patients with Thyroid nodules for diagnosis of MTC ?

 

Basal calcitonin >20 pg/ml is suggestive of MTC and Pentagastrin stimulated Calcitonin >100 pg/ml confirms the diagnosis.

There were no other abnormal findings.

Q  What other tests would you perform ?

Since this patient has MTC, there is a high possibility of patient having MEN2. I would rule out pheochromocytoma and Hyperparathyroidism. I would clinically look for mucosal neuromas and marfanoid habitus.  (though MEN2B is less likely in this case considering the age of the patient).

The presence of a co-existing phaeochromocytoma was biochemically excluded (normal urinary catecholamine and metanephrine levels). Q  What is the ideal  surgery for this patient ?

Since the patient does not have lymph nodes involvement or metastasis and Calcitonin is between 20-200 pg/ml, the guidelines suggest total thyroidectomy with prophylactic central node dissection.

The patient was subjected to total thyroidectomy with clearance of central and lateral lymph node compartments.

The pathology demonstrated a calcified 1 cm nodule consisting of polygonal cells showing positive immunostaining for chromogranin, calcitonin, S-100 and carcinoembryonic antigen (CEA; Fig. 1). The lymph nodes were clear of disease.

Q  What is the next step for the disease ?

Genetic analysis is important to ascertain family risk and person risk of MEN2.

Genetic analysis of peripheral lymphocytes of the RET oncogene (automated sequencing of the flanking exons 10, 11, 13, 14, 15 and 16) did not reveal any germline mutation.

 

Q  How will you follow up this patient ?

I would repeat the Calcitonin and CEA after 3 months.

 

The patient recovered well from the operation, but exhibited persistently elevated plasma calcitonin levels, although she remained asymptomatic. Over the following 3 years, her plasma calcitonin levels were persistently elevated, although with no clear signs of progression (106, 116, 83, 173, 212, 279 and 114 pg/ml).

Q  What is done if calcitonin is persistently high after surgery ?

  1. If it is >150 pg/ml- then imaging is done
    1. USG/CT of neck
    2. CT thorax and abdomen
    3. Bone san
  2. If <150 pg/ml- follow-up.

Since this patient has calcitonin above 150 pg/ml on several occasions, an imaging is indicated.

Her circulating CEA levels remained normal. We suspected persisting or metastatic disease, but further repeated and detailed imaging including computed tomography (CT) and magnetic resonance (MR) scanning of the neck, chest and abdomen failed to reveal any evidence of tumour. Functional imaging with radiolabelled octreotide (Octreoscan) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning demonstrated mild uptake of both tracers in the midline, adjacent to L2, and further CT scanning was undertaken concentrating on this area. No clear abnormality was observed, and it was concluded at this stage that the apparent uptake was due to duodenal ‘physiological tracer elimination’.

However, after 3 years, the patient was found to have developed an iron-deficiency anaemia associated with positive faecal occult blood testing. Endoscopy was undertaken, and it showed chronic atrophic gastritis with intestinal metaplasia, but in addition a large (3 cm) polyp was found in the second part of the duodenum, which was biopsied.

The duodenal biopsy showed a NET, and the patient was subsequently re-explored surgically and partial duodenectomy was performed. Pathological examination confirmed a 2.8 cm well-differentiated NET with positive immunohistochemistry for CAM5.2, ac1-AE3, enolase, chromogranin, synaptophysin and serotonin; the Ki-67 index was <2% .

Q  What does a Ki-67 of <2% suggest ?

That it is a well differentiated neuroendocrine tumor.

Q  What is done for non-metastatic well differentiated carcinoid ?

Surgery and follow up.

Surprisingly, after resection of the duodenal tumour, circulating calcitonin levels remained repeatedly undetectable, and thus the tissue was immunostained for calcitonin; this was strongly positive.

Currently, the patient remains asymptomatic with persistently undetectable serum calcitonin levels and no further anaemia. She remains with mildly elevated serum chromogranin A and gastrin levels (last determination of serum gastrin levels: 591 pg/ml, normal <40; Fig. 3), which we attribute to her chronic atrophic gastritis.

Q  Can calcitonin be produced by other NET ?

Yes. It has been reported to be produced by other neuroendocrine tumors also.  In this case the association between the two seems coincidental.

 

CASE 16- An unusual endocrine cause of heart failure !

Original case by Zhang K

We report on a 51-year-old female patient with MEN1 syndrome characterised by a heterozygous Q453X mutation in exon 10, which was diagnosed 5 years ago.

Q What are the 3 commonest features of MEN1 syndrome ?

  1. Hyperparathyroidism
  2. Pituitary Adenoma
  3. Enteropancreatic neuroendocrine tumors

Q Which gene is involved in MEN1 ?

  • A tumor suppressor gene called MEN1 which encodes for a protein menin
  • Located on chromosome 11

Q Do mutations in MEN1 and clinical features correlate ?

No.  There is little genotype phenotype correlation

Due to hyperparathyroidism and a pancreatic tumour, she underwent parathyroidectomy and pancreatic tail resection in the past.

Q What type of parathyroidectomy is done in patients with MEN1 syndrome ?

Since MEN1 syndrome is associated with parathyroid hyperplasia either of the following is done:

  1. Subtotal parathyroidectomy- 3.5 parathyroid glands are removed
  2. Total parathyroidectomy with auto implantation of parathyroid tissue in the arm.

Histopathology of the pancreatic tumour revealed a glucagonoma with positive immunostaining for glucagon, chromogranin A and synaptophysin; negative immunostaining for gastrin, insulin, serotonin, somatostatin and pancreatic polypeptide. Moreover, the tumour showed the expression of somatostatin receptor type 2 (SSTR2), implicating responsiveness to somatostatin analogue therapy.

Q What are clinical featured of Glucogonoma ?

  1. Hyperglycemia
  2. Weight loss
  3. Anemia
  4. Necrolytic migratory erythema
  5. Aminoacidemia
  6. Diarrhea
  7. Thromboembolism

As comorbidity, a multifactorial terminal kidney failure with haemodialysis three times a week has existed for almost 3 years. In the further course of disease, the glucagonoma relapsed with hepatic metastases, currently controlled as a stable disease under conservative treatment using everolimus 10 mg/day p.o. and octreotide long-acting release (LAR) 30 mg i.m. every 3 weeks.

Q Which drugs are considered for chemotherapy of advance inoperable Pancreatic NET ?

  1. Somatostatin analogues
  2. Sunitinib
  3. Everolimus

Q What kind of drug is everolimus ?

It is an mTOR inhibitor

Everolimus for Advanced Pancreatic Neuroendocrine Tumors
In the present case, the patient came to the emergency room with dyspnoea and cough. Based on atypical bilateral infiltrations in the X-ray and highly elevated c-reactive protein (CRP), she was hospitalised with the diagnosis of pneumonia and treated with antibiotics while everolimus was paused; the last octreotide LAR injection was given 2 weeks prior to this. In the following days, her symptoms improved with normalising infection parameters. After 10 days of hospitalisation, however, her condition rapidly declined with progressive dyspnoea, orthopnoea and somnolence leading to admission to the intensive care unit.

Q Are infections common in patient on everolimus ?

Yes.  In a published meta-analysis the risk of all grade infection was 21% in patient on everolimus. (Ref)

Q Which opportunistic infection should be considered in this case ?

Pneumocystis pneumonia must be considered in this patient.

On admission, the patient showed sinus tachycardia and hypotension. Echocardiography revealed acute heart failure with a severely impaired left ventricular ejection fraction (LVEF) of 10%. Heart disease was not known previously. Only moderate valvular dysfunction and no significant hypertrophy or dilatation was seen indicating a rather recent development of heart disease. Infusions with dobutamine and nitroprusside sodium were immediately started, but could not improve LVEF. Despite treatment, the patient developed cardiogenic shock, leading to intubation. By using PiCCO technology for haemodynamic measurements, we could confirm cardiogenic shock and clearly ruled out septic shock based on the following data: severely decreased cardiac index of 0.8 l/min per m2 (reference 3–5 l/min per m2), highly elevated systemic vascular resistance index of 3800 dyn×s×cm−5×m2 (reference 1700–2500 dyn×s×cm−5×m2).

Q What is the relationship between heart failure and NET ?

Carcinoid syndrome is known to be associated with tricuspid and pulmonary value lesions.

Angiography ruled out coronary artery disease. Myocardial biopsy showed hypertrophy of cardiomyocytes and slight interstitial dilatation, but no signs of inflammation or metabolic heart disease. No cardiotoxic medication could be found in her previous medical history. Serum PCR for cardiotropic viral pathogens including parvovirus B19, coxsackie-A/B-virus, ECHO-virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-1, HHV-2, HHV-6, and HHV-8 was negative. No bacterial or fungal pathogen could be isolated from repeatedly collected samples of body fluids. At this point, the aetiology of heart failure remained unclear.

An association between glucagonoma and heart failure is not known. However, we found one case report by Chang-Chretien et al. (4) describing a 54-year-old female patient with glucagonoma-induced cardiomyopathy. This patient presented an LVEF of 15% with no valvular disease, clean coronary arteries, and in histopathology with only signs of myocardial hypertrophy and interstitial fibrosis – very similar to our patient. Surgical removal of the tumour led to complete normalisation of left ventricular function within 8 months. As pathomechanism, the authors suspected tachycardiomyopathy based on the chronotropic effect of glucagon.

Assuming that glucagonoma induced heart failure in our patient, we started therapy with continuous infusion of octreotide at a rate of 50 μg/h after an initial bolus of 50 μg, as surgery was not an option. In the following days, left ventricular (LV) function gradually improved, catecholamine treatment could be ended and the patient was extubated under stable haemodynamic conditions. Within 3 weeks, LVEF recovered up to 45% with a cardiac index of 3.7 l/min per m2. We determined the levels of chromogranin A, which is used as biomarker in NETs and correlates with hormone secretion (5). The levels of chromogranin A were at 1100 μg/l (reference 19–150 μg/l) under stable disease 1 year ago. Intriguingly, it was significantly increased to 4174 μg/l at the point of acute heart failure, and it markedly decreased after 1 day (1918 μg/l) and was back to baseline after 3 weeks (1223 μg/l) upon continuous octreotide treatment. Glucagon levels could not be determined due to the lack of a reliable test.

 

Learning points from this case

  1. Heart failure can be precipitated by glucagonoma.
  2. IV Octreotide infusion can be used for treatment of this type of heart failure.