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| RESIDENT'S CORNER |
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| Year : 2021 | Volume
: 4
| Issue : 2 | Page : 127-132 |
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Tumors beneath one umbrella: A story of a young man
Anurag Mehta1, Diksha Karki2, Garima Durga2, Divya Bansal2, Vishal Yadav3, Sunil Pasricha2, Meenakshi Kamboj2
1 Molecular and Transfusion Services, Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), New Delhi, India
2 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), New Delhi, India
3 Department of Head and Neck Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), New Delhi, India
| Date of Submission | 15-Dec-2021 |
| Date of Acceptance | 17-Jan-2022 |
| Date of Web Publication | 23-Feb-2022 |
Correspondence Address:
Dr. Diksha Karki
Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), New Delhi 110085
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jco.jco_43_21
How to cite this article:
Mehta A, Karki D, Durga G, Bansal D, Yadav V, Pasricha S, Kamboj M. Tumors beneath one umbrella: A story of a young man. J Curr Oncol 2021;4:127-32 |
| Case Presentation | |  |
A 28-year-old young man presented with complaints of neck swelling for 2 years with a recent increase in size, and a single episode of headache, sweating, and palpitations. No significant past or addiction history was present; however, a family history of thyroid carcinoma in his mother and maternal uncle, and a brain tumor in his brother was found. His vitals recorded were as follows: blood pressure (BP): 140/90 mm Hg and pulse rate (PR): 120/min. On local examination, anterior neck swelling was noted which moved on deglutition, was non-tender and hard in consistency. Bilateral cervical lymphadenopathy (LAP) was also noted. Ultrasonography (USG) of the neck revealed enlarged bilateral thyroid lobes with hypodense nodules of size 4 cm x 3.5 cm on the right side and 2.2 cm x 1.5 cm on the left side, with multiple enlarged bilateral cervical lymph nodes. Fine needle aspiration cytology (FNAC) from the right thyroid lobe was done in another hospital, which was reported as a primary malignant thyroid neoplasm, The Bethesda System for Reporting Thyroid Cytopathology, Category VI. Subsequently, a whole-body PET–CT scan (positron emission tomography–computed tomography) showed a large metabolically active mass in bilateral lobes of thyroid and cervical LAP. In addition, a mildly metabolically active soft-tissue mass was noted in the left adrenal gland measuring 4.4 cm x 3.5 cm.
The patient was referred to an endocrinologist, who discovered an increased plasma-free metanephrine 670 ng/L (Ref. 7. 8–88 ng/L), plasma-free normetanephrine 1610 ng/L (Ref. 20–135 ng/L), serum calcitonin >20,000 pg/mL, and a slightly increased parathyroid hormone (PTH) 73.8 pg/mL (Ref. 14–72 pg/mL). Plasma epinephrine and norepinephrine, serum calcium, serum prolactin, and thyroid function tests were within normal limits.
The patient underwent left adrenalectomy, which on gross examination showed a well-circumscribed, solid tumor, brown to yellow in color, firm in consistency, measuring 5.5 cm x 4 cm x 3.2 cm. A microscopic examination revealed an encapsulated tumor arranged in an alveolar (Zellballen) pattern [Figure 1]A and having polygonal cells with an abundant granular amphophilic cytoplasm [Figure 1]B. Focal areas of mild-to-moderate nuclear pleomorphism with tiny nucleoli and mitotic activity of 4/10hpf were seen [Figure 1]B. Few multinucleated cells and numerous intra/extracellular hyaline globules [Figure 1]C were present. No evidence of any necrosis or capsular or lymphovascular invasion was seen. On immunohistochemistry (IHC), tumor cells expressed chromogranin [Figure 1]D and synaptophysin, and were negative for cytokeratin (CK). S100 highlighted the sustentacular cells [Figure 1]E. Succinate dehydrogenase B (SDHB) expression was retained [Figure 1]F on IHC, and Ki67 proliferation index was approximately 1%. | Figure 1: Left adrenal gland mass showing tumor cells in (A) zellballen pattern having moderate amphophilic granular cytoplasm and tiny nucleoli and (B) areas of multinucleated cells (black arrow), mitosis (green arrow) and (C) intra/extracellular hyaline globules (red arrow). On IHC tumor cells are diffusely positive for (D) chromogranin, (E) sustentacular cells highlighted by S100 and (F) retained SDHB expression in the form of granular cytoplasmic positivity
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Q1. WHAT IS YOUR DIAGNOSIS OF THE ADRENALECTOMY SPECIMEN? WHICH SCORING SYSTEM IS USED FOR THIS TUMOR?
- Answer: a. Pheochromocytoma
- b. PASS
Pheochromocytoma is a tumor of chromaffin cells that arise from sympathetic paraganglia of adrenal medulla.[1] Such tumors are usually sporadic; however, 10%–23% are associated with a familial syndrome, with the most common being multiple endocrine neoplasia (MEN) syndrome.[2] Other syndromes associated with pheochromocytoma are Von Hippel-Lindau syndrome, Paraganglioma-Pheochromocytoma syndrome, Neurofibromatosis type 1, and Carney Stratakis syndrome.[1]
Most of the patients with pheochromocytoma are symptomatic (headache, tachycardia, palpitation, sweating, anxiety, and tremor). However, 50% of the patients with MEN2A syndrome are asymptomatic and are detected during routine endocrine workup.[1]
Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) is a comprehensive scoring system that uses 12 specific histologic features, as tabulated in [Table 1], providing a risk stratification for potential metastasis. A PASS score of ≥4 indicates a biologically aggressive behavior.[3],[4] Irrespective of the score, all cases should be followed up lifelong with laboratory investigations, radiological examination, and clinical features to timely detect any recurrence. Our patient had a PASS score of 3, indicating a benign behavior of the tumor.
Subsequently, after a month of adrenalectomy, the patient underwent total thyroidectomy with central compartment clearance and bilateral level II-V cervical lymph node dissection. A gross examination revealed bilaterally enlarged thyroid lobes, and the cut surface showed a well-circumscribed yellow nodular tumor. On microscopic examination, tumor cells were round, polygonal [Figure 2]A, and plasmacytoid to spindle [Figure 2]B in shape with abundant eosinophilic cytoplasm. Nuclei were round with fine nuclear chromatin, have conspicuous nucleoli, and show a significant mitotic activity. Intercellular areas had amorphous eosinophilic material deposits [Figure 2]C. Bilateral cervical lymph nodes showed metastasis. | Figure 2: Thyroid gland tumor showing (A) round- to (B) spindle-shaped tumor cells with (C) areas of amorphous eosinophilic deposit. On IHC, tumor cells are strongly immunopositive for (D) synaptophysin, and showed (E) diffuse TTF1, and (F) focal PAX8 positivity
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Q2. BASED ON HISTOMORPHOLOGY, WHAT TUMOR YOU THINK IT CAN BE AND HOW WILL YOU CONFIRM IT?
- Answer: a. Medullary thyroid carcinoma (MTC)
- b. IHC panel of synaptophysin, calcitonin, PAX8, and TTF1 (thyroid transcription factor 1).
- Congo red staining for amyloid
The tumor cells in the present case were strongly positive for synaptophysin [Figure 2D], calcitonin, and TTF1 [Figure 2E], and showed focal PAX8 expression [Figure 2F]. On Congo red staining, the amorphous eosinophilic deposits showed apple green birefringence on polarized light, confirming the eosinophilic deposit to be amyloid.
Our case also had an incidental focus of papillary microcarcinoma (3 mm in greatest dimension) in the right thyroid lobe, which expressed TTF1, PAX8 diffusely, and was negative for synaptophysin on IHC.
Q3. WHICH SERUM BIOMARKER IS USED FOR MONITORING DISEASE PROGRESSION IN MTC?
- Answer: a. Serum calcitonin
- b. Serum carcinoembryonic antigen (CEA)
Preoperative and postoperative elevated serum calcitonin and CEA levels are poor prognostic factors for disease-free survival, and these markers are useful for monitoring disease progression in MTC.[5],[6]
In our case, we also received a separate specimen labeled as pretracheal lymph node, which showed a well-circumscribed yellow nodule on the cut surface. On microscopy, it showed a tumor with a thin fibrous capsule, a solid growth pattern, occasional follicles, and focal stromal edema. The tumor cells were uniform and polygonal, with a finely dispersed eosinophilic cytoplasm, bland nuclei, and lacked mitotic figures. A regimented pattern of the nuclei was noted [Figure 3]A. No necrosis or capsular or vascular invasion was seen. On IHC, tumor cells were positive for PAX8, GATA3 [Figure 3]B, and synaptophysin, but were negative for TTF1. | Figure 3: Parathyroid gland nodule showing (A) uniform tumor cells with a granular eosinophilic cytoplasm and a regimented pattern of nuclei (green arrow). Tumor cells are diffusely nuclear positive for (B) GATA3, on IHC
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Q4. WHAT DO YOU THINK THE TUMOR IS? IS IT BENIGN OR MALIGNANT?
- Answer: a. Parathyroid adenoma
- b. Benign
Parathyroid adenoma is typically positive for PTH, GATA3, synaptophysin, and chromogranin. GATA3 is a highly sensitive and specific novel immunohistochemical marker for parathyroid origin of the cells.[7] Parathyroid adenomas should be carefully differentiated from carcinomas by identifying any capsular invasion and/or extracapsular vascular invasion, perineural invasion, or documented evidence of metastasis.
Q5. WITH A FAMILY HISTORY OF MULIPLE AFFECTED RELATIVES, AND MULTIPLE PRIMARY TUMORS IN A YOUNG PATIENT, WHICH SYNDROME DO YOU THINK THE PATIENT MIGHT HAVE?
- a. MEN1 syndrome
- b. MEN2A syndrome
- c. MEN2B syndrome
- d. MEN4 syndrome
Answer: b. MEN2A syndrome
MEN2A (Sipple syndrome) is the most common form of MEN2 syndrome accounting for 80% of cases, followed by familial MTC (15%) and MEN2B (5%). MEN2A is an inherited autosomal dominant syndrome characterized by MTC, unilateral or bilateral pheochromocytoma (50% of cases), primary hyperparathyroidism resulting from parathyroid cell hyperplasia, or adenoma (15%–30% of cases), including associated cutaneous lichen amyloidosis (CLA) and Hirschsprung’s disease (HD).[8],[9]
Most of the patients of MEN2 present with MTC between the age of 5 and 25 years. Unlike the sporadic cases, syndrome-associated MTC is usually bilateral, and multicentric with lymph node metastasis,[10] as seen in our present case. Pheochromocytoma in MEN2 is almost always benign and mostly bilateral. It is frequently diagnosed in the third to fourth decade of life, and in some children aged below 10 years.[8] Only 25% of cases have pheochromocytoma as a chief complaint, whereas 35% present with both MTC and pheochromocytoma.[10] In most instances, pheochromocytoma becomes evident 10 years after the diagnosis of MTC.[2],[11]
Similarly, primary hyperparathyroidism is subtle in presentation in MEN2A syndrome and usually detected during the screening process, which shows elevated serum PTH and calcium levels.[2] The present case had an incidentally detected parathyroid adenoma, with a mild increase in serum PTH and normal calcium levels.
Q6. WHAT ARE THE VARIOUS VARIANTS OF MEN2A SYNDROME?
Answer: There are four variants:[6]
- a. Classical MEN2A (presence of MTC and the less frequent occurrence of pheochromocytoma or hyperparathyroidism or both)
- b. MEN2A with CLA
- c. MEN2A with HD
- d. Familial MTC (families or individuals with RET germline mutations who have MTC but neither pheochromocytoma nor hyperparathyroidism).
Our patient had MTC, pheochromocytoma, and parathyroid adenoma, and hence, falls under the classical MEN2A variant.
Q7. WHAT NEXT INVESTIGATION WILL YOU SUGGEST TO CONFIRM MEN2A SYNDROME?
Answer: RET (RE- arranged during Transfection) germline mutation testing by direct DNA analysis
We performed a RET gene analysis by next-generation sequencing on formalin-fixed paraffin-embedded thyroid tumor tissue using the oncomine focus assay (OFA). A pathogenic germline missense mutation in the RET gene annotated as c.1901G>T, p.Cys634Phe at a variant allele fraction of 51.59% was revealed [Figure 4], confirming the diagnosis of MEN2A syndrome. | Figure 4: Genome browser[13] view of RET missense mutation c.1901G>T. The genomic coordinates and the reference sequence identity are shown in the accompanying box. The inset view shows the Lolliplot obtained from VarSome search engine,[14] and also the high incidence and canonical nature of the above-referred pathogenic missense mutation
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The RET protooncogene is located on chromosome 10q11.2 and encodes a RET receptor, which consists of a six cysteine-rich extracellular domain, a transmembrane domain, and two intracellular tyrosine kinase domains.[2],[9],[10] Approximately 93%–98% of cases of MEN2A are seen to have a missense mutation at one of the cysteine-rich extracellular domains of RET (609, 611, 618, 620, 630 at exon 10 and 634 at exon 11), of which 85% have codon 634 mutations, particularly Cys634Arg.[10] Mutations of these cysteine residues cause dimerization of the receptor in the absence of a ligand, causing autophosphorylation and activation of downstream signaling pathways.[9]
Mutation of RET protooncogene at various exons has been described, which correlates with a specific phenotype.[6],[10] There are three risk categories recommended by American Thyroid Association (ATA) Guidelines Task Force on Medullary Thyroid Carcinoma: “high risk,” and “moderate risk” [Table 2]. The increase in the risk category determines the risk of development of MTC at an early age frequently in association with metastatic disease.[6] The present case falls under the “high risk” category. | Table 2: ATA guideline task force on medullary thyroid carcinoma risk category[6]
Click here to view |
Mutation in a specific RET codon not only correlates with the risk of MTC, but also with the incidence of pheochromocytoma, hyperparathyroidism, CLA, and HD [Table 3]. | Table 3: Relationship of common RET mutations to risk of aggressive MTC in MEN2A and MEN2B, and to the incidence of pheochromocytoma, hyperparathyroidism, CLA, and HD[6]
Click here to view |
Q6. WHAT WOULD BE YOUR NEXT STEP AFTER IDENTIFYING THE GERMLINE MUTATION IN A PATIENT?
Answer: Genetic counseling and genetic testing
Genetic counseling and genetic testing for RET germline mutations should be offered to the following individuals, as recommended by ATA Guidelines Task Force on Medullary Thyroid Carcinoma[6]:
Once the mutation is detected among the relatives, they can be subjected to prophylactic management of MTC depending upon the risk of penetrance of tumor and routine screening for pheochromocytoma. Timing of screening of pheochromocytoma is dependent on mutation at a specific codon. Carriers of mutation in codons 918, 634, and 630 should begin screening by 10 years, as they have a high penetrance for pheochromocytoma.[12]
| Conclusion | | |
MEN2A syndrome is a rare group of inherited tumor syndrome with a variable presentation. All the patients with suspected MEN2A syndrome should be referred to a tertiary center that can offer multidisciplinary management to these patients. All the family members at risk should be identified early and offered genetic counseling and testing.[13],[14]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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| 12. | Machens A, Dralle H Multiple endocrine neoplasia type 2 and the RET protooncogene: From bedside to bench to bedside. Mol Cell Endocrinol 2006;247:34-40. |
| 13. | Rangwala SH, Kuznetsov A, Ananiev V, Asztalos A, Borodin E, Evgeniev V, et al. Accessing NCBI data using the NCBI sequence viewer and genome data viewer (GDV). Genome Res 2021;31: 159-69. |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
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