|Year : 2018 | Volume
| Issue : 1 | Page : 38-41
Clinicopathological study of medullary carcinoma of thyroid: A single institute experience
Chaithra Gowthuvalli Venkataramana, Radha R Pai, Ranjitha Rao, M Nirupama, Flora D Lobo, Kausalya K Sahoo
Department of Pathology, Kasturba Medical College, Mangalore, MAHE Manipal, Karnataka, India
|Date of Web Publication||23-Mar-2018|
Dr. Ranjitha Rao
C/O Dr. B H Krishnamurthy Rao, Anugraha, New Shivabagh Road, Kadri, Mangalore - 575 002, Karnataka
Source of Support: None, Conflict of Interest: None
Context: Medullary thyroid carcinoma is one of the rare thyroid malignancies representing only about 5%–10%of total thyroid cancers.
Aims: To study the age, sex distribution, and various histopathological features of medullary carcinoma of thyroid in our institute over a period of 5 years.
Settings and Design: This is a retrospective descriptional study of the cases diagnosed as medullary carcinoma over a period of 5 years in our institute (i.e., from April 01, 2010, to March 31, 2015).
Subjects and Methods: The study material obtained from departmental records, gross specimens, paraffin blocks or slides and case files from medical record sections. Histopathologically, tumor was identified according to the classical features as described in the World Health Organization of classification of tumors of endocrine organs.
Results: We found 20 cases of medullary carcinoma which accounted for 12% of thyroid malignancies. There was female dominance, and the age group of patients ranged from 20 years to 66 years. Microscopically, tumor cell arrangement was classic in all the cases with some showing pseudopapillary and spindle cell areas. Apoptosis of the tumor cells were seen notably in three cases. Three cases had necrotic areas. One case of micro medullary carcinoma was found incidentally. We had one interesting case where the clinical and cytological features were more in favor of papillary carcinoma.
Conclusions: Medullary carcinoma of the thyroid is rare. Identifying the histopathological features and its variations may show light into understanding of the tumor biology with its implications on patient management and prognosis.
Keywords: Medullary carcinoma, multiple endocrine neoplasia syndrome, thyroid
|How to cite this article:|
Venkataramana CG, Pai RR, Rao R, Nirupama M, Lobo FD, Sahoo KK. Clinicopathological study of medullary carcinoma of thyroid: A single institute experience. Thyroid Res Pract 2018;15:38-41
|How to cite this URL:|
Venkataramana CG, Pai RR, Rao R, Nirupama M, Lobo FD, Sahoo KK. Clinicopathological study of medullary carcinoma of thyroid: A single institute experience. Thyroid Res Pract [serial online] 2018 [cited 2019 Jan 22];15:38-41. Available from: http://www.thetrp.net/text.asp?2018/15/1/38/228377
| Introduction|| |
Medullary thyroid carcinoma is one of the rare thyroid malignancies representing about 5%–10% of total thyroid cancers. Hazard et al. in 1959 reviewed 600 cases of thyroid malignancies where they categorized 21 tumors with unique histological features standing separate from other malignancies. Since then medullary carcinoma gained clinicians as well as pathologist's attention because of their association with multiple endocrine neoplasia (MEN) syndromes, familial association and characteristic histological features. Histological identification of medullary carcinoma depends on typical solid growth pattern, lack of follicular cell differentiation, and presence of amyloid in the stroma.
| Subjects and Methods|| |
This is a retrospective study of the cases diagnosed as medullary carcinoma over a period of 5 years in our institute (i.e., from April 1, 2010, to March 31, 2015). The study material obtained from departmental records, gross specimens, paraffin blocks or slides, and case files from medical record sections. The tissues were routine processed, i.e., formalin fixed and paraffin embedded stained with hematoxylin and eosin. Congo red stain done to demonstrate the amyloid. Immunohistochemistry (IHC) with chromogranin, synaptophysin, and calcitonin was done in selected cases. Tumor was identified according to the classical features as described in the WHO  classification of tumors of endocrine organs.
| Results|| |
Age and sex distribution
We received totally 1084 thyroid specimens in 5-year duration. Of 1084 specimens, 871 (80.3%) were nonneoplastic and 213 (19.6%) were neoplastic. Of neoplastic 49 (23%) were benign and 164 (76.9%) were malignant. Of malignant cases, 20 (12%) were medullary carcinoma which formed the study material. The M: F ratio in medullary carcinoma was 1:3. Age group ranged from 20 years to 66 years. The mean age of men was 44.8 years and that of women was 42.6 years.
Grossly, the tumor size ranged from 0.5 cm to 6 cm. Tumor was gray-white to yellow in color in most of the cases [Figure 1]a. Tumor was located in the right lobe in 13 cases. Isthmus was involved in two cases along with the lobes. Left lobe was involved in five cases and one case had bilateral involvement of both the lobes. Thus, the tumor was unicentric in most of the cases and multicentric in single case. Grossly, the tumor was well circumscribed in 13 cases and infiltrating in 5 cases. Hemorrhagic areas were seen in four cases.
|Figure 1: (a) Well-circumscribed yellow colored tumor. (b) Classic pattern of tumor showing tumor cells arranged in nests separated by thin fibro vascular stroma. (c) Pseudopapillary pattern in medullary carcinoma. (d) Spindle cell pattern in medullary carcinoma|
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Microscopically, the tumors were infiltrating into the surrounding normal thyroid tissue in eight cases. In rest of the cases, tumors were well circumscribed with or without capsule. Tumor cell arrangement was classic in all the cases, i.e., in nests, organoid pattern and sheets [Figure 1]b. Tumor cells were round with eosinophilic cytoplasm and nucleus with fine granular chromatin and absent nucleoli in majority of the cases. Two cases had predominantly spindly areas. Special patterns such as pseudo papillary [Figure 1]c was found focally in three cases. Extensive spindle cell pattern [Figure 1]d was seen in three cases.
Bizarre nuclei with multinucleated giant cell formation were seen in three cases [Figure 2]c. Peripheral palisading of the tumor cells in tumor nests was noted in two cases [Figure 2]a. Mitosis was hardly seen in any of the cases. Apoptosis of the tumor cells was seen notably in three cases [Figure 2]b. Of 20 cases, 14 cases showed amyloid. Amyloid was seen stroma in most of the cases and both in stroma and around blood vessels in some cases. Lymphoplasmacytic infiltrate was prominently seen in single case. Ten out of twenty cases had hemorrhagic areas within the tumor tissue. Three cases had necrotic areas [Figure 2]c. Focal calcification was seen in single case [Figure 2]d.
|Figure 2: (a) Peripheral palisading of tumor cells in tumor cell nests. (b) Apoptotic tumor cells. (c) Bizarre nuclei with multinucleated giant cells and tumor necrosis. (d) Tumor calcification|
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Adjacent thyroid was showing lymphocytic thyroiditis in six cases and nodular goiter in five cases. Thirteen out of twenty cases had lymph node resection and in that eight cases had tumor metastasis. All the cases had involved Level II–IV lymph nodes. One case had ipsilateral supraclavicular nodal involvement. Lymphovascular emboli were seen in three cases. Distant metastasis was not known at the time of surgery in any of the cases.
One case was an incidental finding where the clinical and fine-needle aspiration cytology diagnosis was colloid nodule, and histopathology revealed micro medullary carcinoma (MMC) with a size of only 0.5 cm [Figure 3]a.
|Figure 3: (a) Medullary micro carcinoma found incidentally. (b) Medullary carcinoma showing intranuclear inclusions and grooves (inset). (c) Histopathology of the same tumor showing nuclear grooves. (d) Immunohistochemistry showed calcitonin positivity confirming the diagnosis of medullary carcinoma|
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We had one interesting case where the tumor size was about 10 cm and cytology showed tumor cells with nuclear grooves and nuclear pseudoinclusions [Figure 3]b. Lymph node was also involved. With the history of sudden enlargement in the past 3 months, hard consistency, huge thyroid swelling with mediastinal extension, multiple cervical lymphadenopathy, and the striking nuclear features of papillary carcinoma – the differential diagnosis of (1) PTC progressing into poorly differentiated thyroid carcinoma, and (2) medullary carcinoma thyroid were considered although the huge size seemed to be a rarity. On gross examination, the tumor was gray-white with granular areas. Histopathology showed tumor cells arranged in organoid pattern, nests, and in sheets. The tumor cells were oval to spindly with eosinophilic cytoplasm. Nuclei were showing nuclear inclusion and clearing with grooves [Figure 3]c. Congo red staining for amyloid was negative in the tumor proper. IHC was done for calcitonin which was positive in the tumor cells and then it was called medullary carcinoma [Figure 3]d.
| Discussion|| |
In our study, medullary carcinoma formed 12% of total thyroid malignancies. The disease was more predominant in females with a female to male ratio of 3:1. Furthermore, the disease presentation was earlier in females compared to males. Williams et al. and Saad et al. also found female predominance in their studies on medullary carcinoma. The mean age of patients was 51 and 53.2 respectively in a study done by Chong et al., Forrest et al. which is comparable to our study.
We had three cases with pseudopapillary pattern. These results from tissue fragmentation during processing and true papillae are very rarely seen in medullary carcinoma. These can be differentiated from papillary carcinomas by the lack of characteristic nuclear features.
Amyloid is formed by calcitonin and procalcitonin molecules in the medullary carcinoma. Although earlier it was considered as the diagnostic feature, the absence of amyloid can be found in medullary carcinoma.
Martinez-Tello et al. described an incidence of 0.15% of MMCs in a study conducted on autopsy specimens. Most of the time microcarcinomas are papillary microcarcinomas, and MMCs are uncommonly encountered in thyroidectomy specimens. MMCs are most commonly found in thyroids removed prophylactically. The prognosis for MMC is excellent compared to the tumor more than 1 cm in size.
The presence of apoptotic tumor cells has not been stressed much in the literature. The expression of bcl2 had a higher rate in disease-free individuals than in those with recurrent disease. It is also found to be an independent prognostic factor.
The presence of intranuclear pseudo inclusions, nuclear grooves, psammoma bodies, pale nuclei with powdery chromatin are the usual features of papillary carcinoma thyroid. The tumor cells of plasmacytoid, epithelioid, small cell, spindle cell morphology along with the presence of amyloid, abundant cytoplasm containing bright red granules, salt and pepper chromatin, and prominent cell dispersal are the features of medullary carcinoma in cytology. One of our cases showed spindle cells in tight clusters with nuclear grooves and pseudo inclusions with no amyloid, scant cytoplasm, and no cell dispersal. Thus, the features on cytology showed a morphological overlap of medullary, papillary and insular carcinoma thyroid and were a diagnostic dilemma. Mixed medullary-papillary carcinoma is a neoplasm with two differentiated areas, a papillary and medullary carcinoma. Desai et al. in their study, 234 cases of medullary carcinoma found seven cases of synchronous papillary carcinoma. They also found out that in 22 cases the tumor cells with nuclear features similar to papillary carcinoma were also seen among the tumor cells. The fact that both these tumors involve RET oncogene mutations might explain this relationship. Although the histopathological features are classic the role of IHC markers such as calcitonin, low-molecular-weight cytokeratin, carcinoembryonic antigen, and chromogranin are invaluable in confirmation of the diagnosis.
| Conclusions|| |
Medullary carcinoma is one of the rare entities in thyroid lesions. Identification of medullary carcinoma is important apart from prognostic view to the patient as the family members can be scrutinized for the development of MEN syndrome or familial medullary carcinomas. Early screening and prophylactic thyroidectomies are crucial in the prevention of grave morbidities associated with MEN syndromes. Identifying the histopathological features of medullary carcinoma and its variations may provide more insight into the understanding of the tumor biology and its behavior.
I sincerely acknowledge all the teaching and the technical staff of our department for their guidance and support to conduct this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wells SA, Franz C. Medullary carcinoma of the thyroid gland. World J Surg 2000;24:952-6.
Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 1959;19:152-61.
Gordon PR, Huvos AG, Strong EW. Medullary carcinoma of the thyroid gland. A clinicopathologic study of 40 cases. Cancer 1973;31:915-24.
Matias-Gulu X, DeLellis RA, Moley JF, Gagel RF, Albores-Saavedra J, Bussolati G, et al
. Medullary thyroid carcinoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. World Health Organization Classification of Tumours: Pathology and Genetics. Tumours of Endocrine Organs. Lyon: IARC Press; 2004. p. 86-91.
Williams ED, Brown CL, Doniach I. Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid. J Clin Pathol 1966;19:103-13.
Saad MF, Ordonez NG, Rashid RK, Guido JJ, Hill CS Jr., Hickey RC, et al.
Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 1984;63:319-42.
Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695-704.
Forrest CH, Frost FA, de Boer WB, Spagnolo DV, Whitaker D, Sterrett BF, et al.
Medullary carcinoma of the thyroid: Accuracy of diagnosis of fine-needle aspiration cytology. Cancer 1998;84:295-302.
Fletcher CD, Chan JK, Fletcher C. Tumors of the thyroid and parathyroid glands. In: Fletcher CD, editor. Diagnostic Histopathology of Tumors. 2nd
ed. Boston: Churchill Livingstone Publishers; 2000. p. 959-1056.
Martinez-Tello FJ, Martinez-Cabruja R, Fernandez-Martin J, Lasso-Oria C, Ballestin-Carcavilla C. Occult carcinoma of the thyroid. A systematic autopsy study from Spain of two series performed with two different methods. Cancer 1993;71:4022-9.
Etit D, Faquin WC, Gaz R, Randolph G, DeLellis RA, Pilch BZ, et al.
Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: A study of 42 cases. Arch Pathol Lab Med 2008;132:1767-73.
Guyétant S, Dupre F, Bigorgne JC, Franc B, Dutrieux-Berger N, Lecomte-Houcke M, et al.
Medullary thyroid microcarcinoma: A clinicopathologic retrospective study of 38 patients with no prior familial disease. Hum Pathol 1999;30:957-63.
Wang W, Johansson H, Bergholm U, Wilander E, Grimelius L. Apoptosis and expression of the proto-oncogenes bcl-2 and p53 and the proliferation factor Ki-67 in human medullary thyroid carcinoma. Endocr Pathol 1996;7:37-45.
Viale G, Roncalli M, Grimelius L, Graziani D, Wilander E, Johansson H, et al.
Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. Hum Pathol 1995;26:945-50.
Albores-Saavedra J, Gorraez de la Mora T, de la Torre-Rendon F, Gould E. Mixed medullary-papillary carcinoma of the thyroid: A previously unrecognized variant of thyroid carcinoma. Hum Pathol 1990;21:1151-5.
Desai SS, Sarkar S, Borges AM. A study of histopathological features of medullary carcinoma of the thyroid: Cases from a single institute in India. Indian J Cancer 2005;42:25-9.
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