Head/Neck/Endocrine Pathology

True Mixed Medullary-Follicular Derived Carcinoma

Jennifer L. Hunt
Massachusetts General Hospital
Boston, MA


Clinical History:
This is a 55 year old female with a known history of MEN 2A. She had a total thyroidectomy in 1976 for medullary carcinoma and bilateral adrenalectomy in 1977 for pheochromocytoma. In 2007, she had a new swelling in her neck and an increased calcitonin level. At surgery, she was found to have a 1.5 cm hard lymph node in the lower right jugular chain and a second node in the right central compartment. The lymph node is shown in the histologic slide.

Pertinent Laboratory Data:
Elevated calcitonin level


Slide 1
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Introduction:
The C-cells, or the parafollicular cells of the thyroid are derived embryologically from the branchial pouch and are usually seen in the upper-outer areas of the thyroid gland. The c-cells secrete calcitonin, which is a hormone that plays some role in calcium homeostasis, but the circumstances where it modulates its effects are poorly understood [4, 10]. A painless thyroid nodule is the most common presentation for both hereditary and sporadic cases of medullary thyroid carcinoma. Most affected individuals are adults, although familial cases may present at a younger age. Cervical lymph node metastases are present in up to 75% of cases at initial diagnosis [9, 13, 26]. Distant metastases to lung, bone or liver have been described at initial diagnosis in up to 15% of cases, or they can occur in follow-up in up to 48% of cases [13]. The 10-year overall survival rate for patients with medullary carcinoma is between 50 and 75%, which is significantly lower than that for other well-differentiated thyroid tumors, such as papillary and follicular carcinomas, which have survival rates of approximately 93 and 85% respectively [12, 13]. Tumor stage is currently considered the best predictor of prognosis, but it does not completely predict survival [7, 19]. Other reported favorable factors are young age and extensive cervical lymph node dissection at initial surgery [7]. Distant metastasis is a more consistent adverse prognostic indicator with up to 90% of patients dying within 5 years of presentation [8]. A tumor of the C-cells is always defined as a medullary carcinoma and there is no recognized benign pre-malignant condition neoplasm (such as "C-cell adenoma"). Medullary carcinoma is composed of cells with neuroendocrine differentiation. The tumor cells can have varying morphology, including spindled, epithelioid, or plasmacytoid cell types. In most of tumors, amyloid will be detectable, either on an H&E stain or using a congo red stain. Nearly all MTCs secrete calcitonin (>95%) and carcinoembryonic antigen (CEA, nearly 100%), both of which are features that are used diagnostically with immunohistochemical staining [27].

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
This tumor demonstrates very unusual morphologic findings of both a component of more typical medullary carcinoma and a component of papillary carcinoma, within the metastatic focus in the cervical lymph nodes. The tumor components are intimately mixed within the node. At the immunohistochemical staining level, the follicular derived component stains positive for thyroglobulin and the medullary carcinoma component stains for calcitonin and CEA. The primary medullary carcinoma from this patient was not available for review or comparison.

Differential Diagnoses:
  1. Collision tumor: Papillary carcinoma and medullary carcinoma, co-existing and metastasizing simultaneously, but as separate lesions

  2. True mixed medullary-follicular derived carcinoma

Final Diagnosis:
True mixed medullary-follicular derived carcinoma

Case Discussion:
This case represents a rare case of a mixed medullary-follicular derived lesion, as evidenced by the metastasis that contains well defined, but intimately ademixed components of both papillary carcinoma and medullary carcinoma. Immunohistochemistry supported this diagnosis, by demonstrating both thyroglobulin positivity and calcitonin positivity in the metastatic foci.

Review of the Literature/Treatment Options:
Rare medullary carcinomas have been reported with mixed morphology, including medullary carcinoma components and follicular-derived components (either follicular or papillary lesions) [1, 2, 6, 14, 15, 16, 17, 18, 21, 23, 24, 25, 28, 29]. The literature on these tumors includes well-defined mixed tumors (those that have medullary carcinoma with calcitonin expression and follicular derived tumor components with thyroglobulin expression) and then a host of other medullary carcinomas with unusual growth patterns (follicular and papillary) but no evidence of follicular differentiation. Furthermore, because medullary carcinomas are invasive tumors, the edges of typical tumors can demonstrate neuroendocrine tumor cells overtaking and surrounding normal follicular structures. And, since thyroglobulin can be leaky in the thyroid gland, reliance on thyroglobulin positivity alone, particularly at the edges of lesions, should also be avoided. In general, strict criteria ought to be applied for defining mixed tumors, with inclusion of only those tumors with immunohistochemical or molecular evidence of divergent differentiation (preferably away from the edges of the tumor or in metastatic foci) [23]. Histologically, mixed medullary-follicular tumors have morphologic evidence of these two components, either intimately admixed or in separate areas [23]. When metastases are present, they also can be mixed. The follicular derived component can have follicular, tubular, or solid growth or it can demonstrate papillary growth with papillary carcinoma nuclear features [23, 24]. The amount of each component is highly variable from tumor to tumor. It remains unclear whether these tumors are truly mixed, and the tumor components are arising from a common progenitor cell, or whether they represent collision tumors [16] The molecular genetic events in medullary carcinoma are dominated by the well-characterized mutations in the RET proto-oncogene, which were first isolated and cloned in 1993 [20]. Mutations are clustered in exons 10, 11, and 16 in hereditary cases. Somatic mutations are also seen in sporadic tumors. Mixed medullary-follicular tumors have only been occasionally studied at the molecular level. One study examined 12 cases with an analysis of clonality (using loss of heterozygosity and X-inactivation studies) and RET mutational analysis [29]. Their results suggested that the follicular derived component, at least in some cases, was clonally different from the medullary carcinoma component. Mixed medullary-papillary carcinomas have not been adequately studied at the molecular level for the typical mutations associated with papillary carcinoma (RET/PTC translocation and BRAF gene mutation). Because of lack of effective treatment for recurrence, an aggressive approach at initial presentation, with near- total or total thyroidectomy and selective neck dissection, is recommended for MTC [3]. Patients are then followed with serum calcitonin and CEA to detect early recurrent or metastatic disease. Unlike papillary and follicular carcinomas, which can be treated with radioactive iodine therapy, no medical therapy has proven effective for recurrent or metastatic MTC. The effectiveness of external radiotherapy and chemotherapy remains controversial; recent reports suggest no cures and only partial responses in patients treated with adjuvant therapies [5, 22]. However, surgically unresectable lesions may be treated with palliative radiotherapy [11]. Because so few mixed medullary-follicular lesions have been described in the literature, the prognosis and treatment options are not well understood. It does appear that the behavior is similar to other conventional, pure medullary carcinoma, with a high metastatic and recurrence rate and relatively long-term poor prognosis, as compared to well differentiated follicular derived carcinomas.

Conclusion(s):
This is a rare case of mixed medullary-follicular derived (papillary) carcinoma of the thyroid gland.

References:
  1. Albores-Saavedra, J., T. Gorraez de la Mora, F. de la Torre-Rendon, and E. Gould: Mixed medullary-papillary carcinoma of the thyroid: a previously unrecognized variant of thyroid carcinoma. Hum Pathol 21: 1151-5, 1990.

  2. Apel, R.L., L.C. Alpert, A. Rizzo, V.A. LiVolsi, and S.L. Asa: A metastasizing composite carcinoma of the thyroid with distinct medullary and papillary components. Arch Pathol Lab Med 118: 1143-7, 1994.

  3. Bhattacharyya, N.: A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngology Head & Neck Surgery 128: 115- 23, 2003.

  4. Brown, E.M. and S.C. Hebert: The First Annual Bayard D. Catherwood Memorial Lecture. Ca2+-receptor- mediated regulation of parathyroid and renal function. American Journal of the Medical Sciences. 312: 99-109, 1996.

  5. De Besi, P., B. Busnardo, S. Toso, M.E. Girelli, D. Nacamulli, N. Simioni, D. Casara, P. Zorat, and M.V. Fiorentino: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. Journal of Endocrinological Investigation. 14: 475-80, 1991.

  6. Dionigi, G., P. Castano, V. Bertolini, L. Boni, F. Rovera, M.L. Tanda, C. Capella, L. Bartalena, and R. Dionigi: Simultaneous medullary and papillary thyroid cancer: two case reports. J Med Case Reports 1: 133, 2007.

  7. Franc, S., P. Niccoli-Sire, R. Cohen, S. Bardet, B. Maes, A. Murat, A. Krivitzky, E. Modigliani, and G. French Medullary Study: Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clinical Endocrinology. 55: 403-9, 2001.

  8. Fuchshuber, P.R., T.R. Loree, W.L. Hicks, Jr., R.T. Cheney, and D.P. Shedd: Medullary carcinoma of the thyroid: prognostic factors and treatment recommendations. Annals of Surgical Oncology. 5: 81-6, 1998.

  9. Gharib, H., W.M. McConahey, R.D. Tiegs, E.J. Bergstralh, J.R. Goellner, C.S. Grant, J.A. van Heerden, G.W. Sizemore, and I.D. Hay: Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970. Mayo Clinic Proceedings. 67: 934-40, 1992.

  10. Gimm, O., T. Sutter, and H. Dralle: Diagnosis and therapy of sporadic and familial medullary thyroid carcinoma. Journal of Cancer Research & Clinical Oncology 127: 156-65, 2001.

  11. Heshmati, H.M., H. Gharib, J.A. van Heerden, and G.W. Sizemore: Advances and controversies in the diagnosis and management of medullary thyroid carcinoma. American Journal of Medicine. 103: 60-9, 1997.

  12. Hundahl, S.A., B. Cady, M.P. Cunningham, E. Mazzaferri, R.F. McKee, J. Rosai, J.P. Shah, A.M. Fremgen, A.K. Stewart, and S. Holzer: Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 89: 202-17, 2000.

  13. Hyer, S.L., L. Vini, R. A'Hern, and C. Harmer: Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival. European Journal of Surgical Oncology. 26: 686-90, 2000.

  14. Lax, S.F., A. Beham, D. Kronberger-Schonecker, W. Langsteger, and H. Denk: Coexistence of papillary and medullary carcinoma of the thyroid gland-mixed or collision tumour? Clinicopathological analysis of three cases. Virchows Arch 424: 441-7, 1994.

  15. Macak, J., H. Vaverkova, M. Dushova, and I. Perglerova: Medullary and mixed medullary-papillary carcinoma of the thyroid gland. Pathologica 89: 317-22, 1997.

  16. Matias-Guiu, X., A. Caixas, I. Costa, R. Cabezas, and J. Prat: Compound medullary-papillary carcinoma of the thyroid: true mixed versus collision tumour [corrected]. Histopathology 25: 183-5, 1994.

  17. Michal, M., R. Curik, J. Macak, M. Ludvikova, and K. Dedic: Mixed medullary-follicular and medullary- papillary carcinoma of the thyroid: one or two entities? Zentralbl Pathol 139: 333-5, 1993.

  18. Mizukami, Y., A. Nonomura, T. Michigishi, M. Noguchi, and T. Ishizaki: Mixed medullary-follicular carcinoma of the thyroid gland: a clinicopathologic variant of medullary thyroid carcinoma. Mod Pathol 9: 631- 5, 1996.

  19. Modigliani, E., R. Cohen, J.M. Campos, B. Conte- Devolx, B. Maes, A. Boneu, M. Schlumberger, J.C. Bigorgne, P. Dumontier, L. Leclerc, B. Corcuff, and I. Guilhem: Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'etude des tumeurs a calcitonine. Clinical Endocrinology. 48: 265-73, 1998.

  20. Mulligan, L.M., E. Gardner, B.A. Smith, C.G. Mathew, and B.A. Ponder: Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2. Genes, Chromosomes & Cancer 6: 166-77, 1993.

  21. Nangue, C., L. Bron, L. Portmann, M. Volante, H.B. Ris, P. Monnier, and S. Andrejevic-Blant: Mixed medullary- papillary carcinoma of the thyroid: report of a case and review of the literature. Head Neck 31: 968-74, 2009.

  22. Nguyen, T.D., J.L. Chassard, P. Lagarde, B. Cutuli, R. Le Fur, M. Reme-Saumon, B. Prevost, X. Panis, P. Verrelle, and G. Chaplain: Results of postoperative radiation therapy in medullary carcinoma of the thyroid: a retrospective study by the French Federation of Cancer Institutes--the Radiotherapy Cooperative Group. Radiotherapy & Oncology. 23: 1-5, 1992.

  23. Papotti, M., F. Negro, J.A. Carney, G. Bussolati, and R.V. Lloyd: Mixed medullary-follicular carcinoma of the thyroid. A morphological, immunohistochemical and in situ hybridization analysis of 11 cases. Virchows Arch 430: 397-405, 1997.

  24. Papotti, M., M. Volante, P. Komminoth, M. Sobrinho- Simoes, and G. Bussolati: Thyroid carcinomas with mixed follicular and C-cell differentiation patterns. Semin Diagn Pathol 17: 109-19, 2000.

  25. Parker, L.N., J. Kollin, S.Y. Wu, E.B. Rypins, and G.L. Juler: Carcinoma of the thyroid with a mixed medullary, papillary, follicular, and undifferentiated pattern. Arch Intern Med 145: 1507-9, 1985.

  26. Saad, M.F., N.G. Ordonez, R.K. Rashid, J.J. Guido, C.S. Hill, Jr., R.C. Hickey, and N.A. Samaan: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine. 63: 319- 42, 1984.

  27. Saller, B., G. Feldmann, K. Haupt, M. Broecker, O.E. Janssen, M. Roggendorf, K. Mann, and M. Lu: RT-PCR- based detection of circulating calcitonin-producing cells in patients with advanced medullary thyroid cancer. Journal of Clinical Endocrinology & Metabolism. 87: 292- 6, 2002.

  28. Shiroko, T., N. Yokoo, K. Okamoto, Y. Kitakado, H. Azuma, T. Fukui, and C. Tanaka: Mixed medullary-papillary carcinoma of the thyroid with lymph node metastases: report of a case. Surg Today 31: 317-21, 2001.

  29. Volante, M., M. Papotti, J. Roth, P. Saremaslani, E.J. Speel, R.V. Lloyd, J.A. Carney, P.U. Heitz, G. Bussolati, and P. Komminoth: Mixed medullary-follicular thyroid carcinoma. Molecular evidence for a dual origin of tumor components. Am J Pathol 155: 1499-509, 1999.