We have recently published an articel on our experiences in the preoperative diagnosis of medullary carcinoma.

General consideration

In contrast with other primary thyroid carcinomas in the case of medullary cancer the goal of preoperative diagnosis is not only to raise the possibility of carcinoma but to raise the possibility of the special subtype because the surgical procedure is different in medullary and follicular cell-type carcinomas.

Clinical presentation

Medullary thyroid cancer (MTC) is characterized by a more aggressive clinical presentation than well-differentiated thyroid cancers of follicular origin but is more closer to the latter than to an anaplastic carcinoma.   The clinical presentation raised the suspicion of malignancy in 10 of our first 23 MTC cases including 1 patient with a benign FNAC result. Among 10 patients with a clinical suspicion of malignancy, 3 had palsy of the recurrent nerve with causes determined exclusively within the thyroid. 7 patients had hard nodules with an uneven surface and 9 indicated a rapidly-growing firm or hard thyroid mass among 19 patients with palpable nodules.  The hormonal evaluation has no relevance, patients are usually euthyroid and in contrast with papillary carcinoma the TSH  is not higher  than in benign lesions.

Ultrasonography

MTC occurs in most if not all cases in hypoechogenic nodules. The most characteristic property of MTC is the presence of intranodular hyperechogenic cotton-like patches of amyloid deposits. These are larger than a focus of microcalcification and do not indicate dorsal acoustic shadow according to the entire extent of the hyperechogenic focus. This is the most specific sign of MTC with a sensitivity of 47% and an odds ratio of 31. There are two other findings which occur statistically more often in MTC than in benign lesions: the ratio of the horizontal to the anteroposterior diameter was greater in MTC and a remarkably higher proportion of the nodules had irregular (spiculated) or blurred borders. These signs lack of practical significance; we have found a positive predictive value < than 3%.

Calcitonin screening

There is an ongoing debate in the medical literature about the benefits from routine measurement of plasma calcitonin levels in patients who have thyroid nodules. The new AACE/AME/ETA guidelines regarding the diagnosis and management of thyroid nodules state that "single, non-stimulated calcitonin measurement can be used in the initial workup of thyroid nodules and it is recommended before thyroid nodule surgery". Most of the publications serving as the basis of these guidelines are related to iodine-sufficient regions and this factor led us to analyze our 20 years of experience in a moderately iodine-deficient region.

The question arises about the advantages and disadvantages that would have emerged if we use calcitonin screening in all or in all of the surgically treated nodular goiter patients. Although the new IRMA method (as in our practice) is clearly superior to the previously used RIA technique as the sensitivity and specificity of calcitonin screening with that method had been reported to be 75% and 98% respectively.

In a decision model for a hypothetical group of patients with a 0.78% prevalence of MTC, calcitonin screening seemed to be cost-effective (Cheung et al. 2008). In the presence of iodine deficiency with a lower prevalence of MTC, the cost-efficiency of calcitonin screening would be lower. The use of calcitonin screening to examine all nodular or all surgically treated patients in a moderately iodine deficient region – in case we assume an only 1% false positivity rate – would have meant 182 unnecessary operations or 46 operations with unnecessary radicalism among 22,857 patients with nodular goiter including 4,601  surgically treated patients.

Cytology.

The cytological picture is unusual, not fitting the pattern commonly seen for lesions of follicular cell origin - this is the most important clue to the cytological diagnosis.

Cellular subtypes

The most common pattern is the plasmacytoid one: round or polygonated cells with eccentric nuclei and a moderate amount of well-defined cytoplasm. Other patterns described in the literature are less frequent. These are the giant cell, small cell and spindle cell variants (Li Volsi 1990, Colins 1995). Rosai catalogues twelve variants (Rosai 1992). In our opinion, the distinction of various subtypes is of only limited value in cytologic practice. It is more important to be aware of the possibility of MTC when we are faced with an unusual cytological picture. Any suspicion must be followed by immunocytochemistry or determination of calcitonin in the serum.

Arrangement of tumor cells

The structure of tumor cells lacks the acinar formation seen in follicular cells in general.  In most instances, the characteristic feature is the presence of dissociated tumor cells (Droese 1995). In some cases, no cluster formation can be observed. If loose monolayered clusters are present, a solid, trabecular or lobular growth pattern can be observed (Kini 1984, Schaffer 1984, Kaur 1990, Rosai 1992), with clusters composed of 20-200 cells. Syncytial aggregates with nuclear crowding and overlapping are often seen. Orell states that the characteristic feature shared by several other "neuro-endocrine" tumors is the presence of scattered individual cells with very large nuclei, which are sometimes elongated or bizarre (Orell 1997). Unfortunately, such highly atypical single cells may be seen very frequently in tumorous or non-tumorous thyroid lesions. Binuclear cells are commonly present, and multinucleated cells may be observed (Collins 1995).

Nuclear details

The nucleus has no specific appearance. It is medium-sized, but anisonucleosis can be seen in virtually all cases. The nuclei are round; polymorphism may be observed in only some of the cases. Intranuclear inclusions are identifiable in approximately 50% of the tumors (Zeppa 1990, Bose 1992), while these are only infrequently numerous.

The cytoplasm in MTC

Cells with a well-preserved cytoplasm can be detected in most cases. On the other hand, it is not rare that only a few tumor cells exhibit this characteristic. Monomorphic cellular patterns are more common than pleomorphic ones (Droese 1995). One of the most important cellular signs is the polygonal appearance of the tumor cells. The characteristic triangular form can be detected in most cases (Soderstrom 1975). Another very important cytological sign is the coarse, brigh-red (May-Grunwald-Giemsa) cytoplasmic granulation (Zeppa 1990), which reflects neurosecretory granules.

The detection of amyloid is of great importance in the diagnosis of MTC. The proportion of cases in which amyloid has been found in FNAC series varies in the literature (Bose 1992, Collins 1995); approximately one-third of aspirates are stated to contain amyloid (Droese 1995). It can be detected relatively easily in May-Grunwald-Giemsa smears, but is more difficult to observe in Papanicolau smears (Orell 1997). It stains a deep-magenta color with the May-Grunwald-Giemsa-, and greenish-gray to dense-pink with the Papanicolau stain. The round clumps of dense material have a finely fibrillar texture. The hyaline stroma of hyalinizing trabecular adenoma can be mistaken for amyloid (Orell 1997). It is highly advisable to confirm the detection of amyloid by Congo red staining. After the destaining of routinely stained smears, these are suitable for Congo red staining (Droese 1995).
Amyloid deposition is mainly associated with MTC, but it is also deposited in the thyroid in cases of systemic amyloidosis, or amyloid goiter (Hamed 1995).

Cytolo gical differential diagnostics.

Cases with relatively frequent occurrence

From a practical aspect the most important problem is to differentiate oxyphilic tumors from medullary carcinoma. Polygonal cells with eccentric nuclei, and cytoplasmic granulation are common features in both diseases. On the other hand, the granulations in medullary carcinoma are coarse, while those accompanying oxyphilic tumors are tiny and powder-like. Oxyphilic tumors are characterized by anisonucleosis, and not infrequently even pleomorphism. Both of these features occur only infrequently in medullary carcinoma. The most important aid in distinguishing the two entities is the cellular arrangement. If any doubt arises, thyroglobulin and calcitonin immunocytochemical reactions and first of all serum calcitonin determination are mandatory. It must be remembered that oxyphilic metaplasia is associated with a reduced immunoreactivity for thyroglobulin (Ljungberg 1992, Rosai 1992).
In cases where no cluster formation occurs and a monotonous cell population is present, non-Hodgkin's lymphoma of the thyroid must be taken into account.
Attention should be paid to avoiding confusion with anaplastic carcinoma if a heterogeneous polymorphic cell population is encountered. The presence of well-preserved cells in medullary carcinoma in contrast with the highly degenerated cells of anaplastic carcinoma may be of help. The different clinical presentations must be considered in order to resolve differential diagnostic problems.

Rare possibilities mentioned in the literature

Follicular neoplasm (Orell 1997), hyalinizing trabecular adenoma (Goellner 1989, Strong 1990, Li Volsi 1992), papillary cancer, squamous cell carcinoma, metastasis of bronchial carcinoid (Droese 1995), malignant melanoma, paraganglioma (Soderstrom 1975) and (as a non-neoplastic disease) amyloid goiter (Gharib 1981, Lucas 1989) are encountered under rare conditions, and may cause differential diagnostic problems.