Results F

[F] Long-term follow-up and management

[F1] Goals of long-term follow-up and management of patients with and without residual disease.   For patients with sporadic or familial MTC with no evidence of residual disease after initial surgery based on radiographic and biochemical testing, long-term complete remission is a realistic goal. Early detection of recurrent MTC may reduce the likelihood of local complications or the development of distant metastases, but this has not been studied in a prospective manner. In one large cooperative study of 899 patients from France in which a biochemical recurrence was defined as an elevation of Ct after postoperative Ct ‘‘normalization,’’ the rate was 4.9% (40). In a follow-up study from the same group utilizing a single and more sensitive Ct assay (sensitivity 2ng/L), patients were identified who had an abnormal basal or pentagastrin stimulated serum Ct level >10 ng/L at their last visit. Of these, 3.3% were considered to have recurrent disease because they had previously demonstrated a postoperative pentagastrin-stimulated serum Ct of ≤10 ng/L within 6 months of surgery. Interestingly, one third of these patients had no evidence of nodal metastasis at initial surgery. The recurrences occurred at a mean of 3.2 (range 0.7–7.5 years) after the initial surgery (213). Disappointingly, about 7% of patients undergoing prophylactic thyroidectomy experience biochemical recurrence, although those children had surgery at 13 years of age or later (80). Using the more strict criteria of an undetectable basal and stimulated Ct, Skinner et al. (81) demonstrated a 2% rate of persistent disease after prophylactic thyroidectomy and a 10% rate of recurrence after 5–10 years of follow-up. Eighty percent of these patients with recurrence had no lymph node metastases found at the time of their thyroidectomy and central neck dissection.


    Long-term biochemical monitoring for patients with MTC who achieve a complete biochemical cure should be performed. Grade: B Recommendation


    Long-term biochemical monitoring for MTC patients who achieve a complete biochemical cure should include annual measurement of serum Ct. Grade: C Recommendation

In the setting of residual MTC after appropriate initial surgical resection, it is unlikely that a complete remission will be attained. The goals of follow-up in this setting are to prevent local complications of progressive residual disease and/or limit the likelihood and/or complications of metastatic MTC. Early detection of progressive disease may reduce the likelihood of local cervical complications and also complications of distant metastases located near critical structures, such as the spinal canal.


    Patients with persistent MTC should be monitored by measuring Ct and CEA levels, along with history and physical examinations. The timing of follow-up anatomic imaging may be based on the relative stability of these tests, presence or absence of symptoms, and the location of known or likely sites of metastatic deposits. Grade: C Recommendation


    Patients with detectable basal serum Ct levels postoperatively should have the basal Ct and CEA levels obtained approximately every 6 months to determine their DTs. Ongoing follow-up of these tumor markers and physical examination should occur at one fourth the shortest DT or annually, whichever is more frequent (i.e., follow patient every 6 months if the shortest DT is 24 months). Grade: C Recommendation


    In patients with detectable basal serum Ct levels postoperatively, if the Ct or CEA rises substantially since the previous anatomic imaging evaluation, then a neck US should be performed. The Ct elevation required to trigger this action typically depends on the basal serum Ct and the clinical situation, but elevation by more than 20–100% may prompt this evaluation. If the serum Ct is >150 pg/mL then systemic imaging should be repeated as well. Grade: C Recommendation

[F2] Follow-up of patients without MTC at thyroidectomy (Fig. 5).   The risk of persistent or recurrent disease after prophylactic thyroidectomy reveals normal tissue or CCH is very low (84). Skinner et al. (81) studied 50 patients with MEN2 who underwent prophylactic thyroidectomy and central neck dissection. Sixteen of these patients demonstrated only CCH or normal pathology, and none of them demonstrated any measurable Ct after stimulation testing through a minimum of 60 months of follow-up. Conversely, 6 of their 50 patients demonstrated persistent or recurrent disease, including two patients whose pathology demonstrated only microscopic evidence of MTC and no lymph node metastases. Their follow-up stimulated Ct testing first became abnormal 5–7 years after initial therapy, while their basal levels remained undetectable.


    After prophylactic thyroidectomy demonstrates no evidence of MTC, the risk of developing MTC is low, and the optimal follow-up for these patients is uncertain. Annual measurement of basal serum Ct without measurement of CEA should be considered. Less frequent testing may be considered if there is no evidence of disease after prolonged follow-up. Grade: C Recommendation

[F3] Role of stimulation testing for serum Ct.   In the past and present, some MTC patients have demonstrated undetectable basal serum Ct levels that rise after stimulation testing with pentagastrin, calcium, or both (92). Stimulation testing adds cost to patient follow-up, and pentagastrin frequently causes transient unpleasant symptoms. A rise in serum Ct after stimulation suggests residual or recurrent MTC (81). However, as the functional sensitivity of the Ct assays have become lower, those patients with abnormal testing only after stimulation typically have very low levels of disease that is unlikely to be found by anatomic or functional imaging (231). It is possible that knowledge of likely residual disease may prompt the patient and physician to maintain regular surveillance for disease progression. However, given the low rate of biochemical remission in patients with metastatic MTC, the impact of this knowledge is likely to be low. Further, pentagastrin is not available in many countries, and calcium stimulation testing is accepted as inferior (although demonstrative publications are largely lacking).


    Stimulated serum Ct testing may detect low levels of residual disease despite undetectable basal Ct values. Such minimal disease is currently unlikely to be able to be localized or treated, and therefore this follow-up testing is not recommended (agreement amongst the Task Force was not unanimous). Grade: D Recommendation

[F4] Management of CEA-positive, but Ct-negative patients.   Laboratory factors that may result in falsely low Ct levels were discussed previously. False elevation of serum CEA may result from heterophilic antibodies (340). Other possibility for this scenario include CEA coming from a condition other than MTC or the loss of Ct production by the MTC (341, 342).

CEA may be secreted by cancers of the digestive system, lung, prostate, breast, and ovary. Benign conditions associated with CEA elevation, to varying degrees, have included bronchogenic cyst, gastrointestinal tract inflammatory disease, chronic obstructive pulmonary disease, and benign pulmonary disease.

In patients with MTC, rising CEA levels suggest progressive disease, although the vast majority of such patients also have elevated serum Ct levels (212,269). Some patients with progressive disease demonstrate an increase in CEA while the Ct levels decline, which has been considered a mark of tumor dedifferentiation (343). Rarely MTC patients are described that lack elevation of both serum Ct and CEA which is thought to reflect more advanced dedifferentiation and convey a poor prognosis (234,342).

Mendelsohn et al. (344) studied CEA and Ct in MTC by immunohistochemistry. They found that in most cases, CEA and Ct were similar in the tumors, being expressed by almost every cell. This was especially true for CCH, in early disease (microscopic MTC), and even in gross MTC confined to the thyroid. In contrast, primary and metastatic tumors from patients with invasive disease had an inverse relationship between CEA and Ct staining such that the most aggressive disease had persistent and intense CEA staining but minimal if any Ct staining. They suggested that CEA was a marker for early epithelial differentiation and therefore retained while Ct was a late marker for terminal differentiation and therefore lost.


    Elevated CEA levels that are out of proportion to the serum Ct may occur from several causes, including some unrelated to MTC, which should be considered and evaluated as appropriate based on clinical judgment. Grade: C Recommendation

[F5] Lichen planus amyloidosis.   Lichen planus amyloidosis (LPA) can be associated with MTC in the setting of MEN 2A with codon 634 mutations in RET (46,345–347). Verga et al. (47) reported an incidence of LPA, or pruritis without LPA, in 36% of patients with the 634mutation. The initial classic symptom of LPA is intense pruritis between the scapulae that improves with sun exposure and worsens during periods of stress. Hyperpigmented lesions later develop believed to be secondary to the dermatomal scratching. However, amyloid in biopsies of LPA has been shown to be comprised of Ct using atomic force microscopy and MALDI-TOF analysis, suggesting a potential role for Ct in its development (348). The pruritis is often present in childhood and can pre-date the development of MTC (47,349). The pruritis can be a significant problem for patients as therapy typically provides incomplete symptom relief. Treatments have included moisturizing lotions and creams, local corticosteroids, systemic antihistamines, capsaicin, and phototherapy (47). Two patients with LPA treated with the tyrosine kinase inhibitor vandetanib experienced rapid disappearance of LPA, which reappeared with dose reduction (M. Schlumberger, personal communication, May 11, 2008).


    LPA should be treated symptomatically to minimize pruritis. Grade: C Recommendation