Poorly Differentiated Small Cell and Anaplastic Carcinomas

Poorly differentiated carcinomas purportedly are carcinomas that have clinical outcomes midway between those of well-differentiated and anaplastic carcinomas.84"86 Insular carcinomas and poorly differentiated carcinomas, as they occur in papillary and follicular carcinomas, are the two major forms.

The category of poorly differentiated carcinomas is compromised by the inclusion of tall cell, columnar cell, and mixed tall and columnar carcinoma variants of papillary carcinomas.33 87 88 As noted previously, these tumors can be recognized as follicular cell tumors and so, in the traditional sense, are not poorly differentiated.

Insular carcinomas are characterized by solid masses of round and oval cells separated into islands by thin bands of fibrous connective tissue.84'89 Mitotic figures, areas of necrosis, and invasive growth are common and some show papillary or follicular differentiation.

A review of a large number of cases in the literature showed that insular carcinomas were very aggressive, but another study resulted in a contrary conclusion.22'90 Insular carcinomas within papillary and follicular carcinomas do not appear to affect the prognosis adversely.

Insular carcinomas, in the initial report of such cases, were described as aggressive tumors that caused early deaths in patients. However, a second observer, after examining a series of slides included in the initial report, commented that an array of histologic changes were represented in the slides and only two cases possessed the histology described by the authors.91

Another histologic type of poorly differentiated carcinoma is described in "high-risk" groups of patients with papillary and follicular carcinomas.86 The tumors consist of poorly differentiated carcinoma characterized by solid, trabecular, or scirrhous patterns of neoplastic follicular cells within well-differentiated papillary and follicular carcinomas. The conclusion was that the poorly differentiated areas in papillary and follicular carcinomas are associated with poorer clinical outcomes than with well-differentiated carcinomas but better than with anaplastic carcinomas.

Poorly differentiated carcinoma, as defined before, is difficult to recognize because solid, trabecular, and desmoplas-tic histologic patterns are also found in well-differentiated papillary and follicular carcinomas and do not portend aggressiveness.6'712 Alternatively, tumors with areas of poor differentiation could be designated as high-grade papillary or follicular carcinomas instead of poorly differentiated carcinomas.92

Another report of patients with papillary and follicular carcinomas with areas of poorly differentiated carcinomas, as defined before, included two cases with insular changes and one with columnar cells. The overwhelming number of cases had well-differentiated thyroid carcinomas associated with poorly differentiated carcinoma, so the analysis essentially recapitulates the previous data.87

Age, distant metastases at diagnosis, differentiation, and extrathyroidal invasion were the prognostic factors. Except for the omission of size, the variables in the AGES system are duplicated.

The results highlighted a group of tumors (diffuse, poorly differentiated carcinomas) that were associated with local invasion, large tumor size, and lymph nodal and distant metastases that caused more frequent relapses and poorer outcomes. The conclusion was that diffuse, poorly differentiated carcinoma is an important clinicopathologic entity, with "diffuse" identifying differentiated carcinomas with poorly differentiated areas forming greater than 10% of the neoplasm.

A flaw in the study was the selection of 10% as the cutoff point between focal and diffuse, poorly differentiated carcinomas. Ten percent is a small number and subject to significant interobserver variations. The most important finding was that, as with all well-differentiated carcinomas, the stage of the neoplasm at the time of diagnosis appears to be the most significant prognostic factor.

Solid-trabecular forms of PTCs in adults have been reported as separate pathologic entities.93'94 One study considers the possibility that the cells in the solid-trabecular areas were reminiscent of fetal thyroid cells (primordial cells). Tumors were divided into two groups: those with "insular" components and those with predominantly solid-trabecular areas with minor insular components. The conclusions were as follows:

• No fatalities within 6 months

• No differences in survival rates

• More frequent recurrences and distant metastases with the insular group

• Tumors are aggressive but show slow clinical courses with good response to therapy

The data do not show that the tumors with the solid-trabecular patterns of growth are more aggressive. Descriptions to stage the neoplasms are absent except for sizes of the tumors, the presence of metastases, and infiltration of the mediastinum.

A second study concluded that solid variants of PTC are associated with a higher risk of distant metastases and slightly lower long-term survival.93 The results are such that separation of this histologic type of papillary carcinoma from usual papillary carcinomas is probably not warranted.

In summary, a thyroid neoplasm that can be classified as a poorly differentiated carcinoma has not been definitively described. There is no denying that papillary and follicular carcinomas with less differentiated areas occasionally cause deaths. However, the best prognostic factors are those that have been long identified: age, extrathyroidal invasion, completeness of excision, size, and distant metastases at the time of diagnosis.

Anaplastic thyroid carcinomas constitute approximately 1.5% of all cases of thyroid carcinomas in the United States, an extremely small number of approximately 300 cases per year.95 The rarity of the tumors accounts for the lack of adequate data and expertise to assess the clinical behavior and treatment of these tumors.

They occur more frequently in iodine-deficient geographic areas with a high prevalence of nodular goiters and follicular carcinomas.95 96 Iodine sufficiency, attributed to iodine prophylaxis, may account for the low prevalence in the United States of nodular goiters and follicular carcinomas. It may also have increased the number of papillary carcinomas. Follicular carcinomas occur more commonly in nodular goiters, and the rarity of follicular carcinomas in the United States may account for the very low rate of anaplastic carcinomas.

Anaplastic carcinomas are typically found in women, in older patients (mean age, 57 to 67 years), and in patients who present with rapidly enlarging masses in the neck. Hoarseness and dyspnea are common. Nearly 80% of patients have tumors greater than 5 cm in diameter. Cervical lymphadenopathy (40%), metastases to regional lymph nodes (50%), and distant metastases (50%) are common. Distant metastases commonly involve the lung, followed by metastases to bone and brain.

Microscopically, these tumors consist predominantly of spindle and giant cells (Fig. 25-5). It has been convincingly demonstrated that many, if not all, anaplastic tumors are accompanied by papillary and follicular carcinomas.95"98 They are also associated with medullary carcinoma, although this phenomenon is problematic.95-97 Some consider all anaplastic tumors as originating from preexisting medullary carcinomas. However, this is not the prevailing opinion, although anaplastic carcinomas do occur simultaneously with medullary carcinomas.

The anaplastic areas can resemble soft tissue sarcomas histologically.96 Histologic patterns that replicate osteogenic sarcomas, chondrosarcomas, giant cell tumors of bone, and fibrosarcomas have been documented. This phenomenon makes the diagnosis of primary soft tissue malignancies of the thyroid gland difficult to establish. An exception may be the hemangioendothelioma, a soft tissue sarcoma in the thyroid gland that has been reported nearly exclusively in Europe.97

Immunohistochemical methods play an important role in establishing the diagnosis of anaplastic thyroid cancer.95-97 The most consistent procedure is an immunohistochemical stain for keratin, positive in a great number of these tumors. Stains for thyroglobulin are inconsistent and unreliable.

FIGURE 25-5. Anaplastic carcinoma: spindle cells, giant cells, and neoplastic follicle (follicular carcinoma).

There are two viewpoints concerning the genesis of these tumors.95 97 The prevailing consensus is that the association with well-differentiated carcinomas is consistent; the contrary opinion contends that anaplastic carcinomas arise de novo.

The evidence for the de novo origin of anaplastic carcinomas is based on cytophotometric analysis of anaplastic tumors.95 Only a portion of the differentiated cancers associated with anaplastic cancers shared the aneuploidy of the anaplastic components, demonstrating that anaplastic tumors do originate de novo. However, a contrasting study showed that both elements can be aneuploid, and aneuploidy in differentiated tumors was predictive of anaplastic transformation. Aneuploidy is common in anaplastic cancers but is not a reliable prognostic factor. Coexistent papillary and follicular thyroid cancers in anaplastic carcinomas have similar cytogenetic patterns by comparative genomic hybridization, which suggests that anaplastic cancers may have arisen from the differentiated thyroid cancers.99

The genes and oncogenes associated with anaplastic cancers include p53, c-myc, NM23, and Ras.95 Activation of ras results in the expression of human H-ra.v, a rare phenomenon. Mutations of p53 have been found in most anaplastic cancers as well as in well-differentiated tumors, so the implication of their presence in thyroid tumors is uncertain.

The clinical course of these patients is alarmingly short, a mean survival of approximately 4 months. It is the rare patient who survives beyond a year. Comments have been made that the tumors of patients who survive for a long period should be re-examined for small cell tumors.

Anaplastic cancers occur most commonly in elderly people, but cases in patients younger than 40 years have been described.95"98 The youngest patient was 22 years of age.

The results of treatment of these tumors have been discouraging. The treatment modalities include surgery, external radiation, and chemotherapy. Varying combinations have been attempted, with poor results. Appropriate therapy for these tumors is yet to be developed.

One drastic change in the second WHO classification of thyroid tumors was the exclusion of anaplastic small cell carcinomas of the thyroid gland.8 The rationale was that tumors previously classified as small cell carcinomas had been identified as malignant lymphomas.95 97100 101 Small cell carcinomas of epithelial origin in the thyroid gland are either medullary carcinomas or neoplasms that resemble oat cell carcinomas of lung.102 The latter stain immunohisto-chemically like neuroendocrine tumors but do not contain calcitonin. These tumors were clinically aggressive and caused the deaths of the patients in a short time. These may be carcinomas similar to those that occur in other organs that are tumors of neuroendocrine cells, but are not medullary carcinomas of the thyroid gland.

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