Studer H, Derwahl M
University Clinic of Internal Medicine, Laboratory of Endocrinology, Bern, Switzerland.
Endocr Rev. 1995 Aug;16(4):411-26. doi: 10.1210/edrv-16-4-411.
An important part of clinical endocrinology deals with diseases caused by benign and malignant nodules growing within originally homogeneous endocrine glands. In the search for the pathogenesis of these nodules, two concepts have been advanced: either the hyperplastic tissue is considered to result from chronic intense stimulation by a trophic hormone, eventually causing the growth of polyclonal nodules (a concept known as NNEH) or else, the nodules are thought to represent true clonal tumors. It has been realized rather recently that NNEH accounts only for a small minority of rare endocrine diseases, with the exception of highly prevalent iodine deficiency goiters and, in a broader sense, for Graves' disease. Indeed, secondary hyperplasia of endocrine glands resulting from long-lasting chronic hormonal overstimulation cannot explain a large number of essential features of the diseased glands. As best documented for the thyroid gland, outstanding among the characteristics of hyperplastic glands that do not fit into the simple concept of NNEH are the inevitable nodular transformation, the frequent autonomy and irreversibility of nodular growth, the loss of function in many cells and nodules, and the tremendous regional heterogeneity of growth and function including loss of coordination between these two main features of any living cell. Hyperplasia resulting from long-lasting stimulation by a trophic hormone is not a fully reversible process, as is often thought, but definitely increases the total cell mass and leaves behind, after cessation of the stimulus, a population of newly generated cells. This process is common to NNEH and true neoplastic growth. A review of common and disparate traits between endocrine hyperplasia and neoplasia must be based on the following generally accepted facts (excluding in-depth consideration of malignancy). 1. Many endocrine tumors are clonal while others are polyclonal. For example, pituitary and sporadic parathyroid adenomas are nearly always clonal while in the thyroid, multiple clonal nodules of different origin may coexist with polyclonal nodules. 2. Clonal growth does not necessarily indicate that the autonomous expansion of a tumor is driven by presently known genetic gain-of-function or loss-of-inhibition mutations or by cytogenetic aberrations. 3. Genetic mutations and chromosomal aberration in endocrine tumors are not necessarily primary events in the tumorigenesis but may as well be a late secondary phenomenon in growing tissue. 4. Clonal nodules may overgrow from primarily polyclonal ones. The best evidence to date comes from the rare clonal parathyroid adenomas with allelic loss of chromosome 11 evolving in tertiary hyperparathyroidism.(ABSTRACT TRUNCATED AT 400 WORDS)
临床内分泌学的一个重要部分涉及由原本均匀的内分泌腺体内生长的良性和恶性结节所引起的疾病。在探寻这些结节的发病机制时，提出了两种观点：一种认为增生组织是由促激素的慢性强烈刺激导致的，最终引起多克隆结节生长（这一观点被称为非肿瘤性结节性内分泌增生，NNEH）；另一种则认为这些结节代表真正的克隆性肿瘤。直到最近人们才认识到，除了高度流行的碘缺乏性甲状腺肿以及广义上的格雷夫斯病外，NNEH仅占少数罕见的内分泌疾病。事实上，长期慢性激素过度刺激导致的内分泌腺继发性增生无法解释患病腺体的许多基本特征。以甲状腺为例，增生性腺体的特征中不符合NNEH简单概念的突出表现包括不可避免的结节性转变、结节生长频繁的自主性和不可逆性、许多细胞和结节的功能丧失，以及生长和功能的巨大区域异质性，包括这两个任何活细胞主要特征之间协调性的丧失。由促激素长期刺激引起的增生并非如通常所认为的那样是一个完全可逆的过程，而是肯定会增加细胞总量，并且在刺激停止后留下一群新生成的细胞。这一过程在NNEH和真正的肿瘤性生长中都很常见。对内分泌增生和肿瘤形成之间的共同及不同特征进行综述必须基于以下普遍认可的事实（不深入考虑恶性肿瘤）。1. 许多内分泌肿瘤是克隆性的，而其他一些则是多克隆性的。例如，垂体腺瘤和散发性甲状旁腺腺瘤几乎总是克隆性的，而在甲状腺中，不同起源的多个克隆性结节可能与多克隆结节共存。2. 克隆性生长并不一定表明肿瘤的自主扩张是由目前已知的功能获得性或抑制缺失性基因突变或细胞遗传学畸变驱动的。3. 内分泌肿瘤中的基因突变和染色体畸变不一定是肿瘤发生的原发性事件，也可能是生长组织中的晚期继发性现象。4. 克隆性结节可能从最初的多克隆结节中过度生长。迄今为止最好的证据来自于在三发性甲状旁腺功能亢进中出现的罕见的伴有11号染色体等位基因缺失的克隆性甲状旁腺腺瘤。
