Anaplasia

Definition

Differentiation refers to the extent to which neoplastic cells resemble the corresponding normal parenchymal cells, both morphologically and functionally. Anaplasia is the lack of this differentiation - literally meaning "backward formation" - implying dedifferentiation, or loss of the structural and functional characteristics of normal cells.

Tumors composed of undifferentiated cells are described as anaplastic, and this is a reliable indicator of malignancy. - Robbins & Kumar Basic Pathology, p. 217

Two Mechanisms of Anaplasia

In some cancers, apparently mature (differentiated) cells dedifferentiate during carcinogenesis. In others, tumors arise from stem cells in tissues, and the anaplastic appearance results from a failure to differentiate rather than true reversal. In either case, the end result is an undifferentiated, primitive-looking cell population. - Robbins & Kumar Basic Pathology, p. 217

Morphological Features of Anaplasia

Anaplastic cells exhibit a constellation of cytologic and architectural abnormalities:

1. Pleomorphism

Marked variation in cell size and shape within the same tumor. Cells range from small undifferentiated forms to enormous tumor giant cells, which may have a single huge polymorphic nucleus or two or more large, hyperchromatic nuclei.

Note: Tumor giant cells must not be confused with inflammatory Langhans or foreign body giant cells (which are macrophage-derived and contain many small, normal-appearing nuclei).

2. Abnormal Nuclear Morphology

Nuclei are disproportionately large - the nuclear-to-cytoplasm ratio may approach 1:1 (normal is 1:4 to 1:6)
Nuclear shape is irregular and variable
Chromatin is coarsely clumped, often distributed along the nuclear membrane
Nuclei are hyperchromatic (darker than normal)
Abnormally large nucleoli are common

3. Atypical Mitoses

Undifferentiated cancers contain many cells in mitosis, reflecting high proliferation rates. More diagnostically significant than mere frequency are bizarre, atypical mitotic figures (e.g., tripolar spindles) - these are a hallmark of malignancy.

4. Loss of Polarity

The normal orientation of cells with respect to each other and to basement membranes is markedly disturbed. Sheets or large masses of tumor cells grow in a disorganized fashion with no architectural order.

5. Ischemic Necrosis

The vascular stroma is often insufficient for rapidly growing anaplastic tumors, resulting in areas of ischemic necrosis within the tumor mass. - Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 255-257

Histological Illustrations

Fig. 7.6 - Anaplastic tumor showing cellular and nuclear variation in size and shape. The prominent cell in the center (arrow) has a tripolar spindle representing an abnormal mitosis:

Anaplastic tumor with tripolar mitotic spindle

Fig. 7.8 / 6.4 - Pleomorphic rhabdomyosarcoma showing marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells:

Pleomorphic rhabdomyosarcoma - anaplasia

Functional Consequences

Feature	Well-differentiated tumors	Anaplastic tumors
Resemblance to normal cells	Close	Little to none
Functional retention	Often present	Usually lost
Hormone secretion (endocrine tumors)	Retained	Lost
Keratin production (squamous)	Present	Absent
Ectopic functions	Rare	May emerge

Well-differentiated cancers often retain functional capabilities - thyroid adenocarcinomas may form follicles and secrete thyroid hormone, squamous cell carcinomas produce keratin (keratin pearls), and hepatocellular carcinomas may elaborate bile.

Anaplastic tumors typically lose these specialized functions, but can paradoxically acquire new, unanticipated functions. For example, bronchogenic (lung) carcinomas may secrete ACTH, parathyroid hormone-like hormone, insulin, or glucagon - giving rise to paraneoplastic syndromes. - Robbins, Cotran & Kumar, pp. 256-257

Related Concepts

Dysplasia

Dysplasia (disordered proliferation) is distinct from but related to anaplasia. Dysplastic epithelium shows:

Loss of uniformity of individual cells
Disturbed architectural orientation
Pleomorphism and hyperchromatic enlarged nuclei
Increased mitotic figures, sometimes in abnormal locations (e.g., superficial epithelium)
Loss of normal maturation sequence (e.g., normal basal-to-surface maturation in squamous epithelium)

When dysplastic changes are severe and span the full thickness of the epithelium, the lesion is called carcinoma in situ (CIS) - a preinvasive stage of cancer.

Important: Dysplasia is NOT synonymous with cancer. Mild-to-moderate dysplasia can regress if the causative factor is removed. However, dysplasia adjacent to a frank malignancy marks the tissue as high-risk. - Robbins & Kumar Basic Pathology, pp. 219-220

Summary Table: Differentiation Spectrum

Grade	Description	Example
Well-differentiated	Closely resembles normal tissue	Follicular thyroid adenocarcinoma
Moderately differentiated	Intermediate features	Many common carcinomas
Poorly/Undifferentiated (Anaplastic)	Little resemblance to origin; pleomorphic, mitotic, hyperchromatic	Anaplastic large cell carcinoma, GBM

Anaplasia is a reliable morphologic indicator of malignancy and correlates with aggressive behavior, higher grade, and worse prognosis. - Robbins & Kumar Basic Pathology, p. 217; Robbins, Cotran & Kumar, p. 255

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