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February 2010
Written by Teresa Goldin, MD, PGY-2 Resident, Department of Pathology and Laboratory Medicine, Medical University of South Carolina.

Submitting Pathologist
Wayne Christiansen, MD, Carolinas Medical Center, Charlotte, NC.

Diagnosis
Acute thymic involution due to fatal sepsis from Bordetella pertussis pneumonia.

Case History
This six week old full-term, previously healthy neonate, suffered a one week history of acute illness, complicated by pneumonia, sepsis and death. Cultures and molecular probes were positive for Bordetella pertussis.

Microscopic Description
This neonatal thymus gland exhibits an overall appearance of pallor, shrinkage and separation of lobules due to a relative prominence of interstitial and perivascular fibrous tissue with edema. The lobules show a complete loss of corticomedullary distinction and pronounced cortical lymphoid depletion. Intact, fully developed epithelial elements consisting of Hassall's corpuscles are evident; however, some postmortem autolytic artifact and cystic degeneration are present (see Figure 1).

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The appropriate lobular architecture and presence of intact Hassall's corpuscles provides evidence of normal thymic gland development and discounts the possibility of congenital or acquired thymic dysplasia.

Higher magnification shows rare, small mature lymphocytes with round, dark nuclei and small amounts of pale cytoplasm. Interestingly, this case also features numerous infiltrating eosinophils, the significance of which is not completely understood and is more likely related to the underlying infectious response, rather than a characteristic of the thymic involutional process (see Figure 2).

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Ancillary Studies
Paraffin section immunostains for CD1a, TdT and CD3 are performed. The presence of only faint, focal staining for CD1a and TdT indicates a marked depletion of immature thymocytes within the cortex (see Figure 3).

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A stain for CD3 shows a predominant, yet overall decreased amount of mature, T-lymphocytes in the thymic lobules, with a still undefined corticomedullary junction.

Discussion
Acute "stress" thymic involution, also known as thymic atrophy, is a remarkable reduction in functioning, thymic, lymphocytic tissue secondary to a variety of causes, such as malnutrition, infection (e.g. sepsis or human immunodeficiency virus [HIV]), immunosuppressive or cytotoxic drugs, graft-versus-host disease, and others (1). Stress-related involution appears to be related to aberrancies of the hypothalamic-pituitary-adrenal axis, with particular mediation by adrenocorticotropin hormone (ACTH) (4). Histologically, this entity is characterized by marked thymic lymphocyte depletion, predominantly involving the CD1a+ thymocytes, with intact unaffected epithelial elements (1,2).

The normal thymus gland consists of an encapsulated, lobulated organ with distinct cortical and medullary compartments. The tissue components are divided into endodermally derived epithelial elements, consisting of structural dendritic cells and Hassall's corpuscles, and bone marrow derived T-lymphocytes. The maturing lymphocytes, typically composed of many CD3, CD1a and TdT positive cells, preferentially densely pack the cortex. The thymus gland is functionally responsible for the maturation of T-lymphocytes (2). The gland develops in early fetal life and continues to grow until about one year of life, after which a gradual involution occurs into adulthood.

In 1988, Van Baarlen and colleagues published a reproducible histologic grading system for acute thymus involution that showed a consistent positive correlation with the duration of acute illness (3). A summary of this grading system is as follows:

  • Grade 0: Resting state, with appropriate corticomedullary distinction, closely-packed lobules and absence of lymphophagocytosis in the cortex.
  • Grade 1: Similar appearance to grade 0, yet with some lymphophagocytosis within the cortex.
  • Grade 2: Characterized by more pronounced lymphophagocytosis, giving the cortex a 'starry sky' pattern, early separation of lobules by increased interstitial fibroconnective tissue.
  • Grade 3: Loss of corticomedullary distinction due to advanced lymphophagocytosis, foci of lymphodepletion and increased separation of the thymic lobules.
  • Grade 4: Defined by even more cortical lymphodepletion, with a "reversal" of lymphocyte density, or continued loss of corticomedullary distinction, advanced separation of the lobules with prominence of interstitium and blood vessels.

Overall, the majority of grade 1 or 2 histology was associated 48 hours or less of acute illness and nearly all histologic grade 4 thymuses were found in cases with over 72 hours illness duration (3). Our case, which resulted in an unfortunate fatal outcome, after greater than a week of acute illness, showed severe lymphodepletion, absence of a corticomedullary junction, and advanced separation of the lobules, indicating grade 4 acute thymus involution. Another group found similar morphologic abnormalities of thymuses in fetuses and neonates with chorioamnionitis, with or without the presence of sepsis (4).

The primary differential diagnosis to consider in thymic atrophy is the congenital, inherited thymic malformations, generically grouped under the term 'thymic dysplasia'. Thymic dysplasia may be the result of several inherited conditions, including ataxia telangiectasia, Nezelof syndrome, the incomplete form of DiGeorge syndrome and most commonly the X-linked and autosomal recessive forms of severe combined immunodeficiency syndrome (2). Histologically, these thymic atrophy and thymic dysplasia can be distinguished by the appearance of the epithelial elements, namely, the Hassall's corpuscles. In congenital primary immunodeficiencies, the epithelial elements are morphologically abnormal or absent; whereas, in secondary thymic atrophy, as was present in our case, the lymphoid elements are markedly decreased or absent, and the Hassall's corpuscles, basement membrane material and structural dendritic cells remain intact (1). It is important to note that some inherited T-cell immunodeficiencies, namely bare lymphocyte syndrome (lack of MHC class II expression), Wiskott-Aldrich disease and defective interleukin (IL)-2 disease are associated with a thymic atrophy morphologic picture, rather than thymic dysplasia, and should be eliminated through additional clinical testing, when indicated (1).

References

  1. Nezelof C.
    Thymic pathology in primary and secondary immunodeficiencies.
    Histopathology. 1992; 21: 499-511
    .

  2. Rosai J. Thymus
    Pp. 462-464, in Rosai and Ackerman's Surgical Pathology. 9th ed. Rosai J, ed. Philadelphia, Elsevier, Inc. 2004.

  3. Van Baarlen J, Schuurman HJ, Huber J.
    Acute thymus involution in infancy and childhood: A reliable marker for duration of acute illness.
    Human Pathology. 1988; 19: 1155-1160
    .

  4. Toti P, De Felice C, Stumpo M, et al.
    Acute thymic involution in fetuses and neonates with chorioamnionitis.
    Human Pathology. 2000; 31: 1121-1128
    .

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