Practical Diagnostic Approach to the Presence of Hyphae in Neuropathology Specimens With Three Illustrative Cases

Jesus A. Chavez, MD; Daniel J. Brat, MD, PhD; Steven B. Hunter, MD; Jose Velazquez Vega, MD; Jeannette Guarner, MD

Disclosures

Am J Clin Pathol. 2018;149(2):98-104. 

In This Article

Abstract and Introduction

Abstract

Objectives Early and accurate diagnosis remains crucial in the therapeutic management of invasive central nervous system fungal infections. Different molds have intrinsic resistance to antifungal agents; thus, morphologic differentiation is helpful to clinicians.

Methods Using three examples, we present a guide on how to approach neuropathology specimens where hyphae are identified on initial histologic examination.

Results Hyphae can be classified into three basic groups: hyaline pauciseptated, hyaline septated, and pigmented or dematiaceous. The hyaline pauciseptated group includes the order of the Mucorales (previously Zygomyces) and is frequent in patients with decompensated diabetes and severe neutropenia. Aspergillus species constitutes the most frequently isolated mold in the hyaline septated group. However, other invasive hyaline septated molds include Fusarium species, which is frequently resistant to multiple antifungals, and Candida species Last, dematiaceous molds, although infrequent, can be found in neuropathology specimens, as happened during the outbreak of Exserohilum associated with manufacturing practices in a compound pharmacy.

Conclusions Categorizing hyphae into the three groups described allows pathologists to provide information that is useful for infectious disease treatment with an inclusive differential diagnosis of diverse fungal genera that share the same morphological features.

Introduction

Molds are naturally occurring in the environment, and humans are constantly being exposed to them. However, invasive fungal infections (IFIs) due to molds occur only in those individuals who have certain risk factors, particularly those who are immunosuppressed. The number of immunosuppressed patients has increased as there are more patients receiving transplants (solid organ and hematopoietic stem cells), and immune modulators are given to patients with diverse autoimmune diseases. Also at risk are patients undergoing major surgeries, those on chemotherapeutic agents, patients with diabetes, and those infected with human immunodeficiency virus.[1–4]

The most frequent presentation of a mold infection in the central nervous system (CNS) is rhinocerebral mucormycosis. Patients are usually in ketoacidosis and have fever, respiratory failure, and neurologic deterioration.[5] Nasal endoscopy will demonstrate necrotic ulcers in the nasal mucosa and turbinates, and imaging will determine the extent of disease, which will guide surgical debridement. Aspergillus species and dematiaceous molds can also present with similar symptoms as rhinocerebral mucormycosis. Another presentation of mold infections in the CNS is an abscess. In these cases, mortality can be as high as 85% to 100%, and the causative agent is frequently Aspergillus.[6,7] In imaging, these patients have a polylobulated abscess with peripheral contrast enhancement and substantial inflammation in adjacent structures.[8] Other frequent fungal infections in the CNS include yeasts such as Candida species and Cryptococcus neoformans. It should be noted that although Candida are yeasts from the microbiologic perspective, in tissues sections, these show yeasts (round structures) together with hyphae and pseudohyphae (structures that appear as septated hyaline hyphae), which creates a morphologic dilemma for pathologists.

Histopathologic examination provides rapid diagnostic elements in cases of IFIs as it defines that the mold is invasive and can broadly indicate the type of hyphae present and host inflammatory response.[9] From the morphologic perspective, hyphae can be classified into three basic groups Figure 1: hyaline pauciseptated, hyaline septated, and pigmented or dematiaceous. The hyaline pauciseptated group includes the order of the Mucorales (previously Zygomyces). Aspergillus species constitutes the most frequently isolated mold in the hyaline septated group, although other invasive hyaline septated molds include Fusarium species, Scedosporium species, Paecilomyces species, Candida species, and others. Last, dematiaceous or pigmented molds, although infrequent, can be found in neuropathology specimens, as happened during the outbreak of Exserohilum associated with manufacturing practices in a compound pharmacy. It should be noted that genus and species cannot be determined with certainty when using histopathology and that misclassification of the hyphae can lead to clinical confusion and inadequate treatment.[1,9]

Figure 1.

Algorithm for diagnosis of hyphae. Note that first one has to define if the hyphae have pigment, then the amount of septations. Diverse genera of fungi can be observed in each group.

Following, we present three cases that exemplify a practical approach to diagnosis of molds observed in neuropathologic specimens.

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