Placenta

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 30, and is coccidioidomycosis of the placenta.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

Microscopic sections of the placenta show patchy but pronounced intervillous fibrin deposition with entrapped villi of variable viability. Foci of necrosis with nuclear fragmentation and dust are present in some areas. These areas are associated with a variably scant chronic inflammatory infiltrate. Granulomatous and acute inflammation are not identified. In some slides, similar areas of necrosis also involve the maternal decidua. Spherules and endospores of Coccidioides are abundantly distributed in areas of villous and decidual necrosis. The viable intervening villi show increased syncytial knots but are otherwise unremarkable. These findings are diagnostic of coccidioidomycosis of the placenta.

Coccidioidomycosis or valley fever is a fungal infection caused by Coccidioides immitis (primarily in California) or Coccidioides posadasii (primarily outside of California). The two are morphologically identical. The disease is endemic to the Southwestern states of the United States, with an estimated 150,000 infections and 75,000 deaths annually. The incidence of the disease is increasing, likely due to increasingly sensitive detection methodology, climate change, and increased numbers of elderly moving to endemic areas (eg, Arizona) from nonendemic states.

Although the disease is more common in men, pregnant women are at high risk for disseminated disease (40 to 100 times expected rate). The elderly, diabetics, and immunosuppressed patients are also vulnerable. Enzyme-linked immunoassays and immunodiffusion tests for anticoccidioidal antibodies may be falsely negative in immunocompromised patients, and therefore antigen testing is warranted in immunocompromised patients suspected to have coccidioidomycosis. The high risk for disseminated coccidioidomycosis in pregnancy is attributed to the alterations in cell-mediated immunity in pregnancy. Alterations in Th1, Th2, and Th17 cells, which mediate fetal allograft tolerance during pregnancy, interfere with mounting an effective response to coccidioidal infection. The high hormone levels of pregnancy further permit coccidioidal dissemination. The risk for dissemination increases as pregnancy advances, reaching almost 100% in the third trimester. Maternal disseminated disease was universally fatal before the advent of antifungal therapy, which has led to improved outcomes. Fetal transmission is uncommon and is believed to occur through inhalation/aspiration during delivery rather than from transplacental spread. On occasion, the primary diagnosis of disseminated coccidioidomycosis is made incidentally at placental examination. It is important not to miss this finding, as maternal treatment with antifungal therapy needs to be instituted and the newborn monitored for possible infection.

The gross examination of a placenta infected with Coccidioides most commonly shows multiple infarcts with or without punctate fibrin deposits in the parenchyma. Some authors report purulent lesions. However, these features are neither specific nor distinctive. Microscopically, the infarct-like areas show central necrosis with surrounding fibrotic villi enmeshed in fibrin. Early lesions may show a significant intervillous inflammatory response with neutrophils, plasma cells, and histiocytes. Granulomatous inflammation may be seen. Older, more chronic lesions may be bland without an inflammatory infiltrate. Spherules measuring 20 to 100 μm containing endospores measuring 2 to 10 μm are generally numerous and diagnostic of coccidioidomycosis. These are readily appreciated on H&E stain and are highlighted by PAS, Gomori, or Grocott methenamine silver stains (GMS). Of note, patients undergoing antifungal therapy during pregnancy may show only rare spherules or endospores, and a careful search may be necessary to identify the fungus.

Herpetic placentitis is the primary differential diagnosis for coccidioidal placentitis. Both infections may show bland villous necrosis without inflammation or necrotic villi associated with plasmacellular inflammation. Spherules and endospores may not be evident in treated coccidioidomycosis. However, in general, herpetic placentitis typically shows a more intense plasmacellular inflammation with plasmacellular villitis, funisitis, or deciduitis. Amnion cell necrosis and necrotizing funisitis are features of herpes simplex virus (HSV) infection and have not been reported with coccidioidomycosis. Stromal cells with viral cytopathic changes are diagnostic. Immunohistochemical staining confirms the diagnosis.

Chronic villitis of unknown etiology (CVUE) may mimic more chronic coccidioidal placentitis. CVUE is a relatively common placental lesion characterized by lymphocyte-predominant inflammation of placental villi. However, depending on the severity and activity of the disease, the villi show varying levels of inflammation, agglutination, fibrosis, and avascularity. However, spherules and endospores of Coccidioides are not identified in this setting.

Massive perivillous fibrin deposition is a lesion associated with adverse perinatal outcomes and is closely related to maternal floor infarction. Grossly, the placenta is stiff due to increased intervillous deposition of fibrin often forming a lattice-like network. Microscopically, increased intervillous fibrin entraps and chokes villi. Autoimmune and alloimmune factors are believed to play a role in the genesis of this lesion. Again, fungal organisms are not identified in this setting.

Fetal vascular malperfusion is another lesion associated with adverse perinatal outcome. Patchy, avascular, fibrotic villi admixed with villi showing villous stromal-vascular karyorrhexis and extravasated, fragmented red blood cells are present, indicative of vascular compromise in the fetal circulation. Upstream larger vessels may show fibrin or calcific deposits consistent with ischemic-thrombotic injury. These changes may be seen more globally in intrauterine fetal demise. Inflammation and fungal organisms are not seen.

1. Which of the following is true regarding the occurrence of coccidioidomycosis in pregnancy?
   
   1. Disseminated disease shows no predilection for a specific trimester.
      
   2. There is no risk for disseminated disease in pregnancy.
   3. The risk of dissemination is highest in the first trimester.
   4. The risk of dissemination is highest in the second trimester.
   5. The risk of dissemination is highest in the third trimester.
2. Which is the proposed mechanism for the altered immunologic response to coccidioidomycosis in pregnancy?
   
   
   1. Alterations in cellular immunity
   2. Alterations in endometrial stromal cell function​
   3. Alterations in humoral immunity
   4. Alterations in macrophage function
   5. Alterations in neutrophil function
3. Which of the following favors a diagnosis of herpes simplex virus infection over coccidioidal infection in the placenta?
   
   
   1. Bland villous necrosis
   2. Deciduitis
   3. Necrotizing funisitis
   4. Villous necrosis with granulomatous inflammation
   5. Villous necrosis with plasma cells

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1. The risk of dissemination is highest in the third trimester (e)
2. Alterations in cellular immunity (a)
3. Necrotizing funisitis (c)