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Case Report

Hypereosinophilic Syndrome Associated With Cervical Squamous Cell Carcinoma

Anup Hazra, MD; Richard Siderits, MD; Janusz J. Godyn, MD

While eosinophilia is associated with a host of diseases, prolonged persistence—ie, hypereosinophilic syndrome—is an ominous sign that warrants intensive investigation.

Eosinophils are a normal constituent of blood. Eosinophilia is defined as a serum eosinophil concentration of > 500/UL, and is common in many conditions. The hypereosinophilic syndrome is characterized by eosinophil values of > 1,500/UL for a sustained period of time in the absence of a specific etiology (eg, parasitic infection, allergy, skin disorder, pulmonary disease). This condition leads to multisystem organ dysfunction that includes the heart, central nervous system, bone marrow, kidneys, lungs, gastrointestinal (GI) tract, reproductive system, and skin.

This case presented here involves a 30-year-old woman with high eosinophil levels in the peripheral blood, bone marrow, and tumorous tissues; antemortem findings of a poorly differentiated, metastatic, squamous cell carcinoma (primary unknown) in the left supraclavicular lymph node; and postmortem confirmation of uterine squamous cell carcinoma with widespread metastasis. This case highlights the importance of immediately screening patients with hypereosinophilia of unknown etiology for malignancy.

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CASE REPORT

A 30-year-old, previously healthy Hispanic single mother with four children was admitted to the hospital emergency department for sharp abdominal pain, severe headache, fever of unknown origin, eosinophilia, and loss of appetite. There was no history of vomiting, diarrhea, urinary tract infection, or vaginal discharge. Evidence of smoking and drug or alcohol abuse was likewise absent.

Physical examination revealed a firm, tender mass in the right cul-de-sac and uterine cervix, with no hepatosplenomegaly. Significant laboratory results included high levels of serum calcium, alkaline phosphatase, and leukocytosis, with 13% eosinophils (reduced from 30% prior to admission). A stool test was positive for Clostridium difficile toxin.

Two months prior to admission, the patient had consulted with her internist for headache, when the high eosinophil count was first discovered. Physical and neurologic findings were essentially normal, as were results of blood culture, lumbar puncture, abdominopelvic computed tomography, whole-body bone/joint imaging, and chest radiography. However, there was mild retroperitoneal lymphadenopathy and a slight enlargement of the left supraclavicular lymph node. No exophytic cervical lesion could be identified on pelvic examination, and Papanicolaou findings were negative. Peripheral blood analysis revealed 30% eosinophils and the bone marrow showed a marked increase in the number of mature and immature eosinophils, but myeloblast numbers were not elevated in the peripheral blood or bone marrow. There was also no rise in expression of stem cell marker CD34 in the bone-marrow aspirate cell population.

Eosinophilic leukemia, lymphoma, and other common causes of eosinophilia were excluded at that time, and the etiology of the hypereosinophilic syndrome remained unknown. The enlarged left supraclavicular lymph node was excised, and showed metastatic, poorly differentiated squamous cell carcinoma. This was confirmed by immunohistochemical analysis, which was positive only for cytokeratin antibodies AE-l/AE-3 and the p63 gene. The patient was treated for disseminated squamous cell carcinoma of undetermined primary site. Multiorgan failure and paraneoplastic syndrome ensued, and the patient died.

Autopsy findings were significant for poorly differentiated squamous cell carcinoma originating in the upper uterine cervix, with extensive disseminated systemic lymphovascular and peri-neural invasion. The tumor had infiltrated deep into the cervix and myometrium with no exophytic lesion, explaining the negative gynecologic findings. Metastases extended to the endocardium, myocardium, pericardium, peritoneum, pericolonic adipose tissue, spleen, urinary bladder, adrenal glands, bilateral ovaries, and bone marrow.

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DISCUSSION

The complex pathophysiologic function of the eosinophils involves the release of a large array of mediators (eg, T cells, inflammatory cells, cytokine products) in association with circulatory and/or tissue eosinophilia in allergic diseases, skin disorders, parasitic infestations, infectious diseases, hypereosinophilic syndrome, blood diseases, and other conditions. Eosinophils are derived by hemopoiesis from CD34-positive myelocytic progenitors in the bone marrow. After they enter the circulation, their half-life is only about 1 day. Higher values are normally seen in the evening, with lower levels in the morning. There are four types of mediators in the cell: Lipid mediators and oxidative metabolites are elaborated directly from the cell membrane, while preformed, granule-derived cationic proteins and cytokines, chemokines, and growth factors are released during degranulation after granule-plasma membrane fusion.1

In various disease states, serum eosinophils transmigrate through the endothelium in to the target tissues, modulated by cytokines and chemokines. In some conditions (eg, asthma, allergy, skin disorders, parasitic infestations, certain malignancies), eosinophils are activated, degranulate, and release mediators at the tissue sites. By contrast, conditions such as pulmonary eosinophilias and eosinophilic pneumonia are characterized by inert eosinophilia without degranulation or tissue reaction.

Significant elevations in mean levels of immunoglobulins (IgA, IgE) have been found in patients with squamous cell carcinoma of the head and neck compared with healthy controls, and may be useful in monitoring malignant disease.2 In addition, marked tissue and circulating eosinophilia in association with squamous cell carcinoma of the oral cavity, external genitalia, and anus were correlated with metastases and poor prognosis.3 Similar findings were observed in the case presented here. In another case, metastatic anaplastic carcinoma of unknown primary site was detected 3 years after the diagnosis of eosinophilia.4 Eosinophilic infiltration was reported in sclerosing mucoepidermoid carcinoma related to low malignant potential. 5

Tumor-associated tissue eosinophilia is classified as mild, moderate, or intense. Intense tumor-associated tissue eosinophilia was found to confer a favorable prognosis, suggesting an antitumor function for eosinophils in oral squamous cell carcinoma.6 In some disseminated malignancies of the GI tract, tumor cells often produce interleukin-3, interleukin-5, and granulocyte-macrophage-colony-stimulating factor. These cytokines are known to support differentiation, proliferation, and survival of eosinophils, and appear to play a role in thromboembolism.7 Endomyocardial biopsy findings have shown that endothelial cells in the endocardium and the capillaries were the primary targets of the tissue damage, resulting in thrombosis, endomyocardial fibrosis, and eventual heart failure. Autopsy findings in this case revealed patchy endomyocardial fibrosis and cardiac failure. Here, metastatic carcinoma also caused severe bone pain, hypercalcemia, and renal failure.

Fauci et al8 have published a review of the clinical, pathophysiologic, and therapeutic considerations of hypereosinophilic syndrome. While there is no statistically significant difference in the number of eosinophils per mm2 identified by hematoxylin-eosin or immunostaining techniques in squamous cell carcinoma-associated eosinophilia,9 eosinophils can nonetheless serve as a marker for invasion in squamous neoplastic lesions.10

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CONCLUSION

Peripheral blood eosinophilia should alert the physician to investigate for serious medical or surgical diseases, especially when other common etiologies have been excluded. Specifically, patients with hypereosinophilia of unknown etiology should be screened regularly for malignancy.

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ACKNOWLEDGEMENT

The authors wish to thank Nenita P. McIntosh, MD; Mario D. Abad, Jr, MD; and Wilfredo Causing, MD, for useful clinical discussion in the clinicopathologic conference for this case.

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Anup Hazra, MD, is associate professor; Richard Siderits, MD, is assistant professor; and Janusz J. Godyn, MD, is professor. All are in the Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, and Robert Wood Johnson University Hospital at Hamilton.

References

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2. Vinzenz K, Pavelka R, Schonthal E, Zekert F. Serum immunoglobulin levels in patients with head and neck cancer (IgE, IgA, IgM, IgG). Oncology. 1986;43(5):316-322.
3. Lowe D, Fletcher CD. Eosinophilia in squamous cell carcinoma of the oral cavity, external genitalia and anus—clinical correlations. Histopathology. 1984;8(4):627-632.
4. Abali H, Altundag MK, Engin H, et al. Hypereosinophilia and metastatic anaplastic carcinoma of unknown primary. Med Oncol. 2001;18(4):285-288.
5. Urano M, Abe M, Horibe Y, et al. Sclerosing mucoepidermoid carcinoma with eosinophilia of the salivary glands. Pathol Res Pract. 2002; 198(4):305-310.
6. Dorta RG, Landman G, Kowalski LP, Lauris JR, Latorre MR, Oliveira DT. Tumour-associated tissue eosino- philia as a prognostic factor in oral squamous cell carcinomas. Histopathology. 2002;41(2):152-157.
7. Fridlender ZG, Simon HU, Shalit M. Metastatic carcinoma presenting with concomitant eosinophilia and thromboembolism. Am J Med Sci. 2003; 326(2):98-101.
8. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. 1982;97(l):78-92.
9. Lorena SC, Dorta RG, Landman G, Nonogaki S, Oliveira DT. Morphometric analysis of the tumor associated tissue eosinophilia in the oral squamous cell carcinoma using different staining techniques. Histol Histopathol. 2003;18(3):709-713.
10. Agarwal S, Wadhwa N, Gupta G. Eosinophils as a marker for invasion in cervical squamous neoplastic lesions. Int J Gynecol Pathol. 2003;22(2):213.

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