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A 72-Year-Old Woman With Previous Pulmonary Metastasis and New Peripheral NoduleWoman With a New Pulmonary Peripheral Nodule FREE TO VIEW

Giovanni Maria Comacchio, MD; Chiara Giraudo, MD; Nazarena Nannini, MD; Alessandro Rebusso, MD; Roberta Polverosi, MD; Federico Rea, MD; Fiorella Calabrese, MD
Author and Funding Information

From the Division of Thoracic Surgery (Drs Comacchio, Rebusso, and Rea), and the Pathological Anatomy Section (Drs Nannini and Calabrese), Department of Cardiothoracic and Vascular Sciences, and the Radiology Section (Dr Giraudo), Department of Medicine, University of Padova, Padova; and the Department of Radiology (Dr Polverosi), Hospital of S. Donà di Piave, Venice, Italy.

CORRESPONDENCE TO: Fiorella Calabrese, MD, Department of Cardiothoracic and Vascular Sciences, Pathological Anatomy Section, University of Padova Medical School, via A.Gabelli 61, 35121 Padova, Italy; e-mail: fiorella.calabrese@unipd.it


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):e42-e47. doi:10.1378/chest.14-2598
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A 72-year-old female nonsmoker was admitted to our Thoracic Surgery Unit in 2013 because of a lesion detected on chest CT scan during oncologic follow-up. Her medical history was significant for the development of a single pulmonary metastasis discovered 1 year after sigmoidectomy for colic adenocarcinoma. At that time, the patient was treated with six cycles of neoadjuvant chemotherapy followed by left lower lobectomy. Histologic examination demonstrated a pulmonary metastasis of colic adenocarcinoma with diffuse necrotic areas. The patient underwent subsequent adjuvant chemotherapy with capecitabine and was followed annually with biohumoral oncologic screening (carcinoembryonic antigen, carbohydrate antigen 19-9), chest-abdomen CT scan, and colonoscopy.

Figures in this Article

Three years after the end of chemotherapy, a circumscribed, subpleural nodule in the right lower lobe was newly discovered. CT scan showed a 1 × 1-cm lesion with a low, small central attenuation area and without any contrast enhancement. There was no pleural effusion or enlarged mediastinal lymph nodes (Figs 1A-C). PET-CT scanning was performed to assess the metabolic activity of the nodule, and no pathologic fludeoxyglucose uptake occurred (Fig 1D).

Figure Jump LinkFigure 1 –  A and B, Chest CT scan showing the well-circumscribed subpleural nodule in the posterior segment of the right lower lobe. A, Axial image. B, Coronal image. C, Axial postcontrast chest CT scan (mediastinal window) and magnification of the nodule (C1) demonstrating the absence of contrast enhancement and the central low-attenuation area (arrows). D, Images from PET-CT scan demonstrating the absence of pathologic uptake of the solitary pulmonary nodule (from right to left and top to bottom: axial thoracic CT scan, PET scan, PET-CT scan fusion, and PET scan into coronal plane).Grahic Jump Location

Tumoral markers and other blood investigations, including major infectious assays and coagulation parameters, were negative. Abdominal CT scan and colonoscopy showed no signs of local recurrence. The patient denied any weight loss, fever, or other constitutional symptoms. She had blood hypertension and type 2 diabetes, both under medical treatment. She was a retired farmer and lived in a rural humid area, near a river, with house pets (cats). She had not taken any recent trips abroad.

Because of the previous metastasis, the nodule was considered a suspicious finding interpreted as a neoplastic lesion. The patient underwent wedge resection of the nodule by right video-assisted throracoscopic surgery.

The specimen was formalin fixed and paraffin embedded. Macroscopically, the nodule appeared firm in consistency and grayish-yellow in color. Microscopically, it showed central coagulative necrosis corresponding to the attenuation area on CT scan. The lesion was characterized by a granulomatous reaction with lymphocytes mainly aggregated in follicular patterns, eosinophils, histiocytes, and occasional multinucleated cells (Figs 2A, 2B). Elastic Van Gieson stain showed occlusion of the peripheral pulmonary artery with material strongly positive to Grocott’s methenamine silver and periodic acid-Schiff stains (Figs 2C, 2D).

Figure Jump LinkFigure 2 –  Histology. A, Panoramic view of the nodule (diameter maximum 1 cm) with slight pleural indentation (hematoxylin and eosin [H&E], original magnification × 3). B, At high magnification, the nodule shows coagulative necrosis with a rim of granulation tissue and lymphomonocyte infiltration with follicular pattern (H&E, original magnification × 25). C, Elastic Van Gieson stain shows arterial wall (arrow) (original magnification × 20). D, Periodic acid-Schiff stain highlights strongly degenerating worm fragments (arrows) (original magnification × 20).Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary dirofilariasis
Clinical Discussion

Dirofilariasis is a group of parasitoses caused by a nematode of the genus Dirofilaria (Filarioidea; Onchocercidae) naturally hosted by dogs, cats, and other mammals. It was first described in the 17th century by Birago as canine filariae. The first case of human pulmonary dirofilariasis was described by Dashiell in the United States in 1961.1,2

Among all Dirofilaria species, the most relevant are immitis and repens. The first causes cardiopulmonary dirofilariasis, whereas the latter mainly produces ocular/subcutaneous lesions.

Host-to-host infection is transmitted by mosquitos (Culex, Aedes, Anopheles families), the intermediate vector. When a mosquito bites infected animals, it ingests the worm’s larvae, or microfilariae. Over the next 10 to 16 days, the larvae develop into the infective stage in the mosquito and are transmitted to another host after the bite. In the definitive host, the larvae become mature worms that reside in the site of inoculation or migrate to the right ventricle, producing a debilitating disease involving the pulmonary circle, leading the host to death caused by right-sided heart failure (Fig 3).

In contrast, the human environment is unsuitable for propagation of the parasite’s vital cycle: When an infected mosquito bites a human, the larvae of Dirofilaria develop for a time in the inoculation sites and eventually die, leading to nodule formation. In rare cases, such as conditions of reduced immunosurveillance, immature worms can move to the right ventricle, reach the pulmonary arteries, and lodge in a small caliber vessel, triggering an inflammatory response that destroys the worms, occasionally resulting in pulmonary nodules (Fig 3).1,3,4

This zoonosis has a worldwide distribution with differences among ocular/subcutaneous and pulmonary cases. Whereas the latter is predominant in the Americas, subcutaneous/ocular dirofilariasis is more frequent in the Old World, where pulmonary cases are sporadic. In Europe, 33 cases of pulmonary dirofilariasis had been described up to 2012.1,5 The distribution can be different in the same country because mosquitos are prevalent in wetlands. The patient lived near the Po river, a high-risk area.1 Two other important factors in this case were her occupation (farmers are at higher risk because of increased exposure to the source of infections) and her contact with domestic animals. Reduced immunosurveillance (previous oncologic treatment, history of diabetes, age) could have influenced the risk in this patient.

Patients with pulmonary dirofilariasis are generally adults and asymptomatic; however, cough, chest pain, hemoptysis, fever, and wheezing have been described in some patients.1,6 Lung nodules are accidentally detected on chest radiograph/CT screening generally performed for other reasons. The diagnostic challenge is to differentiate dirofilariasis nodules from malignant lesions. Serologic tests, bronchial washing, and radiologic findings lack specificity for an accurate diagnosis. Indirect hemagglutination tests may be difficult to interpret because of cross-reactions with a variety of human helminthic parasites. Eosinophilia, described in only 15% of cases,1 was absent in the patient. However, even if eosinophilia had been positive, it would not have been helpful in excluding a neoplastic hypothesis because it may be present in a few neoplastic diseases (1%), both primary and metastatic, as paraneoplastic syndrome.

Even if transthoracic fine-needle biopsy is safe for the patient (dead worm), surgical biopsy is mandatory for the final diagnosis because of difficulties in identifying this pathology and in excluding neoplastic disease. In this case, surgical resection was performed for definitive diagnosis and treatment. After nodulectomy, no additional medical treatment is necessary.1,2

Radiologic Discussion

Because a pulmonary infarction is the pathophysiologic mechanism underlying human pulmonary dirofilariasis,7 the main radiographic findings consist of subpleural solitary or multiple noncalcified well-circumscribed nodules. Calcifications are described in the literature as rare and late events.8 The lesions usually measure 1 to 4 cm in diameter.6

There is some controversy about lobe predilection.9 Indeed, some authors have reported (as in our case) a right lower lobe predominance,6,10 whereas Ciferri11 did not find any specific pattern of distribution.

Although in some pulmonary dirofilariasis cases a wedge-shaped pattern has been described (as in classic thromboembolic infarct) together with central high attenuation areas and peripheral ground glass,12 the common pattern of the nodules, on contrast-enhanced CT scan, is composed of well-defined round or oval lesions with a low central attenuation.10 The roundish shape is thought to be the result of centrifugal diffusion of the parasite antigen from the degenerating worm,13 and the low attenuation is presumably caused by the coagulative necrosis occurring in the core. The different imaging features of pulmonary dirofilariasis may be related to the time after onset of arterial occlusion by the parasite. On thin-section contrast enhanced CT scan, a positive vascular sign is often detected, representing the connection between the nodule and the adjacent vascular branch, as well as that with the occluded arterial branch.10

Because pulmonary dirofilariasis appears most frequently as a lung nodule, the main differential diagnosis of pulmonary solitary nodules should always be considered (eg, primary malignant tumor, metastases, carcinoid, hamartoma, TB, fungal infection).14 In our case, the history of a tumor and the basal location of the round lesion, in addition to the lack of peculiar CT scan signs of pulmonary infarct (eg, wedge-shaped lesions, halo sign) and the absence of symptoms and microbiologic evidence of sepsis, were highly suggestive that the nodule was of a metastatic nature (Table 1).

Table Graphic Jump Location
TABLE 1 ]  Main Features of SPNs

SPN = solitary pulmonary nodule; SUV = standardized uptake value.

a 

Previous or current smoker.

b 

Larger nodules (approaching 3 cm in diameter) are more likely to be malignant.

This patient had previously had metastatic colorectal cancer; thus, according to the literature,15 she had a relevant risk of either a primary malignant tumor or metastatic disease. Fludeoxyglucose-PET scanning alone is considered to be an accurate noninvasive imaging test with 96.8% sensitivity and 77.8% specificity for malignant nodules as reported by the meta-analysis of Sim et al.16 As far as we know, pulmonary dirofilariasis has been investigated by PET-CT scan in few cases; a low uptake has been reported in two patients.17,18

In our case, the PET-CT scan was normal. This finding may have suggested a benign lesion. However, PET scanning has limited sensitivity, producing false-negatives in well-differentiated adenocarcinoma, certain kinds of metastases (eg, mucinous cancer type), tumor with internal necrosis, and small lesion (up to 1 cm). The patient’s history of metastatic colon cancer and the controversial meaning of the negative PET-CT scan uptake, considered to be caused by the small size of the nodule, were evaluated overall as signs of recurrent pulmonary metastasis (Table 1). Although there are no specific imaging findings for pulmonary dirofilariasis and the diagnosis is made by histology, a critical awareness of molecular-imaging features (PET-CT scan) and radiologic signs, also those on contrast-enhanced CT scan, may facilitate its differentiation from a malignant nodule.

Pathologic Discussion

According to the Pathology of Infectious Diseases, a pulmonary dirofilariasis lesion consists of coagulative necrosis with a surrounding granulomatous reaction.19 In pulmonary cases, the worm is usually fragmented, and it is often difficult to recognize the cuticular ridges. Regressive processes of the worm and invasion of inflammatory cells may cause modifications of its structure. Careful examination of numerous pulmonary sections is necessary, using more suitable stains than the common hematoxylin and eosin. Elastic Van Gieson, silver methenamine Grocott’s, and/or periodic acid-Schiff stains are usually used to better evaluate vascular and larvae structures and overall for a differential diagnosis with other necrotic granulomatous lesions (eg, TB, fungal infections). Worm fragments are usually found in well-preserved pulmonary artery walls or outside the vessel when partial destruction of the wall occurs. If the parasite is not detectable clearly under the microscope, or has been strongly altered by regressive phenomena, immunohistochemistry on tissue sections with species-specific antisera can be used. Unfortunately, such antisera are not easy to find commercially. More sensitive and specific methods such as polymerase chain reaction, also technically feasible on paraffin-embedded tissue, could be applied in these cases, thus overcoming the limitation of DNA breaks using appropriate primers that amplify a short DNA fragment.20

Peripheral encapsulating walls and adjacent lung parenchyma show inflammatory cell infiltration characterized by eosinophils, lymphocytes (mainly T lymphocytes), occasional multinucleated giant cells, and lymphoid follicles.21 Although the lesion is the result of embolization, up to today, the mechanism of formation of spherical rather than wedge-formed shapes of the worm remains debatable. Some studies have reported the contributory role of inflammatory responses, considering the lesion to be a necrotizing granuloma rather than an infarction, with the spherical shape being attributed to diffusible dirofilarial antigens, as occurs in other granulomatous infections.7,19

Definitive diagnosis of pulmonary dirofilariasis always requires histologic examination. Considering the medical history of this patient, surgical excision of the nodule was indicated, especially with the suspicion of another pulmonary metastasis. In this patient, the presence of a newly discovered nodule in her strict oncologic follow-up undoubtedly influenced the risk stratification of the lesion. This entity should be kept in mind in the differential diagnosis of solitary pulmonary nodules, especially in countries where pulmonary dirofilariasis is endemic.

To date the patient is alive and in good health. She did not receive any therapy, in accordance with the literature.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors thank Judith Wilson, PhD, for English revision of the manuscript. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Simón F, Siles-Lucas M, Morchón R, et al. Human and animal dirofilariasis: the emergence of a zoonotic mosaic. Clin Microbiol Rev. 2012;25(3):507-544. [CrossRef] [PubMed]
 
Rena O, Leutner M, Casadio C. Human pulmonary dirofilariasis: uncommon cause of pulmonary coin-lesion. Eur J Cardiothorac Surg. 2002;22(1):157-159. [CrossRef] [PubMed]
 
Asimacopoulos PJ, Katras A, Christie B. Pulmonary dirofilariasis. The largest single-hospital experience. Chest. 1992;102(3):851-855. [CrossRef] [PubMed]
 
Schmidt LH, Dirksen U, Reiter-Owona I, et al. Pulmonary dirofilariasis in a Caucasian patient with metastasised osteosarcoma in a non-endemic European region. Thorax. 2011;66(3):270. [CrossRef] [PubMed]
 
Pampiglione S, Rivasi F, Angeli G, et al. Dirofilariasis due toDirofilaria repensin Italy, an emergent zoonosis: report of 60 new cases. Histopathology. 2001;38(4):344-354. [CrossRef] [PubMed]
 
Flieder DB, Moran CA. Pulmonary dirofilariasis: a clinicopathologic study of 41 lesions in 39 patients. Hum Pathol. 1999;30(3):251-256. [CrossRef] [PubMed]
 
Milanez de Campos JR, Barbas CS, Filomeno LT, et al. Human pulmonary dirofilariasis: analysis of 24 cases from São Paulo, Brazil. Chest. 1997;112(3):729-733. [CrossRef] [PubMed]
 
Ro JY, Tsakalakis PJ, White VA, et al. Pulmonary dirofilariasis: the great imitator of primary or metastatic lung tumor. A clinicopathologic analysis of seven cases and a review of the literature. Hum Pathol. 1989;20(1):69-76. [CrossRef] [PubMed]
 
Bielawski BC, Harrington D, Joseph E. A solitary pulmonary nodule with zoonotic implications. Chest. 2001;119(4):1250-1252. [CrossRef] [PubMed]
 
Oshiro Y, Murayama S, Sunagawa U, et al. Pulmonary dirofilariasis: computed tomography findings and correlation with pathologic features. J Comput Assist Tomogr. 2004;28(6):796-800. [CrossRef] [PubMed]
 
Ciferri F. Human pulmonary dirofilariasis in the United States: a critical review. Am J Trop Med Hyg. 1982;31(2):302-308. [PubMed]
 
Wand A, Kasirajan LP, Sridhar S. Solitary pulmonary nodule due to dirofilariasis. J Thorac Imaging. 2000;15(3):198-200. [CrossRef] [PubMed]
 
Jarratt M. Solitary pulmonary nodule in a 62-year-old man. Chest. 1995;107(1):271-273. [CrossRef] [PubMed]
 
Winer-Muram HT. The solitary pulmonary nodule. Radiology. 2006;239(1):34-49. [CrossRef] [PubMed]
 
Mery CM, Pappas AN, Bueno R, et al. Relationship between a history of antecedent cancer and the probability of malignancy for a solitary pulmonary nodule. Chest. 2004;125(6):2175-2181. [CrossRef] [PubMed]
 
Sim YT, Goh YG, Dempsey MF, Han S, Poon FW. PET-CT evaluation of solitary pulmonary nodules: correlation with maximum standardized uptake value and pathology. Lung. 2013;191(6):625-632. [CrossRef] [PubMed]
 
Kang HJ, Park YS, Lee CH, et al. A case of human pulmonary dirofilariasis in a 48-year-old Korean man. Korean J Parasitol. 2013;51(5):569-572. [CrossRef] [PubMed]
 
So T, Mitsueda R, Miyata T, et al. Pulmonary dirofilariasis in a 59-year-old man. J Surg Case Rep. 2014;2014(8).
 
Marty AM, Neafie RC. Dirofilariasis.. In:Meyers WM., ed. Pathology of Infectious Diseases. Vol 1. Helminthiases. Washington, DC: Armed Forces Institute of Pathology, American Registry of Pathology; 2000:275-285.
 
Rivasi F, Boldorini R, Criante P, Leutner M, Pampiglione S. Detection ofDirofilaria(Nochtiella) repens DNA by polymerase chain reaction in embedded paraffin tissues from two human pulmonary locations. APMIS. 2006;114(7-8):567-574. [CrossRef] [PubMed]
 
Araya J, Kawabata Y, Tomichi N, et al. Allergic inflammatory reaction is involved in necrosis of human pulmonary dirofilariasis. Histopathology. 2007;51(4):484-490. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  A and B, Chest CT scan showing the well-circumscribed subpleural nodule in the posterior segment of the right lower lobe. A, Axial image. B, Coronal image. C, Axial postcontrast chest CT scan (mediastinal window) and magnification of the nodule (C1) demonstrating the absence of contrast enhancement and the central low-attenuation area (arrows). D, Images from PET-CT scan demonstrating the absence of pathologic uptake of the solitary pulmonary nodule (from right to left and top to bottom: axial thoracic CT scan, PET scan, PET-CT scan fusion, and PET scan into coronal plane).Grahic Jump Location
Figure Jump LinkFigure 2 –  Histology. A, Panoramic view of the nodule (diameter maximum 1 cm) with slight pleural indentation (hematoxylin and eosin [H&E], original magnification × 3). B, At high magnification, the nodule shows coagulative necrosis with a rim of granulation tissue and lymphomonocyte infiltration with follicular pattern (H&E, original magnification × 25). C, Elastic Van Gieson stain shows arterial wall (arrow) (original magnification × 20). D, Periodic acid-Schiff stain highlights strongly degenerating worm fragments (arrows) (original magnification × 20).Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Main Features of SPNs

SPN = solitary pulmonary nodule; SUV = standardized uptake value.

a 

Previous or current smoker.

b 

Larger nodules (approaching 3 cm in diameter) are more likely to be malignant.

References

Simón F, Siles-Lucas M, Morchón R, et al. Human and animal dirofilariasis: the emergence of a zoonotic mosaic. Clin Microbiol Rev. 2012;25(3):507-544. [CrossRef] [PubMed]
 
Rena O, Leutner M, Casadio C. Human pulmonary dirofilariasis: uncommon cause of pulmonary coin-lesion. Eur J Cardiothorac Surg. 2002;22(1):157-159. [CrossRef] [PubMed]
 
Asimacopoulos PJ, Katras A, Christie B. Pulmonary dirofilariasis. The largest single-hospital experience. Chest. 1992;102(3):851-855. [CrossRef] [PubMed]
 
Schmidt LH, Dirksen U, Reiter-Owona I, et al. Pulmonary dirofilariasis in a Caucasian patient with metastasised osteosarcoma in a non-endemic European region. Thorax. 2011;66(3):270. [CrossRef] [PubMed]
 
Pampiglione S, Rivasi F, Angeli G, et al. Dirofilariasis due toDirofilaria repensin Italy, an emergent zoonosis: report of 60 new cases. Histopathology. 2001;38(4):344-354. [CrossRef] [PubMed]
 
Flieder DB, Moran CA. Pulmonary dirofilariasis: a clinicopathologic study of 41 lesions in 39 patients. Hum Pathol. 1999;30(3):251-256. [CrossRef] [PubMed]
 
Milanez de Campos JR, Barbas CS, Filomeno LT, et al. Human pulmonary dirofilariasis: analysis of 24 cases from São Paulo, Brazil. Chest. 1997;112(3):729-733. [CrossRef] [PubMed]
 
Ro JY, Tsakalakis PJ, White VA, et al. Pulmonary dirofilariasis: the great imitator of primary or metastatic lung tumor. A clinicopathologic analysis of seven cases and a review of the literature. Hum Pathol. 1989;20(1):69-76. [CrossRef] [PubMed]
 
Bielawski BC, Harrington D, Joseph E. A solitary pulmonary nodule with zoonotic implications. Chest. 2001;119(4):1250-1252. [CrossRef] [PubMed]
 
Oshiro Y, Murayama S, Sunagawa U, et al. Pulmonary dirofilariasis: computed tomography findings and correlation with pathologic features. J Comput Assist Tomogr. 2004;28(6):796-800. [CrossRef] [PubMed]
 
Ciferri F. Human pulmonary dirofilariasis in the United States: a critical review. Am J Trop Med Hyg. 1982;31(2):302-308. [PubMed]
 
Wand A, Kasirajan LP, Sridhar S. Solitary pulmonary nodule due to dirofilariasis. J Thorac Imaging. 2000;15(3):198-200. [CrossRef] [PubMed]
 
Jarratt M. Solitary pulmonary nodule in a 62-year-old man. Chest. 1995;107(1):271-273. [CrossRef] [PubMed]
 
Winer-Muram HT. The solitary pulmonary nodule. Radiology. 2006;239(1):34-49. [CrossRef] [PubMed]
 
Mery CM, Pappas AN, Bueno R, et al. Relationship between a history of antecedent cancer and the probability of malignancy for a solitary pulmonary nodule. Chest. 2004;125(6):2175-2181. [CrossRef] [PubMed]
 
Sim YT, Goh YG, Dempsey MF, Han S, Poon FW. PET-CT evaluation of solitary pulmonary nodules: correlation with maximum standardized uptake value and pathology. Lung. 2013;191(6):625-632. [CrossRef] [PubMed]
 
Kang HJ, Park YS, Lee CH, et al. A case of human pulmonary dirofilariasis in a 48-year-old Korean man. Korean J Parasitol. 2013;51(5):569-572. [CrossRef] [PubMed]
 
So T, Mitsueda R, Miyata T, et al. Pulmonary dirofilariasis in a 59-year-old man. J Surg Case Rep. 2014;2014(8).
 
Marty AM, Neafie RC. Dirofilariasis.. In:Meyers WM., ed. Pathology of Infectious Diseases. Vol 1. Helminthiases. Washington, DC: Armed Forces Institute of Pathology, American Registry of Pathology; 2000:275-285.
 
Rivasi F, Boldorini R, Criante P, Leutner M, Pampiglione S. Detection ofDirofilaria(Nochtiella) repens DNA by polymerase chain reaction in embedded paraffin tissues from two human pulmonary locations. APMIS. 2006;114(7-8):567-574. [CrossRef] [PubMed]
 
Araya J, Kawabata Y, Tomichi N, et al. Allergic inflammatory reaction is involved in necrosis of human pulmonary dirofilariasis. Histopathology. 2007;51(4):484-490. [CrossRef] [PubMed]
 
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