A Paraneoplastic Leukemoid Reaction in Primary Lung Sarcoma

Pulmonary malignancies are known to have high prevalence and mortality. They are associated with different paraneoplastic syndromes, especially pulmonary carcinomas, because they are more common than pulmonary sarcomas. We present a case of a 56-year-old African American male who was admitted to our institution with a three-month history of a dry cough, progressive shortness of breath, and two to three days of right arm swelling. He had extreme leukocytosis (WBC count of 106,500 cells/mm3). Computed tomography (CT) scan of the thorax demonstrated an irregular, thick-walled 14-cm lung mass occupying the middle and upper hemithorax. CT-guided biopsy of the mass confirmed the diagnosis of lung sarcoma.


Introduction
Lung cancers are characterized by high incidence, prevalence, and mortality. It is known that lung carcinoma is the most common type of lung cancer. Epithelial subtypes of lung cancer are the most encountered ones [1]. Primary pulmonary sarcomas (PPSs) are an exceedingly rare, aggressive, and diverse group of non-epithelial malignant tumors of the mesenchymal tissue of the bronchial wall, vessels, or pulmonary stroma origin. They comprise only 0.013%-1.1% of all malignant lung tumors [2,3]. It has been estimated that the lung carcinoma:sarcoma ratio is around 500:1 [4].
Pulmonary malignancies are associated with many paraneoplastic syndromes. Because lung carcinomas are more common than sarcomas, their paraneoplastic syndromes are also more common and tend to be welldescribed in the literature, especially with small cell lung carcinoma [2]. When leukocytosis exists as a white blood cell (WBC) count of more than 50,000 cells/mm 3 of mature, non-clonally derived neutrophils, which is associated with a malignancy, it is defined as a paraneoplastic leukemoid reaction (PLR). Solid tumors have an association with PLR that has been documented in literature spanning decades [5]. PLR is usually found in 10% of solid tumors [6]. PPS with an extreme leukocytosis has been described only a few times in the literature [7][8][9].
This case report describes a case of a PPS that had PLR. We present the case of a male patient who had a 14cm PPS with a WBC count of up to 120,000 cells/mm 3 , as well as our diagnostic investigation and the outcomes in his hospital course.

Case Presentation
Our patient was a 56-year-old African American male with a past medical history of schizoaffective disorder. He presented to our hospital with a three-month history of dry cough, orthopnea, and two to three days of right arm swelling. He also reported intermittent chest pain and progressive shortness of breath, as well as 10 pounds of weight loss in the past month. He denied hemoptysis and gastrointestinal symptoms. The patient had no consistent medical care. He had 10 pack-year smoking history. There was no known family history of cancer.
On admission, the patient was normotensive with a blood pressure of 130/66 mmHg, slightly tachycardic with a heart rate (HR) of 101 beats per minute, and slightly tachypneic with a respiratory rate (RR) of 20 breaths per minute; his oxygen saturation was 99% on room air and temperature was 37.4 degree Celsius. Physical examination revealed a pale, cachectic patient with prominent superficial vessels on the right chest. He had 2+ pitting edema of his right upper extremity as well as right axillary lymphadenopathy without cervical or supraclavicular lymphadenopathy. He did not have organomegaly. Pulmonary auscultation revealed decreased breath sounds in the right upper lobe with diffuse bilateral rales. No ptosis, miosis, or anhidrosis suggestive of Horner's syndrome was found on examination.
Chest X-ray (CXR) showed a uniform opaque mass occupying the right upper hemithorax of around 16 x 13 cm in size ( Figure 1).

CXR, chest X-ray
Computed tomography (CT) scan of the thorax with contrast showed an irregular, thick-walled, 14-cm lung mass occupying the middle and upper hemithorax and compressing the right mainstem bronchus. It also showed a filling defect in the left atrium, right atrial appendage, and right pulmonary vein. The defect was suspicious for a thrombus or tumor invasion ( Figure 2).

FIGURE 2: CT scan of the thorax with contrast.
An irregular, thick-walled, 14-cm lung mass occupying the middle and upper hemithorax and compressing the right mainstem bronchus. The image also shows a filling defect in the left atrium, right atrial appendage, and right pulmonary vein.

CT, computed tomography
CT-guided biopsy of the mass showed a high-grade malignant tumor. Immunohistochemistry showed tumor cells that were positive for vimentin, and negative for keratins (Cam 5.2, Ae1/Ae3), TTF-1, synaptophysin, chromogranin, p40, LCA, desmin, and actin. Additional immunohistochemical stains were performed to classify the tumor further, which included CD34, S100, CD31, CD45, CD20, and CD3. The tumor cells were negative for all those markers, which ruled out possible anaplastic B+ and T+ T-cell lymphomas, malignant peripheral nerve sheath tumors, and vascular tumors. The conclusion of these tumor marker results was most consistent with a primary lung sarcoma (Figure 3).

FIGURE 3: Histopathology of the mass showing a high-grade malignant tumor suggestive of sarcoma.
Differential diagnoses of the leukemoid reaction included infection and hematological malignancy. The detailed history and physical examination were not suggestive of any infection. The respiratory and blood cultures were negative. Fungal sources were also ruled out by beta-d-glucan level of <31 pg/mL (reference range: <59 pg/mL). CXR and CT scan of the thorax did not show any pneumonia (Figures 1, 2).
The likelihood of hematological malignancies was not high because a peripheral blood smear showed only neutrophilia and occasional pencil cells. Bone marrow biopsy was not performed because sarcomas rarely involve the bone marrow [10].
CT scans of the head, neck, and abdomen/pelvis were negative for any other possible primary malignancies.
Transthoracic echocardiogram showed a 1.8 x 1.7 cm globular and mobile density in the left atrium that appeared attached to the interatrial septum. Transesophageal echocardiogram showed a large, elongated, and mobile mass without a stalk that stretched from the right upper pulmonary vein into the left atrium. It measured at least 6 cm in length and 2 cm in width, suggesting heart invasion ( Figure 4).

FIGURE 4: Transesophageal echocardiogram showing a large and elongated mass of 6 x 2 cm that stretched from the right upper pulmonary vein into the left atrium, suggestive of heart invasion.
The patient was admitted to the medical intensive care unit for further evaluation and treatment. Initially, the patient was maintaining his own oxygen saturation without support. Seven days into his hospital visit, he started to require supplemental oxygen through a nasal cannula. Later, he became tachypneic with an RR of 42 breaths per minute and tachycardic with an HR of 120s with oxygen saturation decline. He was then intubated and required mechanical ventilation.
A multidisciplinary team was involved in the patient's care. After talking to palliative medicine specialists, the family decided to change the patient's condition to comfort measures and to withdraw life support, after which the patient passed away.

Discussion
Primary lung sarcomas are a rare subtype of pulmonary malignancies that infiltrate the lung parenchyma. They usually form well demarcated and nonencapsulated tumors that can spread inside bronchi but rarely infiltrate bronchial epithelium [2]. Thorough clinical history, radiographic evaluation, and tissue biopsy are important in lung sarcomas' evaluation, as it is mandatory to rule out the possibility of an alternate primary sarcoma because the lung is one of the favored metastatic sites for soft tissue sarcomas [11].
There is a strong association between lung malignancies and leukocytosis as it was concluded by many studies, such as the study by Granger  The authors also noted that 16 patients had high serum granulocyte colony-stimulating factor (G-CSF) levels, with 12 tumors staining positively for G-CSF by immunohistochemistry [8].
A correlation between PLR and elevated serum concentrations of the hematopoietic growth factors (G-CSF), granulocyte-monocyte (GM)-CSF, and interleukin-6 in patients with lung cancer was first reported in 1977 by Asano et al. [12]. Further studies suggested a mechanism of an autocrine positive feedback loop, in which cytokines led to auto-stimulation of their respective aberrantly expressed receptors on tumor cells, resulting in tumor proliferation as well as off-target stimulation of granulocytopoiesis and corresponding PLR [6,13]. In one case report of an undifferentiated lung sarcoma in a 54-year-old female with a WBC count of 130,000 cells/mm 3 (96% of neutrophils), the authors reported that G-CSF serum concentration was significantly elevated (6,538 pg/mL) compared to serum levels of normal controls and patients with elevated leukocytes (31 and 387 pg/mL, respectively) [14].
Unfortunately, PLR is considered a poor prognostic sign in lung sarcoma. In the study conducted by Granger and Kontoyiannis, the authors concluded that 76% of patients diagnosed with PLR died within 12 weeks [7]. In general, lung sarcoma itself carries a poor prognosis with the cumulative five-year overall survival of 27%-38% for PPS according to two different studies [2,15].

Conclusions
Malignancies involving the pulmonary system are common. Lung carcinoma is the most common type whereas primary lung sarcoma is very rare. Because carcinomas are more common than sarcomas, they usually have more association with paraneoplastic syndromes including PLR. Our patient was a young male who was diagnosed with a PPS complicated by a PLR, which encouraged us to report to increase the healthcare professionals' awareness regarding such rare encounters.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.