A 53-Year-Old Male Smoker With Advanced Oral Squamous Cell Carcinoma Associated With Paraneoplastic Leukemoid Reaction

Introduction

The normal white blood cell (WBC) count in adults is from 4000 to 11 000 cells/μL, of which 60% to 70% of cells are mature polymorphonuclear neutrophils. Paraneoplastic leukemoid reaction (PLR) is a condition in which the WBC count is equal to or greater than 50 000 cells/μL. Neutrophilia is the most common type of leukocytosis [1,2]. Krumbhaar [3] first introduced the term “leukemoid reaction” in 1926, describing 10 patients with high leukocyte counts. PLR arises in response to infections, intoxication, inflammation, malignancies, or stress [1,2]. An increase in mature neutrophils or a “left shift” in the peripheral blood smear indicates the presence of immature neutrophils, which can resemble leukemia. However, elevated leukocyte alkaline phosphatase levels and the absence of basophilia, monocytosis, and immature leukocytes distinguish PLR from leukemia [1,2,4].

PLR is seen in approximately 10% to 15% of cancer cases, most notably in lung and kidney cancer, lymphomas, melanomas, sarcomas, and head and neck cancers [2,4,5], and is frequently associated with large bulky primary cancer or metastatic disease [5]. PLR and hypercalcemia occurring together in OSCC is a very rare event, and the implications for clinical practice are of primary importance since early recognition can contribute to a major improvement in patient survival. Yoneda et al [6] studied 225 patients with OSCC and reported 10 patients (4.4%) with hypercalcemia only, 11(4.9%) with leukocytosis only, and 5 (2.2%) with simultaneous hypercalcemia and leukocytosis. OSCC tumor cell or keratinocytes has been shown to stain positively for granulocyte colony-stimulating factor (G-CSF), G-CSF receptor, and parathyroid hormone-like hormone in numerous studies [6–9]. Granulocytes and osteoclasts share a common hematopoietic precursor, secreting tumor factors to stimulate both osteoclast formation and granulocyte formation in OSCC cancers [10].

Chen et al [11] in their study of 618 patients with OSCC reported a 9.1% and 7.2% rate of hypercalcemia and leukocytosis, respectively. Multivariate analysis in this study revealed that PLR with hypercalcemia was significantly correlated with primary tumor status, nodal involvement, TNM stage, lymphovascular permeation, and metastasis or recurrence. The authors concluded that PLR and hypercalcemia have an adverse effect for patients with OSCC.

PLR has been shown to be caused by aberrant cytokine secretion of G-CSF, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, interleukin-1, or interleukin-6 (IL-6) from tumor cells [2,9,12–14]. In particular, IL-6 is a pleiotropic cytokine secreted from monocytes, fibrocytes, keratinocytes, endothelial cells, adipocytes, T- and B-lymphocytes, and cancerous cells. IL-6 regulates a plethora of cellular responses, such as inflammation, proliferation, apoptosis, cellular proliferation, and leukemoid reaction. It is correlated with tumor aggressiveness, invasiveness, size, and nodal metastasis in OSCC. Elevated serum IL-6 concentrations were found to cause a decrease in treatment response and survival in patients with head and neck squamous cell carcinoma treated with concurrent chemoradiotherapy [15].

Xiao et al [16] found that IL-6, which is a pleiotropic cytokine, is overexpressed in OSCC tissues and promotes SOX4 over-expression through the JAK2/STAT3 pathway, leading to increased cell proliferation and tumor progression. Our case’s well-differentiated keratinized features may be associated with enhanced IL-6 secretion, thereby triggering PLR. High IL-6 and SOX4 expression was closely related to a larger tumor size (P=0.0123), TNM stage (P=0.0002), and a poorer overall survival in 108 patients with OSCC [16].

PLR and hypercalcemia are quite rare occurrences in OSCC, and their presence can significantly affect how healthcare professionals approach patient care. These rare conditions are not commonly observed in patients with OSCC, which makes their identification and management all the more challenging. The present case adds to the clinical data of PLR combined with hypercalcemia in well-differentiated keratinized OSCC, making the academic contribution of this case more prominent. Therefore, it is crucial for clinicians to be aware of the possibility of these clinically significant paraneoplastic phenomena, as they can affect the overall prognosis and require a more comprehensive approach to patient management. PLR in association with advanced and aggressive forms of squamous cell carcinoma is a rare occurrence and is an indicator of poor prognosis. This report describes the case of a 53-year-old man with advanced OSCC associated with PLR with hypercalcemia.

Case Report

This case involved a 53-year-old man with a current history of tobacco use (30 pack-years), betel nut chewing (20–30 nuts daily), and alcohol consumption (3–5 beers daily). The patient had been a corrugated iron roof construction worker for more than 20 years prior to presentation. He was married and lived with his wife and 2 children in a village. The patient had a history of lower lip papilloma and verrucous hyperplasia, which were excised, and artificial dermis graft reconstruction was performed in 2018. He initially visited the ear, nose, and throat outpatient clinic due to a slow-growing, indurated, ulcerative, painless mass in the right buccal area of a 2-month duration. On close inspection, the buccal mass invaded the floor of the mouth, right retromolar trigone area, and right portion of the lower lip. Multiple skip lesions were observed in the right chin and cheek areas. The tumor covered approximately 80 mm of the right lower mandibular area. Palpation of the neck revealed bilateral enlargement of the cervical lymph nodes (Figure 1).

Computed tomography (CT) revealed a huge right buccal mass lesion with heterogeneous post-contrast enhancement, direct invasion of the right lower lip and right cheek skin, and destruction of the adjacent right mandibular ramus. The tumor size was approximately 53 mm. Multiple necrotic lymphadenopathies, with abscess formation 9 to 26 mm in size in the submental and bilateral submandibular space, were evident at levels IA, IB, II, and III.

Hematoxylin and eosin staining of a lower lip biopsy specimen showed well-differentiated squamous cell carcinoma, with tumor cells exhibiting enlarged hyperchromatic nuclei, abundant eosinophilic cytoplasm, increased keratin formation, and occasional mitoses. The stromal tissue demonstrated desmoplastic fibrosis, and the tumor was negative for p16 immunohistochemistry (Figure 2).

F-18 fluorodeoxyglucose positron emission tomography-CT (Figure 3) showed increased radiotracer uptake in the right buccal region, right retromolar region, right gingiva, right lower lip, and corresponding skin area. Lymphatic metastases were noted in the right parotid, submental, right neck (level IB, II, III, IV, V), and left neck (level IB, II, III, IV) regions. The patient’s clinical staging according to the 8th edition of the American Joint Committee on Cancer was cT4aN2cM0, stage IVA, keratinized, and well-differentiated squamous cell carcinoma.

The patient’s active problem list included the following: (1) upper airway obstruction; (2) superimposed bacterial infection of the right buccal cavity tumor; (3) severe cervicofacial pain involving the neck and mandible; (4) regional lymphadenopathy; (5) hypercalcemia of malignancy; and (6) cT4aN2cM0, stage IVA, keratinized, well-differentiated squamous cell carcinoma of the right buccal cavity. The differential diagnosis included leukocytosis secondary to leukemia.

First, a tracheostomy connected to a T-piece device was performed to relieve airway obstruction. Arterial blood gas analysis every 2 weeks showed normal partial pressures of oxygen and carbon dioxide, and normal oxygen saturation. Second, pus culture of right chin tumor exudates yielded Proteus mirabilis and Streptococcus agalactiae (group B Streptococcus). Broad-spectrum antibiotics, including Augmentin 1.2 g IV every 8 hours and Tazocin 4.5 g IV every 8 hours, successfully resolved the bacterial infection. The neck and chin skin wounds were cleaned twice daily with 5% povidone-iodine solution. Chest X-ray was clear, with no pneumonia noted. Urinalysis was also clear, ruling out urinary tract infection. The patient was afebrile, unresponsive, and unconscious most of the time. A nasopharyngeal tube was inserted to prevent aspiration. The patient’s Glasgow coma scale was 3 to 4 throughout the course of his stay in the ward.

Third, severe pain from the growing oral tumor was managed with morphine 10 mg subcutaneously every 4 hours as needed and a fentanyl transdermal patch 25 μg/h. The patient’s pain remained at a visual analog scale score of 2 to 3 throughout his hospital stay. Fourth, the patient’s WBC count was initially 37 200 cells/μL, increasing to 151 400 cells/μL (reference range, 4500 to 11 000 cells/μL) on hospital day 52, despite broad-spectrum antibiotics (Figure 4). Eighty-two days after initial presentation, peripheral blood smear revealed neutrophilic leukocytosis with toxic granulation (Döhle bodies). The differential count showed mature neutrophils 97.9%, promyelocytes 1%, myelocytes 1%, and metamyelocytes 1%. Leukocyte alkaline phosphatase staining showed a score of 180, ruling out leukemia as a cause for extreme leukocytosis. The patient’s wife refused a bone marrow biopsy for this patient due to personal reasons. Leukapheresis was considered for control of PLR, but it was not available at our institution and would have required transferring the patient to a medical center in the city. This approach was abandoned due to the patient’s poor cardiopulmonary function. Anti-G-CSF antibody therapy was another potential option, but it was also unavailable at our institution and not covered by the patient’s health insurance. Ultimately, the patient’s wife signed a do-not-resuscitate order after discussion with family members and the medical staff, who opted for conservative treatment and pain control management.

The patient’s serum calcium level was 12 mg/dL (reference range, 8.8–10.4 mg/dL) on hospital day 1. Zoledronic acid 4 mg IV and fluid hydration brought the serum calcium level down to 7.9 mg/dL 1 week later. Zoledronic acid 4 mg IV was given again on day 48, bringing the serum calcium level to 9.4 mg/dL on day 52.

Induction chemotherapy with cisplatin 100 mg IV on day 1, taxotere 62 mg IV on day 1, and 5-fluorouracil 1500 mg IV on days 1 to 4 was given followed by concurrent chemoradiotherapy to control the rapidly progressing oral tumor. Weekly cisplatin 60 mg IV and 70 Gy intensity modulated radiotherapy 5 days a week was planned for this patient; however, radiotherapy was terminated on hospital day 53 when the patient suddenly experienced a cardiogenic shock, with blood pressure of 93/35 mm Hg (reference range, 120/80 mm Hg). The cumulative radiation dose received was 10 Gy before it was terminated. The patient experienced cardiac arrest and died on hospital day 54. This unfortunate event was probably secondary to cancer disease progression and adverse effects of PLR-related circulatory hyperviscosity (Figure 4).

Discussion

PLR is sometimes closely associated with underlying malignancy and can mimic the features of true leukemia, creating a diagnostic dilemma. The main challenge is that both PLR and leukemia present with elevated WBC counts. Practical tips for clinicians include performing a thorough review of the patient’s medical history, a comprehensive physical examination, and essential laboratory tests, such as complete blood count, peripheral smear analysis, leukocyte alkaline phosphatase staining, and bone marrow examination. Only after this evaluation can clinicians gain a clearer understanding of the diagnostic dilemma. Management is generally directed at treating the underlying malignancy rather than the leukemoid reaction itself. In some cases, the leukemoid reaction can resolve spontaneously once the cancer is effectively treated. However, in other instances, supportive care can be necessary to manage symptoms and prevent complications, such as infections or bleeding.

Low immature neutrophil counts, such as myelocytes or metamyelocytes, accompanied by neutrophilia, are often seen in PLR reactions, and their presence indicates infection, inflammation, or bone marrow-related disorders [1,2,12,13]. As seen in our patient, the WBC count was 151 400 cells/μL (reference range, 4500 to 11 000 cells/μL), with a differential of mature neutrophils (97.9%), promyelocytes (1%), myelocytes (1%), and metamyelocytes (1%), and the presence of neutrophil toxic granulation Doëhle bodies in the peripheral blood. In contrast, leukemia has a higher immature neutrophil count of 10% to 20% [17,18]. The leukocyte alkaline phosphatase score can distinguish PLR from leukemia. A high leukocyte alkaline phosphatase score favors a benign etiology, whereas a low score should alert us to a possibility of chronic myeloid leukemia or paroxysmal nocturnal hemoglobinuria [2,12]. Leukemia was ruled out for this patient since he showed a high leukocyte alkaline phosphatase score of 180 and mature neutrophils.

Iyengar et al [19] developed a light gradient boosting machine (LightGBM) learning model to reliably discriminate myeloid malignancies from leukemoid reactions (www.Leukemoid.com), achieving a sensitivity and specificity of 100.0% and 96.3%, respectively. The model uses 13 clinical parameters, including the patient’s age, serum lactate dehydrogenase level, WBC count (≥50 000 cells/μL), and differential count. Figure 5 shows that the model predicted our patient to have PLR. Their study showed that the mortality for leukemoid reaction was 6 times higher than that for myeloid malignancies (57.9% vs 9.6% 12-month mortality, P<0.001), and infection (88%) was the most common cause of death, followed by surgery or physiologic stress (5.5%).

Paraneoplastic syndromes are systemic clinical manifestations resulting from the indirect effects of malignancy. These effects are not due to the physical presence of tumor cells in the affected organs or tissues but rather are mediated through biological products produced by the tumor, such as hormones, peptides, and cytokines, or through immune mechanisms. These syndromes can be endocrine, neurologic, musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, or renal [20–24]. These syndromes can affect virtually every organ system and often precede, accompany, or follow cancer diagnosis. The term paraneoplastic is derived from 3 Greek roots: “para” meaning “beside” or “alongside”; “neo” meaning “new”, referring to new cell growth or tumors; and “plasm” meaning “formation” or “mold”, referring to abnormal tissue growth. Paraneoplastic syndromes occur in 1% to 8% of all patients with cancer and can precede, coincide with, or follow the diagnosis of malignancy. The prevalence of head and neck cancer is approximately 2% to 3%, with most cases presenting in advanced stages III or IV.

PLR often arises in the setting of extensive or metastatic disease and presents with WBC counts greater than 100 000/μL. The resulting circulatory hyperviscosity and tumor lysis syndrome can be detrimental and require prompt management. Correction of metabolic abnormalities, fluid hydration, and prevention of tumor lysis syndrome should be started as early as possible to prevent unfavorable outcomes. Leukapheresis is an option used to relieve circulatory hyperviscosity in non-leukemic extreme leukocytosis; however, it was not feasible at our institutional due to unavailability and the patient’s deteriorating condition [12,13]. Unfortunately, our patient died due to cancer disease progression and possibly circulatory hyperviscosity effects caused by a very high leukocyte count of 151 400 cells/μL.

Granger and Kontoyiannis [5] reported that nearly 76% of 71 patients died within 3 months of extreme leukocytosis (WBC range, 40 666–115 000 cells/μL). Shurmann et al [9] reported a cT4bN2cM0 stage IVA oropharyngeal squamous cell carcinoma in a 47-year-old woman who was treated initially with nivolumab at 3 mg/kg of body weight, then 3 cycles of cisplatin chemotherapy, combined with 70 Gy in 35 fraction radiotherapy, and weekly paclitaxel at 90 mg/m2 body surface area. The patient’s absolute neutrophil count increased from 48 000 cells/μL to 180 200 cells/μL, and the serum G-CSF concentration increased from 4.77 to 9.61 pg/mL. Unfortunately, the patient’s condition deteriorated, and she died 1.5 years after her primary diagnosis. Their findings suggest that tumors exhibiting autocrine stimulation by secreting G-CSF and expressing G-CSF receptors would increase tumor growth and progression, leading to a poor patient prognosis.

The occurrence of hypercalcemia and PLR or hypercalcemia-leukocytosis syndrome in OSCC is relatively uncommon and usually implies a more aggressive tumor with a poor prognosis [8]. Yoneda et al [7] reported 3 cases of OSCC subtype associated with the uncommon occurrence of combined hypercalcemia and leukocytosis. There was no evidence of acute infection or leukemia in these patients that could account for their leukocytosis. These 3 patients with OSCC were initially treated with aggressive surgery, chemotherapy, and radiation therapy but later experienced tumor relapse accompanied by hypercalcemia and leukocytosis. One patient also had a high C-reactive protein level. All 3 patients in the report by Yoneda et al died within less than a year of diagnosis. Tumor secretion of humoral parathyroid hormone–related protein, granulocyte-macrophage colony-stimulating factors, and tumor necrosis factor plays an important role in the pathogenesis of hypercalcemia and leukocytosis in OSCC [7].

The pathophysiology of hypercalcemia and leukocytosis in 10 patients with OSCC, as reported by Yoneda et al [6], may be due to epithelial cells overproducing humoral mediators, such as G-CSF, bone resorbing factors, and other colony-stimulating factors. In 5 of the patients, the mean survival was just 4 months. Our patient had a similar course, dying from uncontrolled cancer progression and heart failure due to a circulatory hyperviscosity condition secondary to uncontrolled hypercalcemia and severe leukemoid reaction, despite intensive measures to treat his condition. Hypercalcemia can be attributed to the dissolution or osteolysis of bone secondary to bone metastasis, and the other potential mechanism is the epithelial tumor cell secretion of parathyroid hormone-related peptide. A possible explanation for PLR is that granulocytes and osteoclasts have a common hematopoietic precursor, which may be stimulated by the tumor to form osteoclasts as well as granulocytes [11,25].

Studies, including our own case, have pointed out the rarity of hypercalcemia and leukemoid reactions associated with well-differentiated, keratinized advanced OSCC [10,14,26,27]. A review of 618 patients with OSCC recorded incidences of 5.7%, 3.7%, and 3.5% for hypercalcemia, leukemoid reaction, and hypercalcemia with leukemoid reaction, respectively. Multivariate analysis revealed that regardless of the primary stage, nodal status, and pathological features of cancer, hypercalcemia and leukemoid reaction together significantly affect OSCC survival. Indeed, the median survival time in patients with distant metastasis and hypercalcemia or leukemoid reaction was only 17 days, and it was 43 days for patients with locoregional recurrence, hypercalcemia, or leukemoid reaction [11].

Chang et al [28] reported a rare case of a 72-year-old woman with PLR caused by gastroesophageal junction adenocarcinoma with liver metastasis and HER2 overexpression, which is a first in a White population. Broad-spectrum antibiotics controlled her bacterial pneumonia, making her leukocytosis improve from 50 500/uL to 36 500/uL (reference range, 4500 to 11 000 cells/μL), and systemic therapy with FOLFOX (folinic acid, fluorouracil, oxaliplatin) and trastuzumab regimen controlled her cancer. PLR was resolved, and she remained disease-free 6 months later. This report highlights the importance of effective antineoplastic treatment given early to improve the outcome for solid tumors with PLR.

Conclusions

PLR and hypercalcemia are rarely associated with OSCC, and their presence signals a poor patient outcome. Monitoring of WBC counts and serum calcium levels every 2 weeks is recommended for patients with advanced OSCC and a history of tobacco and betel nut use. Early recognition and management of PLR and hypercalcemia are key to improving outcomes in this patient population. A complete evaluation of the patient should be initiated to assess the patient’s overall condition. Prompt treatment, such as cancer treatment and correction of any hematologic or metabolic disorders, should be administered. Hematologic malignancies, intoxication, and infection should be ruled out. Multidisciplinary teams including oncology, hematology, and supportive care specialists are recommended for managing such complex cases to optimize treatment decisions and improve patient outcome.