Leukemoid reaction: a rare paraneoplastic event in a case of advanced penile cancer and its management

Abstract

Leukemoid reaction is a paraneoplastic phenomenon associated predominantly with solid tumours. Malignancies presenting with leukemoid reaction have a grave prognosis. It is defined as persistent neutrophil count greater than 50×103 cells/µL. We report a case of leukemoid reaction in a patient with metastatic penile cancer. A 60-year-old man with partial penectomy status for squamous cell carcinoma of penis on neoadjuvant chemotherapy, presented with left fungating inguinal lymphadenopathy and total leucocyte count 96×103 cells/µL and hypercalcaemia. Leucocytealkaline phosphatase (LAP) score was excessively elevated. The patient underwent left ilioinguinal block dissection along with vastus lateralis flap for defect reconstruction. Postoperatively, the neutrophil counts and serum calcium level normalised. The patient improved clinically and was discharged.

Background

The term ‘Leukemoid reaction’ (LR) was first coined by Krumbhaar in 1926 to describe a haematological entity that closely resembled leukaemia.¹ It is defined as reactive leucocytosis with persistent neutrophil count greater than 50×103 cells/µL or higher with a shift to left. Depending on the predominant cell, it may be neutrophilic (most common), eosinophilic, lymphocytic or monocytic. Though it can be a feature of various benign etiologies like burns, infections and allergies, it has rarely been reported in patients with genitourinary malignancies, and when present, it portends poor prognosis. It is critically important to differentiate LR from leukaemia for optimal management. LR has 1%–4% incidence in non-haematological malignancies.²

We report a case of locally advanced penile carcinoma with LR and its management.

Case presentation

A 60-year-old man presented with obstructive lower urinary tract symptoms and on physical examination was found to have small ulcereoproliferative growth on the undersurface of the preputial skin. After wedge biopsy, he was diagnosed with squamous cell carcinoma of penis and underwent partial penectomy. Pathological examination demonstrated moderately differentiated squamous cell carcinoma infiltrating the subepithelial connective tissue; corpus spongiosum and urethra were free of tumour with no lymphovascular invasion (T1G2). The patient was kept on regular surveillance in the postoperative period, but he defaulted and presented after 5 months with a large (8×5 cm) left inguinal mass, hard in consistency, mobile and tender. On palpation, contralateral inguinal region was normal.

Investigations

Fine Needle Aspiration Cytology (FNAC) from the mass revealed ‘metastatic squamous cell carcinoma’. Contrast-enhanced CT abdomen revealed 8.3 cm left inguinal lymph node (figure 1). There was no evidence of metastasis elsewhere in the body. The patient was planned for neoadjuvant chemotherapy with paclitaxel and cisplatin. However, after two cycles of chemotherapy, the patient presented with high grade fever with ulceration and purulent discharge from the left inguinal mass (figure 2). Initial white cell count (WCC) was 58×109/L and neutrophil count was 96×103 cells/µL, serum paratharmone level was 553 pg/mL and serum calcium was 14.1 mg/dL. He was treated with systemic antibiotics and the temperature decreased but WCC progressively increased to 106×109/L.

Figure 1.

CT axial plane showing enlarged left inguinal lymph node.

Figure 2.

Metastatic penile carcinoma with fungating left inguinal lymph node.

Differential diagnosis

Due to high WCC, a workup of Chronic Myelogenous Leukemia (CML) was done. LDH level was 371 and Leucocyte alkaline phosphatase (LAP) score was 350, which was markedly high (figure 3). Peripheral smear showed numerous segmented neutrophils and band forms (figure 4). Bone marrow biopsy was suggestive of marked proliferation and maturation of normal myeloid elements with normal morphology. A PCR for BCR−ABL fusion transcript was negative leading to a diagnosis of LR.

Figure 3.

Strongly positive neutrophil alkaline phosphatase reaction with elevated LAP score.

Figure 4.

Neutrophilia in peripheral blood smear (low magnification, 10×).

Treatment

The patient was planned for bilateral ilioinguinal lymphnode dissection. Left side standard ilioinguinal template and right side modified inguinal lymph node dissection was planned. Intraoperatively, there was significant lymphadenopathy in left inguinal region involving skin and subcutaneous tissue leading to complete resection of the overlying skin. An anterolateral vastus lateralis thigh flap was used to cover the left inguinal defect (figure 5). Due to prolonged and complicated procedure, right side inguinal exploration was deferred and was planned in the second setting.

Figure 5.

Postlateral musculocutaneous flap covering the defect after ilioinguinal lymphnode dissection.

Outcome and follow-up

Pathological review demonstrated three lymph nodes positive for metastatic squamous cell carcinoma: two were superficial and one was deep lymph node. In the postoperative period, there was a substantial decrease in WCC to 20×109/L and serum calcium also normalised to 10 mg/dL. Patient improved and was discharged with the plan of right side lymph node dissection after 3 weeks. Since this patient had a high-risk disease with extensive nodal metastasis and LR, our strategy was to keep the patient on regular surveillance once in 3 months for the first 2 years, after right side lymph node dissection. Subsequently, the follow-up can be once in 6 months if there are no recurrences.

Discussion

The exact aetiology of LR in context of a malignancy is still unclear though various cytokines like granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 secreted by neoplastic cells have been postulated to induce LR as evident by decrease in leucocyte count after amelioration of the malignant cause by surgical excision, chemotherapy and radiotherapy.^3–5

Peripheral smear in LR shows mature neutrophils with marked left shift, in contrast to mature neutrophils as seen in CML. Stimulated neutrophils of LR have increased LAP score as compared with decreased LAP score in CML. In bone marrow biopsy, there is marked proliferation and orderly maturation of all normal myeloid elements with normal morphology and no reticular fibrosis. Cytogenetic and molecular studies suggests absence of Philadelphia chromosome in karyotype or t(9;22) translocation or BCR/ABL oncogene in LR. Clonal studies show polyclonal pattern of neutrophils as compared with monoclonal pattern in CML. A high serum level of haematopoietic growth factors like G-CSF is often seen in LR as compared with CML. Serum G-CSF levels often correlate with a higher grade and faster progression of the cancer.⁶ LRs have been reported to correlate with an aggressive clinical course, lower survival time, rapid tumour recurrence, high incidence of systemic metastasis and extremely poor prognosis.⁷

Granger et al ² in their retrospective analysis of 758 non-haematological cancer patients have reported only one case of penile cancer associated with LR. On reviewing the literature, our case seems to be the second such case.

Learning points.

• Leukemoid reaction is an indicator of aggressive nature of malignancy and portends poor prognosis.

• The absence of immature cells, basophilia or monocytosis, increased leucocyte alkaline phosphatase and the absence of the BCR/ABL translocation distinguish LR from CML.

• Treatment of the primary disease generally leads to resolution of leukemoid reaction.

• To the best of our knowledge, this is the second case of penile cancer with leukemoid reaction in published studies.