Paraneoplastic leukemoid syndrome in squamous cell carcinoma of the forearm

Abstract

The paraneoplastic leukemoid reaction is a rare haematological paraneoplastic syndrome, which is typically seen with solid tumours and squamous cell carcinomas. As an indication of bone marrow infiltration and malignancy involvement, it indicates a poor outcome and a grave prognosis. We report a woman in her 50s, who presented with an ulcer over the right forearm. Biopsy revealed squamous cell carcinoma. The patient underwent radiological investigations, which showed the presence of metastatic squamous cell carcinoma. Incidentally, the patient was found to have leucocytosis, which was attributed to a paraneoplastic leukemoid reaction, after ruling out all other causes of leukemoid reaction. Due to metastatic disease, the patient was planned for palliative radiotherapy and the best supportive care.

Background

Leukemoid reaction (LR) is defined as a white cell count of more than 50 x10⁹/ L of blood with mature neutrophilic predominance.¹ This can be caused by multiple causes such as blood infections, malignancies, severe haemorrhage, sudden haemolysis or drug abuse.² The most common malignancies that encounter such a haematological phenomenon include pulmonary malignancies, nasopharyngeal malignancies, gastrointestinal malignancies and genitourinary malignancies. Squamous cell carcinoma (SCC) causing LR is very rare. In contrast to haematological malignancies, an increased leucocyte alkaline phosphatase (LAP) score determines the diagnosis. We present a metastatic SCC of the right forearm, characterised by leucocytosis (>50 x 10⁹/L) and a high LAP score, diagnosed with paraneoplastic LR. It is the first study of its kind to establish whether peripheral SCCs can be associated with such a presentation. We have no previous case reports in the history of medical literature to the best of our knowledge.

Case presentation

A woman in her 50s with no known comorbidities and a history of burns 5 years ago presented with a non-healing ulcer of the right forearm for 1 year. Ulcer over the right forearm was insidious in onset, gradually progressive in size. It was associated with pain and bleeding for 5 months. She also had active ooze from the ulcer site. An 8×8 cm ulceroproliferative growth was found over the proximal part of the forearm of the right hand, encroaching onto the elbow.

Blood investigations showed the presence of severe anaemia (6 g/dL) with severe leucocytosis (>50 000 cells/cm³) (figure 1). The LAP score was high, with peripheral smear showing mature neutrophilic predominance of approximately 90%. The liver function test and renal function test were within normal limits. A biopsy from the lesion was done, which was diagnostic of well-differentiated SCC.

Figure 1.

Peripheral smear showing neutrophilia.

An X-ray of the right forearm demonstrated a vague soft tissue mass infiltrating the underlying muscles without involving the forearm bones (figure 2). MRI of the right forearm showed an irregular lobulated lesion of size 5.8×6×10.2 cm involving the radial aspect of the middle third of the forearm with extension into the adjacent anterior and posterior aspects. In the epicentre of the lesion, there is an ulcerated surface on the skin and subcutaneous plane. The lesion shows patchy areas of diffusion restriction with possible heterogeneous enhancement on post-contrast scans. With the lesion, there is a fascial breach and focal loss of fat planes along the extensor carpi radialis longus and brevis, extensor digitorum and abductor pollicis longus tendons. Visualised bones and bone marrow are normal (figure 3).

Figure 2.

X-ray image showing soft tissue density of the tumour in the right forearm.

Figure 3.

MRI (axial view) of the right forearm (T1-weighted) showing tumour with infiltration to the underlying muscles and without any infiltration to the underlying bones ((A) post-contrast and (B) pre-contrast).

A contrast-enhanced CT of the abdomen and thorax revealed diffuse interlobular septal thickening, more prominent in the lower lobes (figure 4). There was evidence of metastasis in the left posterior basal segment of the lung, mediastinal nodes, paratracheal nodes, paraoesophageal nodes, subcarinal nodes, bilateral hilar region nodes and right axillary lymph nodes. Fine-needle aspiration from the right axillary node showed metastasis from SCC (figure 5).

Figure 4.

MRI (coronal view) of the right forearm showing tumour with infiltration to the underlying muscles.

Figure 5.

High-resolution CT (axial view) of the thorax metastasis to the lungs.

The patient was diagnosed with metastatic SCC of the right forearm and was decided upon palliative radiotherapy. However, the cause of LR was not clear. There was no history of drug or steroid intake that may cause LR. Multiple laboratory tests were done to rule out infectious mononucleosis, tuberculosis or Clostridium difficile infections, and all were negative. The patient was evaluated for other causes of leucocytosis, but no cause could be found. Hence, we attribute that LR is probably a paraneoplastic feature secondary to SCC.

Outcomes and follow-up

Given infiltration into adjoining muscles and metastasis, an option of amputation was offered to the patient for source control. However, the patient deferred and did not give consent. The patient was therefore offered palliative radiotherapy and the best supportive care.

Discussion

Paraneoplastic syndromes (PNSs) are clinical entities caused by substances released from malignant tumour cells but are not caused by direct tissue invasion by the primary or metastatic tumour. A paraneoplastic LR is a haematological PNS described as a white cell count of more than 50 000 cells/mm³ of blood with mature neutrophilic predominance.¹ It may also present with toxic eosinophilia, but the usual feature is a mature neutrophilic predominance without neoplastic precursor cells.³ A high LAP score usually sets it apart from haematological malignancies like chronic myeloid leukaemia.

Paraneoplastic LR is more commonly associated with pulmonary, nasopharyngeal, gastrointestinal and genitourinary malignancies.⁴ Despite a strong association with malignancies, a combination has been reported rarely, with less than five cases. In addition, all the previous cases were limited to head and neck malignancies, whereas our case had SCC of the peripheral body area. It is usually different from hyperleucocytosis, a white cell count of more than 100 000 cells/mm³. This is rarely seen, but the highest malignant count reported in cases of paraneoplastic LR is 180 000 cells/mm³.

Paraneoplastic LR is sometimes the earliest sign of an occult malignancy and indicates a poor prognosis for the patient’s outcome.⁵ Therefore, clinicians must have a high suspicion to diagnose this rare masquerading entity. Paraneoplastic LR usually results from a non-haematolymphoid cytokine-secreting tumour without direct bone marrow infiltration by the primary or metastatic lesions.⁶ It has been described as a paracrine mechanism used by tumour cells to promote tumour mass proliferation. Secreted cytokines theorised would include granulocyte-colony-stimulating factor (G-CSF), interleukin (IL)-1a/1b, IL-3, IL-6 and tumour necrosis factor. The malignant potential to release colony-stimulating factors can develop concurrently with tumour development, or the primary tumour may have acquired secondary de-differentiation features. It has also been seen to be the primary manifestation in non-cytokine-releasing tumours once they have primarily progressed into metastatic disease.⁷

Following the previously mentioned concept of G-CSF production, it has been observed that haematopoietic growth factors such as G-CSF have been known to stimulate the growth of human colon adenocarcinoma tumour cell lines and small cell lung cancer cell lines in in-vitro studies.^{8 9} Additionally, Bussolino et al reported that G-CSF could facilitate tumour cell migration and rapid proliferation in human endothelial cell lines.¹⁰ Nara et al reported a case of SCC that had increased levels of G-CSF. They suggested that the increased level of G-CSF was due to its production from the tumour itself. Accordingly, they proposed that the G-CSF can act as a tumour marker and growth factor for the proliferation of tumour cells.⁸ This reflects that growth factors impact bone marrow cell proliferation index and alter the process of differentiation in the granulocytes. This results in poor differentiation and lethality in the tumour, and a lower overall survival rate because of the ability to metastasise.

In terms of its clinical presentation, which is challenging because of the wide variety of its subsets, paraneoplastic LR initially resembles the underlying malignancy. If the syndrome presents as the initial symptom, it should raise suspicion of occult malignancy. However, it can also occur in benign entities like blood infections, corticosteroid usage, severe haemorrhage, or bone marrow metastasis with possible infiltration or infection.¹¹ In rare cases, it could be masquerading primary myeloproliferative neoplasm with the differentiation achieved in terms of LAP score measurement.

A LAP score higher than normal generally aims towards a benign aetiology, whereas a low score usually points to primary haematological malignancies or paroxysmal nocturnal haemoglobinuria.¹² In addition, the secondary hyperviscosity effects seen in cases of LR are not seen in paraneoplastic LR. Therefore, they do not require the usual treatment with hydroxyurea and leukaemic apheresis. There was no evidence of any benign aetiologies in our case, and a high LAP score sorted the diagnosis towards a paraneoplastic LR.

A diagnosis of exclusion is usually made when diagnosing this rare entity. It is helpful to rule out primary blood cancers by establishing leucocytosis with a peripheral smear and demonstrating the absence of granulocytic precursors, basophilia or monocytosis. Following this, a LAP score assessment would help in the diagnosis of primary haematological malignancies. Further histological examination of the cytokine-secreting tumour with a characteristic dense intratumoural neutrophilic infiltration confirmed by plasma cytokine level assays and bone marrow examination can help solidify the diagnosis. Typically, bone marrow studies in patients with paraneoplastic LR reveal hypercellular marrow with myeloid hyperplasia, but no increase in blast percentage and left-shifted myelopoiesis.^{7 13} The high LAP score, which usually indicates a benign aetiology or an LR, favoured a malignancy-associated cause, as all other casualties were ruled out. Establishing a non-haematological malignancy with an association between leucocytosis and toxic granulation would suggest a possible growth factor-induced phenomenon already established in this clinical spectrum of tumours. In the absence of any other confounding factors and the malignancy background that the patient presented with, the diagnosis of paraneoplastic LR was established.

Treatment of paraneoplastic LR is usually the treatment of the underlying malignancy that triggered the phenomenon. Following surgical excision, radiotherapy and concurrent chemoradiation, the leucocytosis has decreased.¹⁴ Nevertheless, it has also been postulated that patients who develop paraneoplastic LR in the setting of a cytokine-secreting tumour are generally associated with a more adverse prognosis and shortened survival periods.¹⁵ Such patients on the evaluation either have a large primary tumour burden or an extensive metastatic status on primary presentation. Chen et al concluded that the degree of leucocytosis adversely impacts survival in their case report about a paraneoplastic LR in an oral SCC.¹⁶

Mizutani et al have reported a positive correlation between G-CSF levels with high-grade tumour histology and the probability of the malignancy being at an advanced stage.¹⁷ Evidence for an autocrine growth model for such malignancies was confirmed based on an in-vitro study of a cell line obtained from a Japanese patient with bladder cell carcinoma. They showed that the G-CSF is not just a marker of tumour volume. It also indicates invasiveness, aggressiveness and unfavourable tumour histology, which confers a dismal prognosis.¹⁸ This results in reducing the overall survival rates of such patients. The survival period of most patients has been estimated to range from 3 months to 1 year since most of them respond badly to treatment. Furthermore, our patient was diagnosed with metastatic SCC of the forearm and was treated with palliative radiotherapy and best supportive care.

Patient’s perspective.

I presented to the hospital with an ulcer over the forearm. I underwent a biopsy and a few imaging studies. I was informed by the treating doctors that I have cancer of the forearm with a distant spread. I was advised for amputation of the upper limb but I was not willing for the same. I chose palliative care and the best supportive care.

Learning points.

• Leucocytosis in a patient with an established or occult malignancy demands prompt investigation and advent of the primary treatment as it is usually associated with poor prognosis.

• Less than five documented cases in history link paraneoplastic leukemoid reaction (LR) to squamous cell carcinomas (SCCs), which mostly affect the head and neck region. Our case is the first documented case of paraneoplastic LR seen in a case of SCC of the peripheries.

• Initial blood investigations with a routine peripheral smear can help delineate paraneoplastic LR from LR in combination with a leucocyte alkaline phosphatase score and establishment of the primary malignancy.

• Paraneoplastic LR is usually considered a delayed manifestation of malignancies with an abysmal prognosis and median survival period of less than a year. The treatment usually involves treating the underlying primary malignancy with occasional symptoms of hyperviscosity, which is dealt with hydroxyurea and apheresis.

Ethics statements

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