Cutaneous Squamous Cell Carcinoma Producing Granulocyte Colony-stimulating Factor and Parathyroid Hormone-related Protein: A Case Report and Literature Review.

Introduction

Hypercalcemia-leukocytosis, a rare syndrome, is characterized by the co-occurrence of hypercalcemia and leukocytosis in a single malignancy ( 1 ). This syndrome is seldom associated with cutaneous squamous cell carcinoma (SCC).

Hypercalcemia in cancer patients is primarily mediated by parathyroid hormone-related protein (PTHrP) produced by tumor cells. Other mechanisms include the ectopic activity of 1-alpha-hydroxylase, resulting in elevated production of 1,25-dihydroxyvitamin D, and osteoclastic activity from bone metastasis. In addition, ectopic production of parathyroid hormone (PTH) by tumors can contribute to hypercalcemia.

Leukocytosis, a condition characterized by an elevated white blood cell count, is a recognized paraneoplastic syndrome (PNS) that is frequently reported in various malignancies, such as lung cancer. Elevated plasma granulocyte colony-stimulating factor (G-CSF) levels in these malignancies suggest the involvement of G-CSF-producing tumors in the pathogenesis of leukocytosis ( 2 ).

Cutaneous SCC is one of the most common skin cancers and is particularly prevalent in elderly populations and individuals with fair skin who have been exposed to significant ultraviolet (UV) radiation. Common sites for SCC include sun-exposed areas, such as the face, ears, neck, and hands. In addition to UV exposure, other risk factors include chronic inflammation, immunosuppression, and burn scars. The prognosis of cutaneous SCC varies depending on the tumor size, depth, location, and metastasis. Although many cases are successfully treated with surgical excision, advanced or metastatic SCC can have a poor prognosis.

We herein report a rare case of cutaneous SCC that developed from an electrical burn scar accompanied by paraneoplastic hypercalcemia-leukocytosis syndrome. This case report highlights the significant role of cytokines, such as PTHrP and G-CSF, in mediating systemic manifestations, contributing to the limited body of literature on cutaneous SCC associated with such paraneoplastic syndromes. Hypercalcemia-related symptoms, such as fatigue, nausea, and constipation, along with leukocytosis without significant signs of local infection and non-responsiveness to antibiotic treatment, suggest that tumors producing PTHrP and G-CSF should be considered in patients with malignancies.

Case Report

A 76-year-old man presented to our dermatology department with a 1-week history of anorexia, a fever, and malaise. Approximately six months before, the patient noticed a growing tumorous lesion on an electrical burn scar on his left upper arm. Despite treatment at a nearby clinic, the lesion progressively enlarged. A physical examination revealed a cauliflower-like tumor measuring approximately 80×40 mm, with surface necrosis ( Fig. 1A ). No palpable lymphadenopathy was observed in the left axilla. A biopsy revealed the tumor to be a cutaneous SCC, and it was classified as a highly differentiated SCC. ( Fig. 1B-1, 2 ). Although laboratory tests showed an elevated white blood cell count of 15,620 /μL, the patient was advised to return for a follow-up visit 1 week later. However, five days after the final visit, the symptoms gradually worsened, and the patient was unable to move; therefore, he was admitted to our hospital as an emergency case.

The patient had a significant medical history of electrical injury to the left upper arm approximately 50 years prior. He also had diabetes mellitus and hypertension and was being treated with amlodipine (5 mg/day). On admission, he was alert and oriented, with a Glasgow Coma Scale score of 15, indicating full consciousness. His vital signs were as follows: heart rate, 92 beats/min; body temperature, 38.2℃; blood pressure, 151/87 mmHg; and oxygen saturation, 99% on ambient air. The patient did not have pallor in the conjunctiva or jaundice in the sclera. He was lethargic and had a slightly dry mouth. The results of cardiac, respiratory, and abdominal examinations were unremarkable.

The laboratory test results on admission are summarized in Table 1 . His white blood cell count was 12,800 /μL, comprising 84.0% of neutrophils. The C-reactive protein level was 8.33 mg/dL, and the albumin-corrected calcium and phosphorous levels were 13.2 mg/dL and 2.7 mg/dL, respectively. Electrocardiography revealed a normal sinus rhythm with a heart rate of 90 beats/min, prominent peaked T waves, and a shortened QT interval (342 ms). Contrast-enhanced computed tomography revealed a tumor in the left upper arm measuring 87×46×66 mm with heterogeneous contrast enhancement. Mild enlargement of the left axillary lymph nodes was also observed ( Fig. 1C-1, 2 ).

We initiated treatment for hypercalcemia with intravenous administration of normal saline (2,500 mL/day) and an intravenous injection of furosemide (60 mg/day). Further laboratory tests revealed mild suppression of the intact PTH at 17 pg/mL (reference range: 10-65 pg/mL), whereas PTHrP and 1,25-dihydroxyvitamin D levels were elevated at 4.2 pmol/L (reference range: ＜1.1 pmol/L) and 98 pg/mL (reference range: 20-60 pg/mL), respectively ( Table 1 ). Consequently, the patient was diagnosed with malignancy-associated hypercalcemia (MAH), and zoledronic acid (4 mg) was administered on day 3. Albumin-corrected calcium levels decreased over time, and phosphate levels decreased to 1.9 mg/dL. On day 7, the albumin-corrected calcium level decreased to 9.4 mg/dL, and electrocardiography revealed improvement in the peaked T waves and QT interval shortening. Subsequently, the anorexia and malaise improved.

Two sets of blood cultures were obtained, considering the concomitant occurrence of hypercalcemia and leukocytosis. Although intravenous administration of ampicillin-sulbactam at 6 g/day was initiated, the white blood cell count remained elevated. The patient was switched to meropenem (1 g/day) and vancomycin (1 g/day). However, blood tests on day 3 revealed further elevation, with a white blood cell count of 44,580 cells/μL. We further investigated other potential causes of leukocytosis because the blood cultures obtained on admission were negative. We measured the plasma levels of G-CSF and Interleukin (IL)-6, and examined G-CSF expression in tumor tissues by immunostaining. Both plasma G-CSF and IL-6 levels were elevated at 128 pg/mL (reference range: 10.5-57.5 pg/mL) and 73.4 pg/mL (reference range: ＜7.0 pg/mL), respectively ( Table 1 ). Immunohistochemistry of cutaneous SCC with an anti-G-CSF (Ab-1) mouse mAb (5.24) was weakly positive ( Fig. 1B-3 ). Based on the production of G-CSF and PTHrP from cutaneous SCC, the patient was diagnosed with hypercalcemia-leukocytosis syndrome.

Generally, dermatology and orthopedic teams consider surgical intervention as a treatment for cutaneous SCC. The depth of the tumor in this case warranted significant surgical invasion; however, considering the patient's overall condition, surgery was deemed infeasible. The patient was thus referred to a specialized hospital for localized radiation therapy and palliative care.

The patient underwent localized radiation therapy (total dose, 50 Gy) for 1 month. Consequently, his symptoms, hypercalcemia, and leukocytosis gradually improved. Furthermore, after therapy, his plasma PTHrP level decreased from 4.2 pmol/L to below 1.1 pmol/L, and the plasma G-CSF level decreased from 128 pg/mL to below 19.5 pg/mL, within the normal range ( Fig. 2 ). The patient continues to attend outpatient follow-up and remains in remission, without any signs of recurrence.

Discussion

This case is characterized by a rare presentation of cutaneous SCC with hypercalcemia-leukocytosis syndrome. Immunostaining revealed G-CSF secretion in cutaneous SCC, with elevated plasma PTHrP levels.

Cutaneous SCC rarely presents as PNS. MAH is the most common symptom of PNS, seen in 78% of PNS cases ( 3 ). To date, approximately 30-40 cases of cutaneous SCC presenting with MAH have been reported ( 3 ).

Several underlying mechanisms of MAH have been reported. The most common mechanism responsible for approximately 80% of cases is the secretion of PTHrP ( 4 ). PTHrP mimics the action of PTH, thereby stimulating osteoclast activity, augmenting bone resorption, and increasing renal calcium reabsorption ( 5 ). This is commonly observed in malignancies such as SCC, urinary tract cancers, breast cancer, non-Hodgkin's lymphoma, and ovarian cancer ( 4 ). Another significant mechanism, accounting for approximately 20% of cases, involves osteolytic metastases, where malignant cells infiltrate bones, leading to their degradation and subsequent release of calcium into the bloodstream ( 4 ). This mechanism is mostly implicated in breast cancer and multiple myeloma, with factors such as transforming growth factor β ( 6 ) and various cytokines such as receptor activator of nuclear factor-kappa B ligand, IL-3, and IL-6 playing crucial roles ( 7 ).

Furthermore, certain malignancies, including lymphomas and ovarian germ cell tumors, can induce hypercalcemia through the ectopic activity of 1-alpha-hydroxylase (CYP27B1), resulting in elevated production of 1,25-dihydroxyvitamin D and increased calcium absorption ( 4 ). In addition, ectopic production of PTH by tumors such as small cell lung cancer and adenocarcinoma can also contribute to hypercalcemia, although this is a less common mechanism ( 8 ). Parathyroid carcinoma, although rare, can cause excessive PTH production ( 9 ).

In the present case, the diagnosis of hypercalcemia was based on elevated levels of PTHrP and 1,25-dihydroxyvitamin D, which was supported by the absence of bone metastases on imaging studies. Although the mechanism underlying the interaction between PTHrP and 1,25-dihydroxyvitamin D remains unclear, 1,25-dihydroxyvitamin D levels tend to be within the normal to low range in most cases of PTHrP-producing tumors ( 3 ). In the present case, both PTHrP and 1,25-dihydroxyvitamin D levels were high, which is a rare finding. Nonetheless, a few studies have reported tumors that produce both substances ( 10 - 12 ). In this case, there was no evidence of the administration of vitamin D formulations or other factors that could cause elevated levels of 1,25-dihydroxyvitamin D, such as granulomatous diseases. Therefore, PTHrP and 1,25-dihydroxyvitamin D were assumed to be produced by the tumor. However, this remains speculative because we were unable to perform immunohistochemistry of the tumor for PTHrP and 1,25-dihydroxyvitamin D. Considering the low serum phosphate levels, PTHrP may have played a major role in the pathophysiology of this case.

G-CSF is a glycoprotein that promotes proliferation and differentiation of neutrophil progenitor cells in the bone marrow. There have been several reports of G-CSF-producing tumors. Our patient presented with a markedly high white blood cell count upon admission. Although concomitant infection was suspected, no clinical signs were confirmed. Considering the possibility of a G-CSF-producing tumor, a further examination and immunostaining were performed. The diagnostic criteria for G-CSF-producing tumors are as follows: (A) significant leukocytosis without any other identified causes, such as infection; (B) elevated plasma G-CSF levels; (C) decreased white blood cell count and plasma G-CSF levels after cancer treatment; and (D) immunohistochemical evidence of G-CSF production in tumor tissues ( 13 ). Based on our findings showing that all these criteria were met, a G-CSF-producing tumor was diagnosed.

G-CSF-producing tumors are fast-growing and associated with a poor prognosis. A recent in vitro study by Uemura et al. demonstrated the rapid proliferation of the lung cancer cell lines Oka-C-1 and MI-4, which possess G-CSF receptors, in response to G-CSF/granulocyte-macrophage (GM)-CSF. Serum deprivation induces the production of G-CSF/GM-CSF through the NF-κB and p44/42 mitogen-activated protein kinase signaling pathways, further enhancing tumor growth ( 14 ). Therefore, in addition to inducing tumor proliferation, G-CSF is also considered a contributing factor to the poor prognosis of tumors that produce G-CSF.

In addition to G-CSF, some tumors simultaneously produce PTHrPs. The co-production of PTHrP and G-CSF by tumors is uncommon, and its underlying pathogenesis remains largely unknown. In lung cancer patients, tumor cells producing both PTHrP and G-CSF have been shown to harbor mutations in codon 12 of the KRAS gene ( 15 ). However, in the cases reported thus far, there has been little mention of pathological findings, and no specific pathological features characteristic of malignant tumors producing both G-CSF and PTHrP have been identified.

To better understand the clinical characteristics and prognosis of tumors that produce both PTHrP and G-CSF, we conducted a literature review. We identified 39 cases of tumors producing both G-CSF and PTHrP in adults over 20 years old, including our case ( 15 - 50 ) ( Table 2 ). The median age of the patients was 64 ( 32 -90) years old, and 82.1% were men. The primary organs involved were the lungs (8/39), bladder (6/39), and renal pelvis (4/39). SCC was the most prevalent, accounting for 48.7% (19/39) of cases, followed by adenocarcinoma in 15.4% (6/39), and urothelial carcinoma in 12.8% (5/39). The median WBC count was 35,800 (12,700-142,000)/μL, plasma G-CSF was 111 (34.4-1,311) pg/mL, albumin-corrected serum calcium was 14.3 (9.2-19.0) mg/dL, and plasma PTHrP was 12.3 (1.1-31.8) pmol/L. While 2.8% (1/36) of the cases had Stage I disease, 11.1% (4/36) had Stage II disease, 19.4% (7/36) had Stage III disease, and 66.7% (24/36) had Stage IV disease. Distant metastasis was present in 36.8% (14/38) of the cases. The overall survival (OS) was notably poor, with a median OS of 10 ( 8 - 34 ) weeks and a high mortality rate of 91.4% (32/35).

The poor prognosis of tumors that produce PTHrP and G-CSF can be attributed to several critical factors. One is the induction of a highly inflammatory state mediated by cytokines. In this case, the IL-6 level was elevated to 73.4 pg/mL (reference range ＜7.0 pg/mL). IL-6 is a B-cell differentiation factor that induces the final differentiation of B cells into antibody-producing cells and is involved in the immune response, hematopoiesis, cell growth, and acute-phase reactions ( 51 ). The interactions among G-CSF, PTHrP, and IL-6 remain unknown. Several mechanisms have been proposed to date. PTHrP has been reported to stimulate IL-6 secretion from osteoblasts in the bone marrow after binding to its receptor ( 52 ). In addition, some inflammatory cytokines, such as IL-6, may be produced along with G-CSF by tumor cells ( 53 ). IL-6 has also been suggested to act as a promoter of G-CSF, thereby stimulating its production ( 54 ). The interactions between PTHrP, G-CSF, and IL-6 can thus result in synergistic mechanisms that promote inflammation. These mechanisms may induce cachexia and contribute to the poor prognosis of G-CSF- and PTHrP-producing tumors.

The present case involved cutaneous SCC for which surgery was not feasible. For cases of inoperable cutaneous SCC or when surgery is not an option, radiotherapy is recommended as curative treatment ( 55 ). Therefore, we opted for radiotherapy in the present case. Our patient had a favorable outcome following radiotherapy, likely due to the high responsiveness of cutaneous SCC to radiotherapy. In cutaneous SCC, radiotherapy outcomes are particularly good for early-stage lesions ( 56 ). However, even for T3 lesions, as in this case, local control rates of 50-60% have been reported ( 57 ). In addition, cutaneous SCC typically has a low rate of distant metastasis ( 58 ), allowing radiotherapy to be more effective in achieving local disease control.

Generally, tumors that produce G-CSF and PTHrP have a poor prognosis. However, in our case, the absence of distant metastasis and the fact that the pathology was SCC of the tumor likely contributed to the favorable response to radiation therapy and positive treatment outcome.

Written informed consent was obtained from the patient for the publication of this report.

The authors state that they have no Conflict of Interest (COI).

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