Case Report: Modified pulse-dose melphalan therapy for canine colorectal extramedullary plasmacytoma with suspected hepatic dissemination following surgical excision

Abstract

A senior male neutered Maltese dog was diagnosed with a solitary rectal extramedullary plasmacytoma that was completely excised with clean margins. 5 months later, multifocal hepatic plasma cell tumors were identified without evidence of multiple myeloma. Systemic chemotherapy was initiated using a pulse-dose melphalan protocol combined with prednisone. Due to recurrent dose-limiting myelosuppression, the treatment protocol was progressively modified by shortening the duration of melphalan administration within a fixed treatment cycle. The modified protocol was associated with clinical improvement, progressive ultrasonographic regression of hepatic lesions, and prolonged disease control, with survival exceeding 19 months following diagnosis of hepatic involvement. Recent reports suggest that some extramedullary plasmacytomas may possess greater metastatic potential than previously recognized. Although limited to a single case, this report describes a practical individualized pulse-dose melphalan adjustment strategy that may serve as a clinical reference for management of biologically aggressive or disseminated extramedullary plasmacytomas in dogs.

1. Introduction

Extramedullary plasmacytoma (EMP) is the most frequently diagnosed plasma cell neoplasm in dogs, accounting for approximately 2.4% of all canine tumors (1). The most commonly affected sites include the skin (86%), oral cavity (9%), and rectum (4%) (1, 2). Less common locations, representing approximately 1% of cases, include the stomach, spleen, genital tract, eyes, kidneys, lungs, uterus, liver, and rare intracranial sites (2–16).

Cutaneous and oral EMPs in dogs are typically benign and highly responsive to local surgical therapy (2, 17–22). In contrast, EMPs arising at non-cutaneous sites may exhibit greater malignancy potential, and carry a higher risk of lymphatic and visceral dissemination compared with cutaneous forms (23). Reported local recurrence rates range from 1.7 to 31.5% (1, 2, 17, 19, 20, 24), while nodal or distant metastasis has been documented in 0.8% to 10% of cases (2, 19, 22, 25–28). Multifocal involvement of EMPs affecting multiple organs is considered rare in dogs, with only a limited number of cases reported in the literature (2, 15, 28–32). Although the development of myeloma-related disorders (MRDs), the contemporary term encompassing canine multiple myeloma, has been described in dogs with pre-existing EMPs (25), the mechanism underlying progression from EMPs to MRDs remains unclear (3, 21). Furthermore, progression to MRDs in dogs with EMPs appears to be much less frequent than in humans (2, 19, 20).

Colorectal EMPs are uncommon in dogs; however, colorectal plasmacytomas are associated with comparatively higher local recurrence rates, reported at 22.2 and 31.5% (1, 2). Despite this, dissemination following complete excision of colorectal EMP remains uncommon (1, 2, 27). Consequently, systemic chemotherapy is more frequently considered for non-cutaneous and non-oral EMPs, particularly when metastatic disease is identified preoperatively (2, 23, 26, 29). Nevertheless, prospective randomized studies evaluating which cohorts of EMP patients may benefit from chemotherapy are currently lacking, and surgical excision therefore remains the recommended first-line treatment. Furthermore, it remains unknown whether rectal EMPs respond favorably to chemotherapy protocols similar to those used in the treatment of MRDs.

Melphalan, an alkylating agent, is considered the chemotherapeutic drug of choice for plasma cell neoplasms in dogs, particularly for the treatment of MRDs (23, 33–35). Melphalan, administered singly or in combination with prednisone or prednisolone, has been used in dogs with metastatic or visceral EMPs, although published evidence is limited to a small number of case reports (15, 19, 26, 27, 29, 36). In most reported EMP cases, melphalan has been administered using a low-dose, continuous dosing schedule, with dosing intervals ranging from every 24 to 72 h (6, 27, 37, 38). Alternative melphalan treatment protocols, including pulsed-dose regimens and 10-day cycling protocols, have also been shown to be effective in the management of MRDs (33, 34); however, their use has not been reported in dogs with EMPs.

The present report describes a rare case of a dog that developed multifocal hepatic plasma cell tumors 5 months after complete surgical excision of a solitary rectal EMP. To the author's knowledge, this is the first report describing the use of a pulse-dose melphalan protocol for treatment of suspected disseminated canine EMP, resulting in a survival time exceeding 19 months after diagnosis of hepatic involvement.

2. Case description

2.1. Initial presentation and diagnostic workup

An 11-year-5-month-old male neutered Maltese dog, weighing 3.78 kg, was presented on an urgent basis for acute rectal prolapse that developed after a routine bowel movement. The dog had a 4-year history of inflammatory bowel disease that was well controlled with a prescription low-fat diet.

Physical examination revealed a firm, raised, pink intraluminal mass measuring approximately 1.4 cm in diameter on the ventral wall of the colorectal lumen, located approximately 4 cm cranial to the anal opening. The surrounding mucosa was grossly unremarkable. Fine-needle aspiration of the mass revealed a monomorphic population of round cells morphologically consistent with plasma cells. The rectal prolapse was manually reduced without complication.

Initial diagnostic evaluation included a complete blood count, serum biochemistry panel, and urinalysis. Abnormalities included borderline neutropenia (2.84 K/μl; reference interval [RI] 2.94–12.67 K/μl), and mild hypochloremia (104 mmol/L; RI 108–119 mmol/L). Serum albumin, globulin, and total calcium concentrations were within reference interval, and no proteinuria was detected. Abdominal ultrasonography revealed no evidence of intra-abdominal lymphadenopathy. The liver was normal in size and echogenicity; no focal lesions were identified. Thoracic and full-body radiographs revealed no evidence of pulmonary metastases or osteolytic bone lesions. Based on these findings, a diagnosis of solitary rectal EMP was made; however, definitive exclusion of MRDs could not be achieved in the absence of complete staging.

2.2. Surgical excision and histopathology

The mass was surgically excised under general anesthesia via a transanal approach. The rectal wall was everted through the anus, and the lesion was exposed using four circumferential stay sutures placed in the rectal mucosa with gentle caudal traction. Two additional stay sutures were then placed cranial and caudal to the mass to aid in exteriorization and surgical manipulation.

The mass was located between the 4 o'clock and 7 o'clock positions within the rectum. An elliptical submucosal resection was performed, with the incision oriented parallel to the rectal axis. Gross surgical margins of approximately 0.5 cm beyond the visible lesion were obtained. A portion of the underlying muscularis layer was included in the excision to help ensure complete removal. The surgical site was closed in a simple continuous pattern. Intraoperative hemorrhage was minimal. After removal of the stay sutures, the rectum was returned to its normal anatomical position within the pelvic canal.

The postoperative course was uneventful, with no complications reported. Histopathological examination confirmed a colorectal plasma cell tumor with complete surgical margins (Figure 1A). Neoplastic round cells with plasmacytoid features and scattered binucleated and multinucleated cells were observed.

Figure 1.

Histopathology of the rectal mass and liver biopsy. (A) Rectal mass, 0.5 × (hematoxylin and eosin [HE] stain): Nodular submucosal mass with complete excision margins (scale bar = 2 mm). (B) Rectal mass, 60 × , HE stain: Neoplastic round cells with eosinophilic cytoplasm, eccentric round-to-oval nuclei, and occasional perinuclear clearing; scattered binucleated and multinucleated cells are present (scale bar = 20 μm). (C) Liver biopsy, 20 × , HE stain: Neoplastic cells with scattered binucleated and multinucleated forms and occasional mitotic figures; a small number of hepatocytes are present along the biopsy margin (scale bar = 50 μm). (D) Liver biopsy, 20 × , Immunohistochemical staining for MUM-1 (scale bar = 50 μm).

2.3. Follow-up and hepatic involvement

18 weeks following surgery, the dog was presented for routine re-evaluation. The owner reported no gastrointestinal or systemic signs; however, mild cranial abdominal sensitivity was noted on physical examination. Abdominal ultrasonography revealed diffuse hepatomegaly with multiple round, target-like hypoechoic lesions distributed throughout all liver lobes (Figure 2). No intra-abdominal lymphadenopathy was identified. No colorectal mass was detected on abdominal ultrasonography or digital rectal examination. Thoracic and skeletal radiographs remained unremarkable.

Figure 2.

Abdominal ultrasonographic images of the liver obtained before (A) and after (B) melphalan therapy. Images in panel (A), acquired 18 weeks following rectal mass removal, demonstrate multifocal, mildly hypoechoic, round hepatic lesions with a target appearance involving multiple liver lobes. Images in panel (B), obtained 40 weeks after initiation of melphalan therapy, demonstrate persistent hypoechoic target-appearing hepatic lesions with a substantial reduction in lesion number and mild interval increase in the size of the remaining lesions.

Recheck hematology revealed borderline nonregenerative anemia (Hematocrit: 37.3%; RI 37.3%−61.7%) and mild thrombocytosis (507 K/μl). Serum biochemistry demonstrated progressive elevations in alkaline phosphatase (499 U/L) and alanine aminotransferase (203 U/L), while serum globulin and total calcium concentrations remained within the reference interval.

2.4. Hepatic biopsy and diagnosis

Laparoscopic hepatic biopsy was performed using 5-mm cup biopsy forceps. Intraoperative visual inspection demonstrated diffuse pathological involvement characterized by moderate hepatomegaly and multiple capsular nodules (Figure 3). A total of nine samples were collected for histopathologic examination, obtained from the right medial, left medial, left lateral, and caudate liver lobes. Histopathology revealed sheets of neoplastic plasma cells exhibiting mild to moderate anisocytosis and anisokaryosis, with occasional multinucleation and karyomegaly. Background hepatocytes were diffusely vacuolated. Immunohistochemistry staining with Multiple Myeloma Oncogene 1 (MUM-1) was performed to confirmed the diagnosis of hepatic EMP (Figure 1).

Figure 3.

Intraoperative laparoscopic images obtained during liver biopsy. Multiple hepatic masses are visible on the surface of the liver lobes (black arrows).

2.5. Treatment and clinical course

Referral to a veterinary oncologist was recommended; however, the owner elected continued treatment at the primary care facility. Two weeks post-biopsy, repeat complete blood count demonstrated persistent mild nonregenerative anemia (Hematocrit: 32.1%) and thrombocytosis (583 K/μl), with a normal neutrophil count (9.43 K/μl). Systemic chemotherapy was initiated with prednisone (0.72 mg/kg orally once daily) in combination with a pulse-dose melphalan protocol (7 mg/m² orally once daily for five consecutive days, followed by a 16-day drug-free interval). A complete blood count was performed every 21 days prior to initiating each subsequent melphalan cycle. A manual blood smear review was performed with each complete blood count.

Fourteen days after initiation of chemotherapy, the dog developed anorexia and lethargy. Hematology revealed severe neutropenia (0.09 K/μl) and thrombocytopenia (23 K/μl). Serum biochemistry findings were unchanged from previous evaluations. As hospitalization was declined by the owner, melphalan therapy was discontinued while prednisone was continued, and supportive care was instituted, including subcutaneous fluid therapy, antiemetics, and oral antimicrobials. Complete blood counts were monitored weekly until resolution of neutropenia and thrombocytopenia. Hematologic parameters normalized within 4 weeks.

Melphalan therapy was reintroduced using a modified pulse-dose protocol consisting of the same daily dose administered for four consecutive days, followed by a 17-day drug-free interval, resulting in a 21-day treatment cycle. Complete blood counts were obtained on days 1 and 14 of each cycle. The dog tolerated this protocol well for 15 treatment cycles. Serial abdominal ultrasonography at three-month intervals demonstrated progressive reduction in the size and number of hepatic lesions (Figure 2). Liver enzyme activities remained mildly elevated but stable throughout this period.

After 327 days of treatment, pancytopenia recurred (HCT 31.8%; neutrophils 0.41 K/μl; platelets 77 K/μl) on day 14 of the treatment cycle, prompting discontinuation of melphalan therapy. Despite these hematologic abnormalities, the patient remained clinically normal. As in the previous episode, the owner declined hospitalization, and similar outpatient supportive care was instituted to manage the pancytopenia crisis.

Twenty-four days later, hematologic parameters had normalized; however, the dog subsequently developed abdominal discomfort accompanied by marked elevations in liver enzyme activities (ALT 505 U/L; ALP 2310 U/L). Given the recurrence of clinical signs, melphalan therapy was resumed using a further modified protocol consisting of the same dosage administered for three consecutive days, followed by an 18-day drug-free interval, resulting in a 21-day treatment cycle. This regimen was well tolerated for an additional 5 months (Figure 4).

Figure 4.

(A) Modification of the pulse-dose melphalan protocol administered in repeated 21-day cycles. (B) Timeline summarizing the clinical course, diagnostic findings, and treatment interventions.

Prednisone therapy (0.72 mg/kg orally once daily) was continued throughout the treatment course. The neoplasia-to-liver area ratio, quantified on ultrasound images using ImageJ software (v1.54t; National Institutes of Health, Bethesda, MD, USA), decreased from 54 ± 1% to 17 ± 1% over the treatment period, with the final measurement obtained 5 weeks before the patient's terminal presentation (Figure 2). No recurrent colorectal masses were detected on abdominal ultrasonography or digital rectal examination.

2.6. Outcome

The dog later presented with lethargy and decreased appetite on day 19 of a treatment cycle. Blood work revealed kidney injury, characterized by increased blood urea nitrogen (97 mg/dl; RI, 7–27 mg/dl), creatinine (3.6 mg/dl; RI, 0.5–1.8 mg/dl), hyperphosphatemia (7.8 mg/dl; RI, 2.5–6.8 mg/dl), and hyperkalemia (6.2 mmol/L; RI, 3.5–5.8 mmol/L). Urine specific gravity was 1.008, while the remainder of the urinalysis was unremarkable. Follow-up urine culture results were negative.

The patient was hospitalized in a referral center and treated with intravenous fluid therapy for 48 h to promote diuresis; however, neither renal parameters nor clinical signs improved. Given the presence of multiple comorbidities and the patient's declining quality of life, the owner elected humane euthanasia. Postmortem examination was declined.

3. Discussion

This report describes the use of a modified pulse-dose melphalan protocol for long-term management of multifocal hepatic extramedullary plasmacytoma (EMP) in a dog following surgical excision of a colorectal primary mass. Progressive adjustment of the treatment schedule, while maintaining the same dose per administration day, allowed prolonged disease control with improved tolerability. To the authors' knowledge, this represents the first published report describing an adapted pulse-dose melphalan protocol specifically for the management of disseminated EMP in dogs.

The relationship between EMP and MRDs, the current classification that includes canine multiple myeloma, remains controversial; however, most investigators consider EMP to represent a distinct disease process. A diagnosis of MRD requires the presence of at least two of the following criteria: bone marrow plasmacytosis, osteolytic bone lesions, hypercalcemia, and detection of a monoclonal (M-component) protein in serum or urine (23). In the dog described in this report, these criteria were not fulfilled. Skeletal radiographs did not reveal osteolytic lesions, serum and urine protein concentrations were within normal limits, and serum total calcium concentration remained normal throughout the disease course. Bone marrow aspiration was declined by the owner. Based on these findings, combined with the clinical presentation, a diagnosis of EMP was suspected.

Serum and urine protein electrophoresis were not performed in this case due to financial constraints; therefore, the presence of a monoclonal gammopathy or light chain–associated disease cannot be definitively excluded. This limitation is particularly relevant in light of the patient's renal failure, which may be associated with paraprotein-related nephropathy. As the autopsy was declined in this case, the other myeloma-related diseases like monoclonal gammopathy, light-chain-associated diseases are incompletely excluded.

EMPs are generally considered locally invasive tumors, particularly when arising in cutaneous, oral, or colorectal locations. Complete surgical excision is typically curative and dissemination is infrequently reported (1, 2, 19, 20, 26, 39). When disseminated disease occurs, it is most often identified at the time of initial diagnosis or in association with incomplete excision or biologically aggressive visceral primaries (2, 20). In the present case, complete excision with clean margins of a solitary colorectal plasmacytoma was achieved, and no evidence of hepatic disease or intra-abdominal lymphadenopathy was identified at the time of diagnosis, underscoring the unusual nature of the subsequent delayed hepatic involvement.

Colorectal EMPs similarly demonstrate a range of biological behavior, with many cases achieving long-term disease control following surgical excision (1, 2). Earlier studies report local recurrence rates ranging from 1.7 to 22.2%, while a more recent study reported recurrence in up to 31.5% of cases (2). Nodal or distant metastases remains uncommon, occurring in approximately 0.8%−2% of affected dogs in previous publications, although one recent study identified a higher metastatic rate of 10% (2). This case further highlights the importance of ongoing clinical surveillance in dogs with colorectal EMPs, even when complete surgical excision with clean margins is achieved. Although colorectal EMPs are generally associated with low metastatic potential, delayed metastatic or multifocal disease can occur. Therefore, periodic re-evaluation, including follow up imaging, should be considered to facilitate early detection of multifocal visceral involvement or presumed metastatic disease.

The relationship between the original colorectal plasmacytoma and the subsequently identified hepatic plasma cell tumors could not be definitively established in this patient. Although both lesions were histopathologically consistent with plasma cell tumors, the hepatic lesions may represent either dissemination from the primary colorectal EMP or the development of a second, independent primary EMP. No evidence of hepatic abnormalities or intra-abdominal lymphadenopathy was identified at the time of diagnosis of the colorectal mass. Given the rarity of primary hepatic plasmacytomas in dogs and the temporal association between diagnoses, a shared clonal origin is considered more likely; however, this could not be confirmed in the absence of molecular clonality testing.

From a research perspective, advanced imaging modalities such as computed tomography (CT) at the time of diagnosis of the rectal mass, followed by periodic reassessment during treatment with melphalan, would be preferable for improved disease staging and monitoring. CT is more sensitive than ultrasonography for detecting subtle metastatic or multifocal disease and may reduce interpretive variability associated with ultrasonographic assessment. However, in general practice settings without dedicated research funding, repeated advanced imaging, along with molecular clonality testing, is often financially prohibitive for clients. As a result, a definitive classification of disease origin may not always be achievable.

Clinically, differentiation between disseminated disease and a second primary EMP did not alter patient management in this case, as the hepatic lesions were not amenable to surgical excision and systemic therapy was indicated regardless of tumor origin. This highlights a practical consideration in veterinary medicine, where treatment decisions are frequently guided more by disease distribution and biological behavior than by definitive determination of tumor clonality.

Melphalan is widely regarded as the chemotherapeutic agent of choice for plasma cell neoplasms in dogs, particularly multiple myeloma (23, 33–35). In EMPs, melphalan has most commonly been administered using continuous low-dose protocols (6, 27, 29, 37, 38). In canine multiple myeloma, however, both cyclical and pulse-dose melphalan protocols have been described (23, 33–35).

In this case, the pulse-dose melphalan protocol previously described for management of MRD (33) was initially adopted due to client concerns regarding chemotherapeutic drug exposure. The regimen consisted of repeated 21-day treatment cycles with oral melphalan administered at 7 mg/m²/day for 5 consecutive days followed by a 16-day drug-free interval. However, the patient developed severe dose-limiting myelosuppression, characterized by marked neutropenia and thrombocytopenia, necessitating temporary interruption of therapy. Rather than permanently discontinuing treatment, a stepwise modification of the dosing strategy was implemented while maintaining the same 21-day treatment cycle. Melphalan administration was progressively reduced from 5 consecutive treatment days per cycle to 4 days, and eventually to 3 days in response to recurrent cumulative myelosuppression over time (Figure 4A). This progressive shortening of treatment duration within each cycle allowed continued melphalan administration while permitting adequate bone marrow recovery between treatment cycles.

This individualized approach enabled prolonged melphalan therapy with acceptable hematologic tolerance and meaningful clinical benefit, including improvement in abdominal discomfort, stabilization of hepatic enzyme activities during treatment, and ultrasonographic regression of hepatic lesions. Notably, temporary discontinuation of melphalan due to recurrent myelosuppression was followed by clinical deterioration, characterized by recurrence of abdominal discomfort and marked increases in serum liver enzyme activities within approximately 4 weeks of cessation. These changes were interpreted as disease progression rather than drug-related hepatotoxicity. Reintroduction of melphalan at a further reduced treatment duration within each cycle again resulted in clinical improvement and biochemical stabilization, supporting continued melphalan responsiveness despite dose modification.

The modified pulse-dose protocol was selected in part to minimize chemotherapy handling by the owner and reduce potential environmental exposure within the home. In addition, the cyclical treatment schedule facilitated routine monitoring through regularly scheduled hematologic evaluations and abdominal ultrasonographic examinations.

Overall, this case describes application of a progressively modified pulse-dose melphalan protocol for management of disseminated visceral EMPs in a dog. Stepwise reduction in treatment duration within a fixed 21-day cycle allowed continued melphalan administration despite recurrent cumulative myelosuppression and was associated with prolonged clinical response and maintenance of acceptable quality of life. Recent veterinary literature has increasingly recognized that some EMPs may demonstrate more aggressive biological behavior and greater metastatic potential than previously appreciated. As a single case report, these findings are preliminary and do not establish efficacy of this modified protocol; however, this approach may provide a practical reference for individualized melphalan dose adjustment strategies in similar patients with disseminated or biologically aggressive EMPs that develop treatment-limiting hematologic toxicity.

Funding Statement

The author(s) declared that financial support was not received for this work and/or its publication.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement

Ethical approval was not required for the studies involving animals in accordance with the local legislation and institutional requirements because Client owned canine, all procedures were part of standard clinical care. Written informed consent was obtained from the owners for the participation of their animals in this study. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Author contributions

YC: Writing – original draft, Writing – review & editing.

Generative AI statement

The author(s) declared that Generative AI was not used in the creation of this manuscript.

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