Complete Regression of Rhabdomyosarcoma in an Adult Secondary to Postoperative Wound Infection Following Limb Salvage Surgery: A Case Report



 

Andrew S Fang MD1; Lee Jae Morse MD2; Rosanna Wustrack MD3; Ryan Huber MD4; Minggui Pan MD5

Perm J 2020;25:20.172 [Full Citation]

https://doi.org/10.7812/TPP/20.172
E-pub: 12/16/2020

ABSTRACT

Case Presentation: A 33-year old man presented with a 25-cm lower extremity embryonal rhabdomyosarcoma with presumed extensive nodal metastasis on positron emission topography scan. Neoadjuvant chemotherapy and radiation provided minimal response. Following limb salvage resection and flap coverage, a prolonged postoperative infection occurred requiring intravenous antibiotics and wound care over 5 months. Given the infection, no postoperative radiation or chemotherapy was administered. Eight months following surgery, positron emission topography scan showed complete regression of local and nodal disease. The patient has remained in complete remission for more than 4 years.

Conclusion: Postoperative wound infection leading to complete regression of embryonal rhabdomyosarcoma has not been reported. Stimulation of the innate and adaptive immune system through infectious elements is an area of ongoing immunotherapy research to improve sarcoma treatment outcomes.

INTRODUCTION

Embryonal rhabdomyosarcoma is a connective tissue malignancy found primarily in children and adolescents. Adult embryonal rhabdomyosarcoma is very rare and often presents with an aggressive course and poor prognosis. Treatment options include chemotherapy, radiation therapy, and surgical resection. We present an adult patient with a very large embryonal rhabdomyosarcoma and presumed nodal metastases on positron emission topography (PET) scan who failed to respond to conventional treatment. Subsequent postoperative infections following limb salvage surgery resulted in complete regression of his disease, and he has remained free of disease for > 4 years since the initial diagnosis.

Studies have shown improvements of prognosis in cancer patients following postsurgical infection. We review the relevant literature and discuss the possible mechanisms of infectious immunotherapy.

CASE PRESENTATION

A 33-year-old man presented with a large left lower leg mass enlarging for 2 years. Magnetic resonance imagery of the extremity showed an enhancing infiltrative mass of approximately 12 × 10 × 25 cm occupying nearly the entire anterior compartment (Figures 1A and 1B). A PET scan showed 18F-labeled fluorodeoxyglucose (FDG) avid subcentimeter retroperitoneal lymph nodes and FDG avid lymph nodes involving the right common iliac region, including a 1.3-cm left common iliac node with a standardized uptake value of 10, right common inguinal lymph node, as well as several nodes involving the bilateral external iliac, right obturator, and bilateral inguinal regions, in addition to the left lower extremity mass (Figures 1C and 2A-C). A tru-cut biopsy revealed that the mass was morphologically and histologically consistent with rhabdomyosarcoma (Figures 3A and 3B). Immunostaining was positive for myogenin (Figure 3C), vimentin, desmin (Figure 3D), and smooth muscle actin and mildly positive for muscle specific actin and was negative for S100, CD34, CD68, CD31, and pancytokeratin. Mouse double minute 2 amplification was negative. The exact subtype was confirmed to be embryonal rhabdomyosarcoma, spindle cell type, after the resection of the mass.

Figure 1

Figure 1. MRI and PET scan images of the tumor in left lower extremity. (A) Sagittal fat-suppressed T2-weighted MRI shows heterogeneous T2 hyperintense mass, occupying and expanding nearly the entire anterior compartment of the lower leg. (B) Axial fat-suppressed gadolinium chelate-enhanced T1 weighted MRI shows intense heterogeneous enhancement of partially necrotic mass. (C) PET scan image shows FDG-avid mass with tumor necrosis. Red arrows indicate position of the tumor.

Figure 2

Figure 2. PET scan before and 4 months after surgical resection. Patient developed wound infection 2 weeks after surgery with chronic infection until 5 months after surgery. (A) Axial image of the pelvis showing and FDG-avid pelvic lymph node prior to surgery. (B) Axial image of pelvis indicating resolution of the FDG-avid lymph node seen in (A). (C) Axial image of the pelvis indicating FDG-avid lymph nodes prior to surgery. (D) Axial image of the pelvis showing marked improvement of the FDG-avid lymph nodes. (E) Sagittal image of the abdomen/pelvis showing FDG-avid retroperitoneal lymph node. (F) Sagittal image of the abdomen/pelvis showing resolution of the FDG-avid lymph node seen in (E). Red arrows indicate the position of the lymph nodes.

Figure 3

Figure 3. Hematoxylin and eosin (H&E) staining and immunostaining for myogenin and desmin. (A) H&E 20×. (B) H&E 40×. The malignant cells were short and spindled with significant atypia and were forming vaguely defined fascicles, with elongated, hyperchromatic eccentrically located nuclei and pink cytoplasm. (C) The malignant cells showed strong nuclear staining of myogenin. (D) Cytoplasmic staining of desmin.

The patient was started on chemotherapy with vincristine, adriamycin, and cyclophosphamide alternating with ifosfamide and etoposide for 5 cycles with minimum tumor shrinkage. Next, he received radiation to the left lower leg mass with 50 Gy in 25 factions, concurrently with chemotherapy (ifosfamide and etoposide) for 3 cycles. PET scan after completion of therapy showed that some lymph nodes had increased FDG uptake, whereas the left leg mass remained unchanged in size and in FDG uptake. The patient then underwent limb salvage surgical resection of the leg mass. The entire anterior compartment of the left lower leg was removed down to bone with the periosteum. Brachytherapy catheters were placed at the time of surgery to allow for additional postoperative radiation therapy. A latissimus free flap was used to cover the massive defect. Pathology revealed a 19 × 14 × 10 cm sarcoma with 30% necrosis and positive deep margin.

On postoperative day 11, the patient developed sepsis due to an extensive wound infection. Cultures showed a heavy growth of pan-sensitive Staphylococcus aureus. Given the infection, the brachytherapy catheters were removed before being used, and no further chemotherapy was administered. The patient was treated with intravenous antibiotics and wound care for the next 5 months. At that time, the patient again developed sepsis associated with osteomyelitis at the site of wound. The wound cultures showed heavy growth of S. aureus and moderate growth Streptococcus agalactiae (Group B). Following weeks of additional local wound care and intravenous antibiotics, the wound was skin grafted and went on to complete healing.

Approximately 4 months after the surgery, while the patient was recovering from the wound infection, a PET scan showed markedly decreased FDG uptake of all the previously FDG-avid lymph nodes, and the left lower leg showed FDG uptake consistent with inflammatory changes related to the wound healing (Figure 2D-F). Approximately 8 months after the surgery, a PET scan showed complete resolution of all the previously FDG-avid lymph nodes. His most recent PET scan performed more than 3 years after the surgery and greater than 4 years after the initial diagnosis demonstrated complete remission.

DISCUSSION

Cancer immunotherapy in the form of administering infectious agents has been used throughout the centuries. In the 17th and 18th centuries, inducing infection at the site of cancer was routinely performed, and spontaneous tumor regression was observed.1 In 1891 Dr William B. Coley injected streptococcal organisms into patients with sarcoma after observing and researching Fehleisen’s regression of tumors following bouts of erysipelas.2,3 He initially used live streptococcal organisms to achieve a cure in 3 out of 5 sarcoma patients. Due to the complications of using the live organisms, Dr Coley refined his treatment using a heat-killed streptococcal organism combined with a second organism, Serratia marcescens. Despite reporting good results, his work was quite controversial at the time due to the variability of the Coley’s toxin formulation, the lack of follow-up, and difficulty by other physicians in replicating his results.4-6

Host- and tumor-specific characteristics affect the immune stimulation and response.7 Some malignancies, like melanoma, release abundant neoantigens and are often highly infiltrated by immune cells, whereas others, including sarcomas, contain little neoantigen to stimulate response.7 Improved host immunocompetency has been found with early vaccination and childhood illness. A population study from Italy showed childhood infection with measles and pertussis was associated with decreased risk of chronic lymphocytic leukemia in adults.8 Several other studies have also shown decreased risk of leukemia, lymphoma, and melanoma associated with childhood infection of tuberculosis or Bacille Calmette–Guérin (BCG) vaccination.9-13

The protective effect secondary to postoperative infection in patients with sarcoma has been reported in several studies. Jeys et al reviewed 547 patients with osteosarcoma and found improved overall survival in 41 patients who developed a deep infection within 1 year of endoprosthetic reconstruction.14 The 10-year survival for these 41 infected patients was 84.5%, compared with 62.3% in the noninfected group.14 A similar observation was made in dogs. A review of 47 dogs with osteosarcoma treated with limb salvage surgery found 68% developed a postoperative wound infection. The dogs that developed infection were half as likely to develop metastases and die compared with the dogs that did not develop infection.15 The protective effect of bacterial infections have been also shown in other solid tumors, like head and neck cancer, lung cancer, etc.16,17

Taking advantage of these observations, approaches using infectious agents or elements have been attempted, including immune peptide and immune checkpoint inhibitors. 7 Muramyl dipeptide is a motif present in the cell wall of gram-positive and gram-negative bacteria that has been found to elicit immune response.18 Muramyl dipeptide has significant toxicity in humans; however, its synthetic analogues, including mifamurtide ( liposomal muramyl tripeptide phosphatidyl ethanolamine), were shown to improve overall survival and were associated with a trend of reducing the risk of relapse in patients with osteosarcoma in the Children’s Oncology Group clinical trial.18-20 Mifamurtide activates the molecules (nucleotide binding and oligomerization domain [NOD]2 pathway, etc.) that recognize pathogenic patterns and the corresponding intracellular signaling pathways. NOD2 is part of a family of pattern recognition molecules in the innate immunity system that includes NOD and toll-like receptors. Other approaches to activate innate immunity for cancer treatment include using Clostridium spores and polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose (Hiltonol; Oncovir, Washington, DC).21,22 A preclinical study using canines found that administration of Clostridium noyi-NT spores generated a 37.5% response rate and reduced tumor burden.22 Recently, CD47, a “don’t eat me” signal molecule, was found to be a valid target for immunotherapy as well.23

One challenge in infectious immunotherapy remains the inconsistent and toxic effects of infection on malignancy and the host. In a retrospective review of 396 soft tissue sarcomas with evenly matched cohorts, no difference in survival, local recurrence, or metastasis was found in patients with postoperative infections.24 One explanation for the inconsistent effect from postoperative infection may involve the duration and chronicity of the infection. Our patient developed a chronic wound infection lasting for 5 months that required prolonged intravenous antibiotics. A longer length of bacterial infection may be needed for generating the sustained innate and adaptive immunity for tumor regression. This may explain the difference in benefits seen in cases of osteosarcoma versus soft tissue sarcoma. Endoprosthesis and allograft infections are known to be difficult to treat and eradicate due to the presence of a large foreign body that shields the pathogen. Treatment of prosthetic infection typically requires weeks of antibiotics and multiple surgeries, all of which can provide additional inflammatory and immune system stimulation. Similarly, the current regimens for the treatment of superficial bladder cancer using BCG vaccination requires several administrations.25

The exposure of tumor antigen to immune effector cells is critical for generating an anticancer immune response, either through activating cytotoxic T cells, triggering an innate immune response, or both. Our patient might have benefited from positive margins after the palliative debulking that left a potentially useful tumor antigen load for immune stimulation at the time of the postoperative infection. After being attacked by the initial innate immunity reactions created by the postoperative infection, the residual tumor cells in the tumor bed likely released neoantigens that were recognized by the antigen-presenting cells that attracted the cytotoxic T cells, which infiltrated the residual tumor and eliminated the sarcoma cells. Recently, it was shown that CD4-positive cytotoxic cells may play critical roles in infiltrating and eliminating solid tumors as well.26 In a study of 1092 patients with sarcoma who underwent resection, 407 patients had reresection of the tumor bed for positive margin and showed significantly higher 5-year disease-free survival compared with the rest of the patients who had 1 definitive resection performed (88% vs 70%), suggesting that a local inflammatory response triggered by surgery in the tumor bed that contains residual tumor antigen may have a protective effect.27

CONCLUSION

Adult embryonal rhabdomyosarcoma is associated with a poor prognosis. We have presented an adult patient who developed 2 episodes of prolonged postoperative wound infection that led to complete regression of the extensive disease more than 4 years after the initial diagnosis. The severity and the chronicity of the infection may be the contributing factors for such a favorable outcome. Infectious immunotherapy is an area that holds promise for improving cancer outcomes. The exact mechanisms and pathway still need to be elucidated.

Ethics approval and consent to participate

Case reviewed by facility research committee and given the retrospective case review nature; formal IRB approval was not deemed necessary.

Consent for publication

Case reported patient has given consent for publication.

Availability of Data and Materials

All case data, details and imaging available in Health Connect (Kaiser Permanente’s electronic medical record system).

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

Acknowledgments

Claudia Haynes MD for providing pathology imaging preparation and review. Daniel Lim MD for assistance in radiology imaging preparation and review.

Authors’ Contributions

Andrew Fang, MD, was the treating physician and participated in data collection and analysis as well as drafting the final manuscript. Lee Jae Morse, MD, and Rosanna Wustrack, MD, provided background research and analysis and participated in drafting the final manuscript. Ryan Huber, MD, provided nuclear imaging review and participated in drafting the final manuscript. Minggui Pan, MD, was a treating physician, provided data analysis, and participated in drafting the final manuscript. All authors have given final approval to the manuscript.

Funding

No funding was requested or required for this case report.

Author Affiliations

1Permanente Medicine, Department of Musculoskeletal Oncology, Kaiser South San Francisco, South San Francisco, CA

2Permanente Medicine, Department of Musculoskeletal Oncology, Kaiser Oakland, Oakland, CA

3Department of Orthopedics and Musculoskeletal Oncology, UCSF, San Francisco, CA

4Permanente Medicine, Department of Nuclear Medicine, Kaiser Santa Clara, Santa Clara, CA

5Permanente Medicine, Department of Hematology and Oncology, Kaiser Santa Clara, Santa Clara, CA

Corresponding Author

Andrew S Fang, MD ()

How to Cite this Article

Fang AS, Morse LJ, Wustrack R, Huber R, Pan M. Complete regression of rhabdomyosarcoma in an adult secondary to postoperative wound infection following limb salvage surgery: A case report. Perm J 2020;25:20.172. DOI: 10.7812/TPP/20.172

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Keywords: immunotherapy, infection, limb salvage, soft tissue sarcoma

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