Anaplastic Classic Kaposi Sarcoma: PD-L1 Expression and Response to Immunotherapy: A Case Report and Review of the Literature

Ivan Lolli; Anna Maria Valentini; Angela Dalia Ricci; Raffaele Armentano

doi:10.6004/jnccn.2022.7091

Anaplastic Classic Kaposi Sarcoma: PD-L1 Expression and Response to Immunotherapy: A Case Report and Review of the Literature

Authors:

Ivan Lolli

Ivan LolliOncology Unit of National Institute of Gastroenterology “S. De Bellis,” Research Hospital Castellana Grotte, Bari, Italy

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Anna Maria Valentini

Anna Maria ValentiniHistopathology Unit of National Institute of Gastroenterology “S. De Bellis,” Research Hospital Castellana Grotte, Bari, Italy

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Angela Dalia Ricci

Angela Dalia RicciOncology Unit of National Institute of Gastroenterology “S. De Bellis,” Research Hospital Castellana Grotte, Bari, Italy

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Raffaele Armentano

Raffaele ArmentanoHistopathology Unit of National Institute of Gastroenterology “S. De Bellis,” Research Hospital Castellana Grotte, Bari, Italy

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Volume/Issue:: Volume 21: Issue 5

Online Publication Date:: 07 Apr 2023

DOI:: https://doi.org/10.6004/jnccn.2022.7091

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Anaplastic classic Kaposi sarcoma (CKS) is an extremely rare pathologic variant of CKS characterized by high aggressiveness and poor prognosis. We report the clinical course of this malignant histologic form in an otherwise healthy 67-year-old male from Apulia in Southern Italy. The anaplastic progression arose during a long history of CKS and developed after multiple local and systemic treatments. The extremely aggressive and chemorefractory nature of the disease dictated amputation of a lower limb and, later, surgery for metastatic pulmonary involvement. At subsequent relapse, therapy with the anti–PD-1 inhibitor pembrolizumab was started. The immunotherapy was selected based on the PD-L1 expression in the tumor and tumor microenvironment. Remarkably, PD-1 blockade induced a complete and durable response in the patient, with a disease-free survival that has exceeded 18 months, and follow-up is still ongoing.

Kaposi sarcoma (KS) is an angioproliferative tumor of endothelial origin associated with human herpesvirus-8 (HHV-8) infection, more frequently afflicting individuals with immunodeficiencies. Epidemiologically, 5 histologically similar forms of KS have been classified¹: classic or sporadic KS,² African or endemic KS,³ epidemic or AIDS-associated KS,⁴ iatrogenic or immunosuppression-associated KS,⁵ and nonepidemic KS. Classic KS (CKS) typically occurs in middle-aged and older people of Mediterranean and Eastern Europe origin. KS is primarily a skin tumor.¹ Skin lesions manifest as macular eruptions or purple-blue pigmented patches that progress to nodular lesions on any skin area. CKS has an indolent clinical course, with the skin lesions usually being confined to the lower extremities, and <10% show mucosal, visceral, or lymph node involvement. Anaplastic CKS (ACKS) is an extremely rare histopathologic variant that displays prominent cellular and nuclear atypia and pleomorphism with a high mitotic index and features a more aggressive clinical evolution. Anaplastic histology has been well described in the context of African and AIDS-associated KS. In any clinical context, it is associated with poor prognosis due to its high local aggressiveness, propensity for deep invasion, and increased metastatic capacity.²

Immune checkpoints are immune regulatory molecules functioning as the gatekeepers of immune responses, but tumor cells can target immune checkpoints as a mechanism for immune evasion.³ PD-1 is a checkpoint molecule that negatively regulates antigen receptor signaling of T cells, including CD8+ effector T cells. The immune checkpoint inhibitors (ICIs) disrupt T-cell inhibitory pathways established by tumor cells, and therefore reactivate the host’s antitumor immune response. Since the demonstration of the expression of PD-1 and its ligand PD-L1 in KS, the clinical use of ICIs has emerged as a possible treatment option in this disease.⁴

Case Report

In September 2015, a 67-year-old male was admitted to the hospital on dermatologic referral to undergo excisional biopsy of a subcutaneous, fast-growing vascular proliferation in the medial region of the left thigh. His past clinical history was linked to the natural evolution of a CKS, diagnosed in 1987 after biopsy of a violaceous macule on the skin of the left leg (Figure 1A–C). The disease was initially treated with low-dose IFN-α until 1995. In 1997, when the first progression occurred, chemotherapy with epirubicin, 50 mg/m²; bleomycin, 10 IU/m²; and vincristine, 1.4 mg/m² (2 mg single-dose maximum) every 21 days for 6 cycles produced long-lasting remission. In later years the disease spread proximally, with lymphatic involvement resulting in painful lymphedema despite chemotherapy with pegylated liposomal doxorubicin (PLD; 20 mg/m² intravenously every 3 weeks) and paclitaxel (80 mg/m² intravenously every 3 weeks).

In December 2014, fractionated doses of radiotherapy (30 Gy/10 fractions) were administered, eliciting a good response. Physical examination showed multiple violaceous patches and plaques of varying sizes on the legs, especially on the left, and another tumor lesion in the left popliteal fossa. Thoracic-abdominopelvic scans showed bilateral micronodules with a peribronchovascular distribution and areas of “ground glass” in the pulmonary parenchyma, as well as lombo-aortic and pelvic lymph adenopathies. MRI demonstrated 2 nodular lesions with a tendency to infiltrate deeply into the popliteal fossa and medial region of the left thigh. HIV antibody was negative. Serum positivity for HHV-8 DNA and anti–HHV-8 IgG antibody was detected. Histopathologic examination of specimens revealed an infiltrative, solid proliferation of epithelioid and spindle cells exhibiting marked nuclear atypia and cellular pleomorphism, separated by a slit-like space containing erythrocytes. The Ki-67 index was >50% (clone MIB-1, Dako Omnis; Agilent). Areas of necrosis and inflammatory infiltrate with extravasated erythrocytes and hemosiderin deposits were present. Immunohistochemical staining was positive for HHV-8 LANA-1 and vascular markers CD31 and CD34, and negative for pancytokeratin. Both histopathologic and ancillary evaluations were consistent with the diagnosis of ACKS (Figure 2 and supplemental eFigure 1, available with this article at JNCCN.org). After discharge, the patient underwent further treatments with intravenous gemcitabine (1,000 mg/m² on days 1 and 8 of each 21-day cycle), intralesional administration of vincristine (0.03–0.08 mL), and rechallenge with PLD (20 mg/m² intravenously every 3 weeks) and paclitaxel at a fixed dose of 100 mg weekly, but only transient efficacy was achieved.

In April 2019, a further local progression of the disease occurred, with extensive involvement of the popliteal fossa and the vascular-nerve bundle. Because conservative surgery was not possible in the opinion of a tertiary care center, transfemoral (above the knee) amputation of the left leg was performed. In July 2020, CT control showed a nodular vascular proliferation (∼30 mm in longest diameter), largely colliquated, with irregular, poorly definite borders and marginal ground glass areas in the right upper lung lobe associated with lombo-aortic and pelvic lymph adenopathies (supplemental eFigure 2). Also in July 2020, integrated PET/CT with 18F-FDG PET showed pathologic uptake of the tracer in 2 nodules (about 32 and 26 mm in largest diameter at coregistration CT) in the soft tissues of the left lower limb stump (SUV_max 23.3) and in a nodular vascular proliferation in the upper lobe of the right lung (SUV_max 21.7), compatible with metastatic lesions (Figure 3A).

In September 2020, the patient underwent surgical removal of the pulmonary nodule. Histologic examination showed tumoral proliferation of cells, medium to large in size, for the most part epithelioid, some fusiform, with a nucleus exhibiting heterogenous chromatin, and a generally prominent nucleolus. Immunohistochemically, positivity for HHV-8 and the vascular markers CD34, CD31, and von Willebrand Factor (vWF), and negativity for pancytokeratin were present (Figure 4A, B). The Ki-67 index was 70%. Extensive areas of necrosis and an inflammatory moderate infiltrate were present (supplemental eFigure 1 and Figure 4A). These findings were consistent with diagnosis of pulmonary metastasis of anaplastic KS. In November 2020, 2 subcutaneous nodules developed on the distal end of the amputation stump. The nodules enlarged rapidly, with a tendency to painful ulceration and permanent secretion of a malodorous serous exudate. An MRI CONTROL of the left lower limb stump was performed in the same month and confirmed the presence of 2 solid formations measuring 40 × 37 mm and 32 × 27 mm in diameter, respectively, prominent on the skin surface and deeply infiltrating the myofascial plane (Figure 5A). CT control, performed in December 2020, showed the scarring outcomes of the pulmonary metastasectomy and lombo-aortic and iliac adenopathies that were considered nontarget lesions according to RECIST criteria (supplemental eFigure 2). Further amputation at a higher level (a highly mutilating hip disarticulation) was proposed. On December 18, 2020, a reevaluation of the early-stage CKS (patch; collected in May 2007), late-stage ACKS (skin nodule; collected in September 2015), and lung metastasis (pulmonary metastatic nodule; collected in September 2020) specimens was performed in the hope of finding potentially targetable driver mutations. All specimens tested were microsatellite stable, but presented significant variation for immunostaining PD-L1 expression. The combined positive score (CPS) was <1% in the early patch stage, although it was 36% and 70% in the cutaneous excisional biopsy and in metastatic pulmonary nodule specimens, respectively (cutoff = 1% for PD-L1 CPS positivity, patterns of PD-L1 immunopositivity: membrane immunopositivity; clone E1L3N [Cell Signaling Technology Inc.]).⁵ In the histologic specimens, a substantial number of infiltrating macrophages based on morphology were observed in the tumor microenvironment, and PD-L1 expression did not significantly differ between the peritumoral immune cells and intratumoral areas (Figure 4C–E).

Given the lack of a therapeutic consensus concerning ACKS after progression in patients with chemotherapy-refractory disease, and the absence of approved therapeutic options except for recourse to highly mutilating surgery, refused by the patient, rescue treatment with immunotherapy was proposed. After obtaining the patient’s informed consent, on December 31, 2020, off-label treatment was started with the anti–PD-1 monoclonal antibody pembrolizumab as a single-agent at fixed doses of 200 mg every 3 weeks. The treatment induced a progressive resolution of the cutaneous stump lesions that improved remarkably after 2 cycles and showed complete clinical remission after cycle 6 (Figure 5). CT scans showed repair processes in the right lung lobe and a marked decrease of the lombo-aortic and iliac adenopathies (supplemental eFigure 2). In June 2021, 18F-FDG PET/CT was performed to confirm the substantial clinical improvement. In comparison with the previous (pretreatment) examination, 18F-FDG uptake had decreased almost completely in the soft tissues of the left lower limb stump (SUV_max 1.9 vs 23.3), and there was no uptake in the right upper lung lobe at the site of the surgically removed metastasis (Figure 3B). A whole-body scan using ^99mTc-labeled methylene diphosphonate (^99mTc-MDP) to detect bone metastases showed tracer uptake at the distal cortical level of the left femoral stump due to bone remodeling. The patient completed 1 year of treatment with pembrolizumab, receiving a total of 18 cycles from December 31, 2020, through January 13, 2022, when the patient requested a drug holiday.

No significant immune‐related toxicities were observed, except for grade 2 (G2) asthenia, and no abnormal laboratory findings (CBC with differential and serum chemistry) were detected before or during the treatment.

No progressive disease was observed at the latest follow-up (July 2022), when CT of the thorax and abdomen, MRI of the limb stump, and 18F-FDG PET/CT confirmed a complete response (Figure 6 and supplemental eFigures 3 and 4).^6,7 At the time of writing, the total disease-free survival has exceeded 18 months and follow-up is still ongoing.

Written informed consent was obtained from the patient prior to publication of this case report, and all procedures performed were in accordance with the ethical standards of the institutional research committee (IRCCS Giovanni Paolo II, Bari, Italy).

Discussion

Exceptional as a de novo disease, ACKS generally arises in patients with a long history of CKS with a predilection for an acral location. Potential factors held responsible for inducing anaplastic progression include disease duration, chronic lymphedema, previous treatments with chemotherapy and/or radiotherapy, immunosuppression, and level of immune impairment in patients with HIV.⁸ In our HIV-negative patient with no personal or family history of immunodeficiency disorders, anaplastic transformation was diagnosed 28 years after the onset of the disease. At that time, the disease, complicated by chronic lymphedema, had already been heavily treated with biotherapy and multiple lines of chemotherapy and radiotherapy.

The clinical course of the ACKS is mostly characterized by an aggressive evolution and the scarce information available is derived from case reports or small patient series. No distant metastases were reported in 2 case series,^9,10 but metastatic locations in the lymph nodes, liver, spleen, and stomach were described by other authors.^11,12 There is no therapeutic consensus concerning ACKS. In advanced cases, chemotherapy is generally proposed, with variable response rates to a plethora of agents reported. Although paclitaxel and liposomal doxorubicin are efficacious according to certain authors, only one patient in a case series presented a lasting partial response to paclitaxel.^9,10 Some authors recommended an aggressive nonconservative surgical approach associated with systemic treatment.⁹ For patients whose disease is refractory to chemotherapy, optimal management is unknown and there is a tendency to consider mutilating surgery as a rescue therapy. In one patient with an ACKS of the wrist previously treated with vinblastine, bleomycin, and radiotherapy, the ineffectiveness of chemotherapy with etoposide and mitoxantrone for treating a recurrence on the right forearm with a large osteolytic area of the ulna led to surgical treatment with amputation of the right arm at the lower third of the humerus.¹³ Transtibial or transfemoral amputation due to deep tissue invasion was required in 5 of 8 and 2 of 5 patients in 2 case series, respectively.^9,10 Clearly, alternative systemic treatments are needed for patients with chemorefractory ACKS. In the present case report, the disease aggressiveness led to transfemoral amputation of the left leg and a lung metastasectomy. Further amputation at a higher level was proposed at the subsequent relapse at the left stump level.

The choice of immunotherapy with pembrolizumab as an “extrema ratio treatment” in this rare orphan disease was due to several reasons: the major disease progression in this patient with chemorefractory ACKS, the lack of consensual guidelines or standard approved treatments, and, above all, the pressing need to treat our patient, who already underwent amputation, with an effective therapeutic option alternative to the only other strategy: a highly disabling hip disarticulation surgery.

The presence of PD-L1 expression on tumor cells and tumor-associated immune infiltrates is usually considered to be a predictor of the anti–PD-1 response, but few anecdotal data are available regarding KS.^14–16 Recently, Delyon et al¹⁷ reported the preliminary results of a proof-of-concept phase I prospective study in which 17 patients with CKS and 9 with endemic KS were treated with pembrolizumab, with a promising best overall response rate of 71%. In this study the exploratory role of PD-L1 as a predictive biomarker was not confirmed due to the small number of patients enrolled.¹⁷

Unfortunately, to the best of our knowledge, there are no published reports evaluating the response, duration of response, and safety of anti–PD-1 antibodies used to treat metastatic chemorefractory ACKS.

The PD-1 pathway, consisting of the coinhibitory receptor PD-1 on T cells and its ligand (PD-L1) on antigen-presenting cells (APCs: macrophages, dendritic cells), is a major mechanism of tumor immune evasion. Binding between T-cell PD-1 and APC PD-L1 triggers inhibitory signaling to oppose the T-cell response. The ICIs disrupt these T-cell inhibitory pathways and, thus, reactivate the host’s antitumor immune response. In the TME context, proinflammatory (M1) macrophages promote cytotoxic and antitumor T-cell responses. In patients treated with anti–PD-1 therapy, high PD-L1 expression levels on macrophages are associated with an increased CD8+ T-cell infiltration and a better response to immunotherapy than in patients with PD-L1 expression in tumor cells only.¹⁸

Notably, the application of PD-L1 testing via immunohistochemistry as a predictive biomarker is associated with several issues.¹⁹ Temporal effects, along with spatial tumor heterogeneity, are unavoidable practical limitations for assessing PD-L1 status. Essentially, the expression of PD-L1 on tumor cells and infiltrating immune cells is dynamic, exhibiting differences in regions within each tumor and among different tumors, as well as among primary sites and metastases. Moreover, PD-L1 expression may be modulated by prior exposure to other treatments, such as radiation therapy or chemotherapy, as well as by changes in the tumor microenvironment (eg, tissue hypoxia) during the development of treatment resistance. Actually, the PD-L1 expression showed significant variations with the disease progression and in accordance with different histologies in our patient’s specimens (Figures 2D and 4C).

Use of archival tissue may not be optimal for PD-L1 testing because it may not reflect the true PD-L1 status, which can be affected by variations in tissue fixation, storage, and antigen retrieval, all of which can impact the PD-L1 expression readout.²⁰

Despite the good concordance in our report between PD-L1 expression and response to immune checkpoint blockade directed at the PD-1 axis, PD-L1 expression as an exclusionary predictive biomarker remains an imperfect tool.²¹ Indeed, a durable clinical response to PD-1 blockade has been observed in both patients with PD-L1–negative and those with PD-L1–positive disease, but a large portion of patients, including those with PD-L1 expression, do not experience response to blockade therapy.¹⁵ Interestingly, it has been determined in metastatic melanoma that PD-L1 expression in early on-treatment biopsies (1.4 months after the start of treatment), compared with PD-L1 expression in pretreatment samples, is highly predictive of response to PD-1 blockade.²² Moreover, increased baseline serum levels of PD-1/PD-L1 (measured within 6 weeks before therapy) are found to be associated with poor therapeutic outcomes to PD-1, but not to BRAF inhibition therapy in metastatic melanoma, and this quantification may be useful in selecting patients for PD-1–based versus BRAF-based therapeutic strategies.²³ The complexity of tumor-directed immune responses may likely preclude the use of a single biomarker to determine treatment responses. Importantly, pembrolizumab has received FDA approval for the treatment of unresectable or metastatic solid tumors with a tumor mutational burden (TMB) >10 mutations/megabase (TMB-H) and the first approval as a tumor-agnostic therapy for use in microsatellite instability (MSI)-high/deficient mismatch repair cancer after progression on first-line treatment.²⁴ In this context, data about other biomarkers, such as TMB, MSI, tumor gene expression profile, and blood-derived host factors, combined with PD-L1 tumor expression, may be more informative in predicting response to immunotherapy.

This study has some limitations that must be considered in light of the fact that treatment for this patient with physical disability due to previous limb amputation was started and conducted during the second wave of the COVID-19 pandemic. Within that period, oncology activities were severely endangered by this infectious threat, and there was a significant reduction of healthcare activities due to contamination of physicians and caregivers.

The first limitation is the partial adherence to instructions and guidelines regarding baseline lesion evaluation prior to starting treatment (never more than 4 weeks) and subsequent evaluations during treatment (every 8 weeks) and after treatment (every 4 months).⁶ Baseline evaluation of the pulmonary parenchyma after metastasectomy was performed via CT scan in December 2020, whereas evaluation of the stump lesions was performed via MRI in November 2020 at 3 and 7 weeks before the start of treatment, respectively. Obviously, in the PET examinations the complete response achieved in lung metastasis was due to metastasectomy and occurred prior to ICI therapy, whereas the complete decrease of FDG uptake and SUV_max in the soft tissues of the left lower limb stump was surely related to pembrolizumab therapy (Figure 3B).

Another limitation is the use, for determining microsatellite stability and PD-L1 expression, of archival tissue obtained months to years before the start of treatment, which may not reflect the true PD-L1 status, because PD-L1 expression has temporal and spatial heterogeneity and can be altered by exposure to prior therapies.²⁰ In any case, PD-L1 expression as an exclusionary predictive biomarker remains an imperfect tool, but it is possible that even patients with ACKS with low or no expression of this biomarker may also benefit from anti–PD-1 therapy.

Conclusions

ACKS is a rare tumor, and currently, no effective systemic therapeutic option is available for patients with advanced disease, and the prognosis remains very poor. The efficacy of an anti–PD-1 blockade in reports of advanced CKS refractory to multiple lines of chemotherapy suggests that this tumor might be responsive to anti–PD-1 treatment. Our case supports these observations and provides evidence that even patients with ACKS, a more aggressive disease than the classic form, may experience a response to pembrolizumab. To our knowledge, this report is the first to describe a clinical and radiologic response to anti–PD-1 antibody pembrolizumab therapy during a chemorefractory anaplastic progression of a CKS.

Moreover, this remarkable anecdotal response obtained with immunotherapy could raise questions about the role of mutilating surgery as a salvage treatment in advanced ACKS. Nevertheless, additional clinical data are needed to confirm the safety and efficacy of immune checkpoint blockade with pembrolizumab in this rare tumor. However, if our result is supported by further studies, treatment with anti–PD-1 could offer a more acceptable alternative therapeutic option to surgery as rescue therapy in patients with chemorefractory advanced ACKS.

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Submitted March 14, 2022; final revision received October 20, 2022; accepted for publication October 20, 2022. Published online April 7, 2023.

Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Ivan Lolli, MD, Oncology Unit of National Institute of Gastroenterology “S. De Bellis,” 70013 Via Turi 27, Castellana Grotte, Bari, Italy. Email: ivanlolli53@gmail.com

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Case Report
Discussion
Conclusions
References

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Figure 1.

(A) Cutaneous CKS (hematoxylin-eosin, original magnification ×40). (B) CKS (hematoxylin-eosin, original magnification ×200): sheets of plump spindle cells with obvious channels of blood or extravasated red blood cells. (C) Immunohistochemistry staining of HHV-8 in primary cutaneous lesion (original magnification ×100).

Abbreviation: CKS, classic Kaposi sarcoma.

View raw image

Figure 2.

ACKS in cutaneous nodular lesions. (A) Vascular spaces lined by infiltrative solid poorly differentiated proliferation of spindle cells with severe cellular and nuclear pleomorphism and prominent mitotic figures. Presence of extravasated erythrocytes and hemosiderin depots (hematoxylin-eosin, original magnification ×200). (B) Immunohistochemistry staining for HHV-8 LANA-1 (original magnification ×100). (C) ACKS with necrosis (hematoxylin-eosin, original magnification ×100). (D) Immunohistochemistry staining of PD-L1 in cutaneous nodular lesion (original magnification ×200).

Abbreviation: ACKS, anaplastic classic Kaposi sarcoma.

View raw image

Figure 3.

18F-FDG PET/CT maximum intensity projection (A) before and (B) after lung metastasectomy and 9 cycles of treatment with pembrolizumab (axial caption). Red arrows are metastatic lesions.

View raw image

Figure 4.

ACKS lung metastasis. (A) HE staining of lung metastasis of ACKS showing large focus of necrosis (original magnification ×100). (B) Strongly positive immunohistochemical staining of HHV-8 in lung metastasis of ACKS (original magnification ×100). (C) PD-L1 immunoreactivity in lung metastatic lesion invading the bronchial wall. Lack of PD-L1 immunoreactivity in normal bronchial epithelium (original magnification ×40). (D) Clear PD-L1 immunoreactivity in infiltrating macrophages, based on morphology, in tumor microenvironment of lung metastatic lesion (original magnification ×100). (E) PD-L1 immunoreactivity in lung metastatic Kaposi cells (original magnification ×100).

Abbreviations: ACKS, anaplastic classic Kaposi sarcoma; HE, hematoxylin-eosin.